Review

Oncogene (2004) 23, 6445–6470. doi:10.1038/sj.onc.1207714

Highly penetrant hereditary cancer syndromes

Rebecca Nagy1, Kevin Sweet1 and Charis Eng1

1Clinical Cancer Genetics Program and Human Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

Correspondence: R Nagy, The Ohio State University Clinical Cancer Genetics Program, 2050 Kenny Road, 8th Floor Tower, Columbus, OH 43221, USA. E-mail: nagy-1@medctr.osu.edu

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Abstract

The past two decades have brought many important advances in our understanding of the hereditary susceptibility to cancer. Approximately 5–10% of all cancers are inherited, the majority in an autosomal dominant manner with incomplete penetrance. While this is a small fraction of the overall cancer burden worldwide, the molecular genetic discoveries that have resulted from the study of families with heritable cancer have not only changed the way these families are counselled and managed, but have shed light on molecular regulatory pathways important in sporadic tumour development as well. In this review, we consider 10 of the more highly penetrant cancer syndromes, with emphasis on those predisposing to breast, colon, and/or endocrine neoplasia. We discuss the prevalence, penetrance, and tumour spectrum associated with these syndromes, as well as their underlying genetic defects.

Keywords:

inherited cancer susceptibility, familial cancer syndromes, breast cancer, colon cancer, endocrine neoplasia

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Introduction

Over 200 hereditary cancer susceptibility syndromes have been described, the majority of which are inherited in an autosomal dominant manner. Although many of these are rare syndromes, they are thought to account for at least 5–10% of all cancer, amounting to a substantial burden of morbidity and mortality in the human population (Figure 1). While characterized by their markedly increased risk of malignancy, these syndromes often predispose to benign tumours and generalized disease, as seen in Cowden syndrome (CS) and the multiple endocrine neoplasias. When the benign and malignant manifestations are considered together, many of these syndromes show almost complete penetrance by age 70.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

While the majority of most common cancers are sporadic, 5–10% are inherited and arise due to highly penetrant germline mutations. An additional 10–15% are referred to as 'familial' and may be caused by the interaction of low-penetrance genes, gene–environment interactions, or both

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An inherited cancer susceptibility is suspected in families with the following characteristics: two or more relatives with the same type of cancer on the same side of the family; several generations affected; earlier ages of cancer diagnosis than what is typically seen for that cancer type; individuals with multiple primary cancers; the occurrence of cancers in one family, which are known to be genetically related (such as breast and ovarian cancer, or colon and uterine cancer); and the occurrence of nonmalignant conditions and cancer in the same person and/or family (e.g. Marfanoid habitus and medullary thyroid cancer in multiple endocrine neoplasia type 2B (MEN 2B)). Because of phenotypic variability, age-related penetrance, and gender-specific cancer risks, however, many families with an inherited cancer syndrome will not meet these criteria. Also, because cancer is relatively common in the general population, it is possible to have a chance clustering of the same or related cancers within a family. These familial clusterings are most likely due to low-penetrance alleles that are more common than mutations in genes such as BRCA1 or BRCA2. Thus, they will potentially account for a larger proportion of cancer in the general population than the rare, highly penetrant alleles that are discussed here. Localization and characterization of low-penetrance alleles are the focus of much research, but the challenges are great due to the multifactorial nature of cancer and the underlying genetic heterogeneity (reviewed by Houlston and Peto in this issue).

For the reader's reference, we have included a comprehensive table of over 25 inherited cancer syndromes (Table 1). From this longer list, we have chosen 10 syndromes that effectively underscore the concepts of variable expression, pleiotropy, penetrance, and heterogeneity of risk. They also highlight some of the exciting advances that have been made in our understanding of cell–cell interaction, intracellular signalling, DNA replication and repair, and apoptosis.


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Hereditary nonpolyposis colon cancer

In 1931, Aldred Warthin first reported on a family with a hereditary pattern of stomach and endometrial cancer (Warthin, 1931). 'Family G' was further characterized by Henry Lynch 40 years later (Lynch and Krush, 1971), and subsequently, the autosomal dominant pattern of inheritance of gastrointestinal and gynaecologic cancers became known as hereditary non-polyposis colon cancer (HNPCC, MIM 114500). Many still prefer the term 'Lynch syndrome' to describe these families with colorectal, endometrial, and other extracolonic cancers.

HNPCC is the most common form of hereditary colorectal cancer, affecting as many as 1 in 400 individuals, and is caused by a germline mutation in any one of five DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2). Molecular screening of all Finnish patients with colorectal cancer has shown that at least 3% are attributable to germline alterations in either MLH1 or MSH2 (Aaltonen et al., 1998; Salovaara et al., 2000). The International Collaborative Group on HNPCC established diagnostic criteria, known as the Amsterdam criteria, in 1991 (Table 2) (Vasen et al., 1991). These criteria were further modified in 1999 (Amsterdam II Criteria) in an attempt to incorporate extracolonic cancers (Vasen et al., 1999). However, studies have shown that only 40–80% of families that meet the original criteria, and no more than 50% meeting the modified criteria, have mutations in the associated mismatch repair genes (Bisgaard et al., 2002). For this reason, a third set of criteria, the Bethesda criteria, were developed. When compared to the Amsterdam I and II criteria, the Bethesda criteria are the most sensitive, especially in identifying HNPCC families with pathogenic mutations (Syngal et al., 2000). However, the specificity of the Bethesda criteria is significantly lower than that of its counterparts. It should be noted that the Bethesda criteria were recently revised (Umar et al., 2004), and the sensitivity and specificity of the new criteria are not known.


Penetrance in HNPCC is typically high and the phenotype is quite variable within families. Males with HNPCC have virtually a 100% chance of developing colorectal cancer by age 70 (Aarnio et al., 1999b). Women appear to have a higher lifetime risk of endometrial cancer (42–60%) than colorectal cancer (54%) (Vasen et al., 1996; Aarnio et al., 1999b; Millar et al., 1999). However, for both men and women whose first tumour is not treated with subtotal colectomy, the risk of developing a second primary colorectal cancer is 30% within 10 years after the original surgery, and 50% within 15 years. The lifetime risk for stomach cancer is 13–19%, although this may be much higher in families of Asian descent (Aarnio et al., 1999b; Park et al., 2000). Women with HNPCC have a 9–12% lifetime risk of developing ovarian cancer (Aarnio et al., 1999b). Other cancers seen in HNPCC include small intestine, pancreas, brain, hepatobiliary tract, and urinary tract, for which the lifetime risk is in the range of 2–4% (Aarnio et al., 1999a). Sebaceous gland tumours, multiple keratoacanthomas, basal cell carcinomas, and possibly breast cancer may be more common in the Muir-Torre variant (MIM 158320) of HNPCC. The Turcot variant (MIM 276300) should be considered when the family history includes glioblastoma mutiforme.

The colorectal cancer of HNPCC differs from sporadic colorectal cancer in several ways. The average age of onset is approximately 45 years, as compared to 63 years in the general population (Lynch et al., 1988). Typically, there is a paucity of adenomatous colonic polyps as compared to other familial polyposis conditions. The proximal or 'right' colon is the preferred site (60–70%) and there is significant risk for synchronous and metachronous cancers. The progress from adenoma to carcinoma also occurs more rapidly in HNPCC (2–3 years) than in sporadic tumours. Histologically, these tumours are often poorly differentiated, with distinct mucoid and signet-cell features, and noted presence of infiltrating lymphocytes. Despite this more rapid growth pattern and the adverse histologic features seen on pathologic analysis, these lesions are associated with a better prognosis than sporadic colon tumours (Lynch and Smyrk, 1996; Sankila et al., 1996; Watson et al., 1998).

Characteristic errors of DNA replication known as microsatellite instability (MSI) are the hallmark of colorectal tumours in HNPCC. Microsatellites are short repetitive stretches of DNA that occur throughout the genome, and occur in both coding and noncoding regions. In cells that are deficient in mismatch repair (MMR), either as a result of a constitutional mutation in a DNA repair gene (e.g. MLH1 or MSH2 mutations in HNPPC) or due to epigenetic silencing of such gene(s) (e.g. MLH1 promoter methylation in sporadic colon tumours), these repetitive stretches of DNA are prone to expansion or contraction (i.e. instability). When this occurs within a coding microsatellite sequence, the deletion or the addition of one or more nucleotides can result in a frameshift mutation, that is, can disrupt normal gene expression. The first example of this, as it relates to HNPCC and colon cancer, was described in 1995 when mutations in the transforming growth factor beta receptor 2 (TGFBR2) gene were detected in eight MMR-deficient human colon cancer cell lines (Markowitz et al., 1995). All of the mutations occurred in the same polyadenine tract (A)10 (also called BAT-RII), and resulted in decreased expression of the type II receptor and dysregulation of the TGF-beta/RII signalling pathway (see Figure 2). Since one of the major ligands for the type II receptor, TGFbeta, is a key tumour suppressor in colon cancer, this discovery provided a direct link between DNA repair deficiency and dysregulation of gene expression in colon epithelial cells. Since that time, the presence of somatic frameshift mutations in coding microsatellite repeats has been documented in both sporadic and hereditary tumours of various organs. For example, somatic frameshift PTEN mutations are found in approximately 15–20% of MSI-unstable colorectal cancer, whether sporadic or HNPCC-associated (Zhou et al., 2002b), as well as a significant proportion of HNPCC-associated endometrial cancers (Kuismanen et al., 2002; Zhou et al., 2002a). Of note, the majority of the mutations identified in these studies occurred in one of two (A)6 repeats found in exons 7 and 8 of the PTEN gene, suggesting that they are the direct result of MMR deficiency. Similar results have been shown for the RIZ (retinoblastoma protein interacting zinc-finger) gene in gastrointestinal tumours (Chadwick et al., 2000; Piao et al., 2000; Sakurada et al., 2001). RIZ also contains two coding poly(A) tracts, and one of its isoforms (RIZ1) has been implicated in cell cycle arrest and apoptosis (He et al., 1998; Jiang et al., 1999; Jiang and Huang, 2000).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

TGFbeta–SMAD signalling pathways. Members of the TGFbeta superfamily of receptors, such as TGFbeta receptors I and II or type 1 and 2 bone morphogenic protein receptors (BMPR1A and 2A) form receptor complexes after binding of their respective ligands, TGFbeta and BMP. This leads to type 1 receptor-mediated phosphorylation of the SMADs, which transduce signal to the nucleus after complexing with a co-SMAD, such as SMAD4. The SMAD complex can then regulate transcription of a number of target genes through repression or activation. Adapted from Kretzchmar (2000) and Eng (2001b)

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As mentioned above, germline mutations in specific DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2) cause HNPCC. Affected patients generally have inactivation of one copy, with subsequent somatic loss of the wild-type allele in cells that develop into a tumour. Over 400 different pathogenic mutations have been registered in the international HNPCC database (http://www.nfdht.nl). Two genes, MLH1 and MSH2, account for the majority (90%) of all identified HNPCC alterations. Most of these are mutations that lead to a truncated protein, although upwards of 30% of MLH1 and 16% of MSH2 mutations are of the missense variety (Lynch and de la Chapelle, 2003). The MSH6 gene accounts for almost 10% of HNPCC families, with the majority having missense mutations (Kolodner et al., 1999). Cases of HNPCC caused by mutations in PMS2 and PMS1 are so few in number that genetic analysis has only been performed on a research basis to date. The fact that genomic rearrangements and mutations that affect control regions or the splicing apparatus may be missed by use of conventional methods alone, allelic separation, Southern hybridization and multiplex ligation-dependent probe amplification may be warranted, especially for families in which immunohistochemistry suggests a germline mutation but sequencing is negative (Wijnen et al., 1998; Gille et al., 2002; Nakagawa et al., 2002). Of note, a recent study by Wagner et al. (2003) found genomic rearrangements accounting for 24% of all mutations in a cohort of 59 clinically selected North American HNPCC families.

Some studies have suggested that the lifetime risk of developing colorectal or endometrial cancer may be higher in MSH2 than in MLH1 families (Vasen et al., 2001); other studies have failed to detect statistically significant differences (Parc et al., 2003). However, reports do substantiate that endometrial cancer may be more common in families with germline MSH6 alterations as compared to the other mismatch repair genes. In particular, study of a large Dutch family with an MSH6 alteration not only showed reduced penetrance of colorectal cancer (only 32% by age 80) but endometrial cancer was the most common tumour type among carrier females (Wagner et al., 2001). Both colorectal and endometrial cancers in this family occurred at later ages of onset than expected in HNPCC (Wagner et al., 2001). Wijnen et al. (1999) also noted a lower tumour frequency, delayed age of cancer onset, and incomplete penetrance in MSH6 mutation carriers in their study cohort. In the Muir-Torre variant of HNPCC, the vast majority of germline mutations identified have been in MSH2, with a few families harbouring MLH1 alterations. One-third of patients with Turcot's syndrome have mutations in MSH2.

In certain populations, founder mutations in MLH1 and MSH2 have been identified. In the Finnish population, for example, two mutations in MLH1 (a 3.5 kb genomic deletion in exon 16; a splice-acceptor site mutation of exon 6) account for 63% of all disease-causing mutations in families with HNPCC (Nystrom-Lahti et al., 1995). The MLH1 W714X mutation appears to have a founder effect in the Swiss (Hutter et al., 1996). A 1.8 kb deletion involving exon 11 of MLH1 may represent a founding mutation in HNPCC families originating in southern China (Chan et al., 2001). The MSH2 1906G>C mutation is highly penetrant and accounts for approximately one-third of Ashkenazi Jewish families that meet the Amsterdam criteria (Foulkes et al., 2002). Of note, recent studies identified a deletion of exons 1–6 in MSH2 in nine distantly related North American families (Wagner et al., 2002; Lynch et al., 2004). Genealogic, molecular, and haplotype studies show that this deletion represents a common founder mutation that can be traced back to an 18th century German family (Wagner et al., 2002, 2003; Lynch et al., 2004).

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Familial adenomatous polyposis

Familial adenomatous polyposis (FAP, MIM 175100), which accounts for approximately 1% of hereditary colorectal cancer, is characterized by the development of hundreds to thousands of adenomatous polyps throughout the colon and rectum, with an extremely high lifetime risk of colon cancer. It is an autosomal dominant condition caused by germline mutations in the adenomatous polyposis coli (APC) gene and affects about 1 in every 5000–10 000 people (Burn et al., 1991; Jarvinen, 1992). Most individuals (75–80%) will have an affected parent, while the remainder are the result of a new mutation. While penetrance is almost complete, there is significant variability within and between families.

The clinical diagnosis of FAP is made if an individual has greater than 100 colorectal adenomas. In all, 75% of individuals will develop polyps by age 20, and nearly 90% by age 30. Although the polyps are benign initially, at least a subset will proceed to malignancy. The average age of colorectal cancer diagnosis is 39 years; 90% of untreated patients will have malignancy by age 50 (Bussey, 1975). Historically, the presence of both colonic and extracolonic features has been referred to as Gardner's syndrome (Gardner and Richards, 1953), which we now know is allelic to FAP. The extracolonic features of FAP include congenital hypertrophy of the retinal pigment epithelium (CHRPE), which is found in 60–88% of affected individuals. These discrete, flat, pigmented lesions do not affect vision and are usually bilateral or multifocal in FAP, as compared to the isolated or unilateral lesions seen in the general population (Burn et al., 1991; Soloman and Burt, 2004). Dental anomalies (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigenous cysts, and odontomas), epidermoid cysts (notably on the scalp), and osteomas of the mandible (90%), skull, fingers, toes, and long bones occur more often in individuals with FAP. Mesenteric fibrosis may occur after surgery or pregnancy, but can also occur spontaneously. Soft-tissue desmoid tumours typically develop in the abdominal cavity but can occur anywhere in the body. Desmoid tumours occur in approximately 5–10% of children and adults with FAP (Bertario et al., 2001). Lastly, polyps of the upper gastrointestinal tract, including the gastric fundic glands, antrum, and duodenum, can also be present (Bulow et al., 1995).

Individuals with FAP can also develop extracolonic malignancies. While gastric adenomas and fundic gland polyps are common, affecting 10 and 50% of patients, respectively, the associated risk for cancer is small (Bulow et al., 1995). There is more concern for the adenomas that invariably form in the second and third portions of the duodenum (97%), especially in the periampullary region, as these present an increased risk (4–12%) for malignancy (Bulow et al., 1995; Heiskanen et al., 1999; Kadmon et al., 2001). Papillary thyroid carcinoma occurs in approximately 2% of individuals with FAP, most often in female carriers, and at an average age of 28 years (Cetta et al., 2000). Other cancers observed in FAP include hepatoblastoma in children (risk of 1.6% to age 6 years), pancreatic carcinoma (approximately 2% lifetime risk), and CNS tumours in the Turcot variant (MIM 276300) (Giardiello et al., 1993, 1996).

There is a mild clinical variant of FAP known as attenuated FAP (AFAP), which is characterized by fewer polyps (between 10 and 100, with an average of 30) and a later age of colon cancer diagnosis (50–55 years). The adenomas in AFAP tend to aggregate more often in the proximal colon, although they can be present anywhere in the colon and in the upper gastrointestinal tract. The lifetime risk for colon cancer in AFAP is also high, although evidence suggests that desmoid tumours and CHRPE are rare or absent in AFAP (Burn et al., 1991).

The gene for FAP was first mapped to chromosome 5 in 1987 (Bodmer et al., 1987), and identified as the APC gene in 1991 (Groden et al., 1991; Kinzler et al., 1991; Nishisho et al., 1991). The gene contains 15 exons, with the last exon comprising more than 75% of the coding sequence. Biallelic somatic APC mutations are found in the very earliest stages of the adenoma–carcinoma sequence in colonic epithelial cells, supporting its role in tumour initiation. The normal protein product is a tumour suppressor that has a multitude of important functions in the cell, including cell cycle control, differentiation, migration, and apoptosis. The role of APC in many of these processes occurs through its interactions with beta-catenin in the Wnt signalling pathway. APC binds to beta-catenin and targets it for degradation by the cell. This, in turn, prevents beta-catenin from entering the nucleus and participating in the Tcf-mediated transcription of a number of target genes, including MYC (Rubinfeld et al., 1993; Korinek et al., 1997; Chung, 2000; Goss and Groden, 2000). More recently, studies in mice heterozygous for Apc mutations show a role for APC in kinetochore–microtubule attachment and chromosome segregation at mitosis (Kaplan et al., 2001). Furthermore, Fodde et al. (2001) showed that APC, which forms a complex with EB1 proteins, is critical for the stabilization of microtubule–kinetochore interactions. Thus, inactivation of APC may contribute to chromosomal instability (CIN) and an enhanced mutation rate, promoting tumour growth in colorectal cancer (Fodde et al., 2001).

Over 500 germline mutations have been described (http://archive.uwcm.ac.uk/uwcm
/mg/search/119682.html
). Truncating mutations between codons 169 and 1393 result in the classic FAP phenotype. The two most common germline mutations, 5 bp deletions in codons 1061 and 1309, occur in the mutation cluster region of exon 15, and correlate with a high number of adenomas at an early age (Soravia et al., 1998; Wallis et al., 1999; Friedl et al., 2001). Retinal lesions are commonly associated with alterations between codons 463 and 1387 (Olschwang et al., 1993; Moisio et al., 2002). Desmoid tumours and mandibular osteomas, as seen in the Gardner variant, occur with mutations between codons 1403 and 1578 (Wallis et al., 1999; Moisio et al., 2002). In contrast, the attenuated FAP phenotype results from mutations either in the 5' part of the APC gene (5' to codon 158), the alternatively spliced exon 9, or in the far 3' part of the gene beyond codon 1595 (Spirio et al., 1993; van der Luijt et al., 1995; Friedl et al., 1996; Walon et al., 1997; Soravia et al., 1998; Moisio et al., 2002). A mutation discovered at codon 1307 of the APC gene generates a hypermutable polyadenine tract among the Ashkenazim (Laken et al., 1997). This I1307K variant is found in 6% of Ashkenazi Jews in the general population, and 10% of those with colon cancer (Laken et al., 1997). It confers a twofold increased risk for colon cancer, but does not cause significant polyposis.

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MYH gene and autosomal recessive heritable colorectal cancer

For patients with polyposis coli who test negative for a mutation in APC, or for those with a more attenuated phenotype (between 15 and 100 colorectal adenomas) and a family history compatible with autosomal recessive inheritance, recent studies have found that biallelic alterations in the MYH gene may be the cause (Sieber et al., 2003).

MYH is a base-excision repair gene, whose protein product is responsible for the removal of adenines from mispairs with 8-oxoguanine that arise during replication. Al-Tassan et al. (2002) first described a British Caucasian family with three siblings with colorectal cancer and each was found to be a compound heterozygote for the MYH missense variants Y165C and G382D. Follow-up study of seven additional unrelated patients with greater than 100 adenomas identified three individuals of British Caucasian descent either homozygous for the Y165C mutation or compound heterozygotes (Y165C/G382D) (Jones et al., 2002). Another three were homozygous for the exon 14 nonsense mutation E466X and were of Indian descent. The tumours of these carriers all exhibited an excess of somatic G : C>T : A transversions when compared to sporadic tumours, as would be expected given MYH's role in base-excision repair (Jones et al., 2002). A larger series of 152 patients with multiple adenomas (3–100), and 107 patients with polyposis coli and without germline APC mutation was then screened for germline mutations; approximately one-third of those with 15–100 adenomas had biallelic germline MYH mutation (Sieber et al., 2003). For those with classic polyposis, 7.5% had disease due to MYH. More recently, the two common MYH mutations were examined in a population-based series of Finnish colorectal cancer patients and showed that only 0.4% (4/1042) were homozygous (Enholm et al., 2003). Although the mutation frequency in CRC patients was small, it reached statistical significance when compared to the frequency in Finnish controls (0/424). Of those who were homozygous, the average age at onset of colon cancer was 55 (range 40–66 years) and all four individuals had multiple polyps, ranging from only 5 in one patient to 50–100 in another. This study underscores the importance of clinical history and also cautions against widespread population testing for MYH mutations.

To further clarify the role that MYH and base-excision repair might play in bowel neoplasia, Lipton et al. (2003) determined the genetic pathway in 130 colorectal adenomas and 19 carcinomas from 22 patients with MYH-associated polyposis (MAP). They concluded that the MAP pathway of carcinogenesis differed from both the CIN and MSI pathways, while sharing elements of both. MAP tumours showed a high frequency of APC mutation (21% of adenomas and 43% of cancers), but no evidence of beta-catenin mutation. Interestingly, all of the APC protein-truncating mutations were G>T transversions. Similarly, the same G>T mutation (G12C) in the KRAS gene was found in 9 of 14 (64%) of cancers and 13 of 30 (43%) of adenomas, suggesting other targets of genetic instability in these tumours. Most MAP cancers were near diploid (CIN-), showed no microsatellite instability, and had low frequencies of loss of heterozygosity (LOH).

Clearly, further studies are needed to extrapolate these findings, but early results imply that highly penetrant recessive susceptibility genes such as MYH may very well account for a significant proportion of hereditary colon neoplasia. The fact that two MYH variants (Y165C and G382D) comprise 86% of the mutations in white European patients, while all patients identified of Indian descent (n=4) have the E466X variant, implies that founder mutations may confer susceptibility in various ethnic populations (Marra and Jiricny, 2003; Sampson et al., 2003; Sieber et al., 2003). Data so far suggest that the heterozygous state alone may not increase risk, although larger well-controlled population-based series are needed. Interestingly, an initial study of unselected sporadic colorectal tumours did not find somatic MYH mutation or absence of mRNA and protein; this suggests that MYH loss may be rarely involved in the pathogenesis of sporadic bowel cancer (Halford et al., 2003).

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Juvenile polyposis

Juvenile polyposis (JPS, MIM 174900) is a rare autosomal dominant hamartoma syndrome characterized by the development of multiple juvenile polyps throughout the gastrointestinal tract, congenital anomalies, and an increased risk for malignancy (McColl et al., 1964; Jarvinen and Franssila, 1984). It has almost complete penetrance, with two-thirds of individuals manifesting clinical features by early adulthood. Approximately half of all cases have no family history (Coburn et al., 1995). JPS is caused by mutations in at least two different genes, MADH4 and BMPR1A. The clinical diagnosis is made if an individual meets any of the criteria as outlined in Table 3 (Jass et al., 1988).


Juvenile polyps occur in 1–2% of the general population, with most found in children and adolescents (Helwig, 1946; Toccalino et al., 1973). These are often solitary juvenile polyps, and as such are not associated with an increased risk for malignancy. The average age of diagnosis of solitary juvenile polyps is 3–5 years (Horrielleno et al., 1957; Roth and Helwig, 1963; Toccalino et al., 1973). In contrast, the frequency of JPS is suggested to be 1 in 100 000 individuals. The mean age of diagnosis is 16 years (Coburn et al., 1995; Sayed et al., 2002); however, some cases present in infancy and others much later in life, even in the seventh decade (Burt et al., 1993). Polyp number varies between individuals, even in the same family, but can be anywhere from 5 to 200 (Desai et al., 1994). They are most often found in the lower bowel (98%) but can also develop in the stomach (15%) and small intestine (7%) (Desai et al., 1994). There is also an increased lifetime risk for malignancy of 10–60% for gastrointestinal (colorectal, gastric, and duodenal) and pancreatic cancer (Jarvinen and Franssila, 1984; Jass et al., 1988).

Histopathology plays a critical role in the diagnosis of JPS (Helwig, 1946). The typical JPS polyp is unilobulated and pedunculated, spherical in shape with a smooth outer surface. In contrast to other hamartomatous polyps, these lack a smooth muscle core but instead show an internal dense inflammatory response, with predominant mesenchymal stroma that entraps normal epithelial cells, often forming dilated cysts (Jass et al., 1988). Less typical (20%) are JPS polyps that are multilobulated, with each lobe separated by well-defined clefts (Jass et al., 1988).

Congenital anomalies have been reported in 11–20% of individuals with JPS, more often in sporadic cases (Coburn et al., 1995). These can involve the gastrointestinal tract (including malrotation of the gut), heart, central nervous system, and genitourinary system (Desai et al., 1998; Guillem et al., 1999). Clubbing of the fingertips is common, macrocephaly and hypertelorism less so, and cleft lip/palate is infrequently seen.

Juvenile polyposis is caused by mutations in at least two genes. Germline mutations in MADH4 (also known as SMAD4, DPC4) encoding SMAD4 account for 15–30% of familial and sporadic cases (Howe et al., 1998). Mutations in the bone morphogenic protein receptor 1A gene (BMPR1A) may account for an additional 20–40%, especially those families originating from Europe (Howe et al., 2001; Zhou et al., 2001a; Sayed et al., 2002). Both MADH4 and BMPR1A belong to the TGFbeta superfamily. BMPR1A is phosphorylated by, and dimerizes with, a specific type II BMP receptor. In turn, this activated complex signals through the intracellular SMAD1 or related SMAD5 and SMAD8 proteins, increasing their affinity for SMAD4, and gaining access to the nucleus for the transcriptional regulation of downstream target genes (see Figure 2) (Massague, 2000; Eng, 2001b).

To date, the only genotype–phenotype correlation observed in JPS is the marked prevalence of gastric polyps in individuals with MADH4 mutations as compared to those with germline BMPR1A alterations (Friedl et al., 2002). It is likely that there is at least one other JPS gene that has not been identified yet. While other members of the TGFbeta–SMAD superfamily would be ideal candidates, no germline mutations in the genes encoding SMAD1, SMAD2, SMAD3, and SMAD5 have been identified to date (Bevan et al., 1999).

It is known that MADH4 acts as a tumour suppressor gene in tumours of the pancreas. However, the exact mechanism(s) for tumour formation in the gastrointestinal tract for both MADH4 and BMPR1A remains open for debate. Woodford-Richens et al. (2000) performed fluorescence in situ hybridization studies to demonstrate that biallelic inactivation of MADH4 occurs in the trapped epithelial layers and stromal cells of JPS polyps. This suggests that malignant progression occurs through the epithelial component of the hamartomatous polyp. Less is known of the role of BMPR1A in tumour initiation. Initial studies by Jacoby et al. (1997) showed that LOH on chromosome 10q22–23 occurred predominantly in the lamina propria rather than the epithelial cells of juvenile polyps. This might suggest that a 'landscaper' effect results in an abnormal stromal microenvironment leading to epithelial dysplasia and tumour formation in some forms of JPS.

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Peutz–Jeghers syndrome

Peutz–Jeghers syndrome (PJS, MIM 175200) is another rare hamartomatous polyposis condition, affecting approximately 1 in 200 000 people. It is autosomal dominant with nearly complete penetrance (Hemminki et al., 1997). The original description is credited to Peutz in 1921 (Peutz, 1921), followed by Jegher's review in 1949 of 10 families with gastrointestinal polyposis and mucocutaneous pigmentation, with illustration of the risk for invasive carcinoma (Jeghers et al., 1949). The most common location of PJS polyps is the small bowel, specifically the upper jejunum (78%). However, these hamartomatous polyps can occur anywhere along the gastrointestinal tract. Rarely, they are seen within the oesophagus, nasopharynx, and urinary tract. The main complication is intussusception, which can result in intestinal obstruction, bleeding, and anaemia. These are the usual presenting signs and symptoms and occur most often in the mid- to late teenage years, but may even occur in infancy. Approximately one-half of cases are due to germline mutation in the LKB1 gene. A clinical diagnosis of PJS is made if an individual meets any of the criteria as outlined in Table 4 (Aaltonen et al., 2000).


As with JPS, histopathology is critical in making the diagnosis of PJS, as the PJS polyp has a diagnostically useful central core of smooth muscle that extends, in a tree-like manner ('arborization'), into the superficial epithelial layer (reviewed by Aaltonen et al., 2000). Invagination of the epithelial layer occurs, essentially trapping these cells within the smooth muscle component, and causing 'pseudo-invasion' of the bowel wall that can be misdiagnosed as cancer (Shepard et al., 1987). This involvement of the three tissue layers predisposes to intussusception and the formation of the distinctive lobulated PJS polyp.

Cutaneous melanin deposition is the other cardinal feature of PJS. This most often occurs in the perioral region or buccal mucosa but can also be seen on the genitalia, anus, hands, or feet. Although the pigmentation usually appears in infancy and fades at puberty, pigmented spots have been reported to appear as late as age 70. Similar skin pigmentation can be seen in other hereditary conditions such as the Laugier–Hunziker syndrome, Carney complex, and LEOPARD syndrome, but the associated intestinal polyposis is not seen in these conditions (Veraldi et al., 1991; Chrousos and Stratakis, 1998).

The risk of malignancy in PJS is 10- to 18-fold increased over the general population, and these malignancies often occur at a relatively young age (Giardiello et al., 1987; Boardman et al., 1998). The most common locations are the colon, small intestine, and stomach (Giardello et al., 1987). Additionally, pancreatic carcinoma, breast carcinoma, Sertoli cell tumours of the testis in prepubescent males, and sex cord tumours with annular tubules (SCTAT) of the ovary or adenoma malignum (multicystic adenocarcinoma) of the uterine cervix in females, occur with increased frequency (Cantu et al., 1980; Young et al., 1982).

Germline mutations in LKB1 (STK11), on 19p13.3, encoding a multifunctional serine/threonine kinase, were found in a proportion of PJS individuals and kindreds in 1998 (Hemminki et al., 1997, 1998; Olschwang et al., 1998). LKB1 mutations have been found in only 50% of cases, leading to the suggestion of locus heterogeneity. LKB1 has nine exons, and the normal protein product acts as a tumour suppressor, a notable role for a protein kinase. Studies show that biallelic inactivation of LKB1, either through germline mutation plus somatic mutation, or more commonly promoter hypermethylation of the wild-type allele, causes hamartomatous polyps to develop (Gruber et al., 1998; Miyaki et al., 2000; Entius et al., 2001). Given that adenomatous changes occur in these polyps, and the associated gastrointestinal tumours are adenocarcinomas, analysis of the genes involved in the adenoma–carcinoma sequence has been performed. This has revealed somatic mutation of the beta-catenin gene and TP53 gene, but not of the APC gene, in PJS polyps (Miyaki et al., 2000). However, somatic APC mutation was seen in four of five PJS-associated carcinomas studied by Entius et al. (2001), indicative of some role for APC in the later stages of carcinogenesis. KRAS mutation was a rare event in either hamartoma or carcinoma (Gruber et al., 1998). In all, these results suggest that the abnormal growth of the PJS polyp leads to additional somatic mutation, such as in the beta-catenin gene, resulting in a change from hamartoma to adenoma, with continued progression to malignancy via alternative pathways from most sporadic carcinomas (Esteller et al., 2000; Miyaki et al., 2000; Entius et al., 2001). The observation that LKB1 mutation and LOH of markers in the 19p region are infrequent in randomly selected sporadic colorectal tumours lends further evidence to this theory (Avizienyte et al., 1998; Gruber et al., 1998; Miyaki et al., 2000; Entius et al., 2001).

LKB1 is widely expressed in many tissues (Hemminki et al., 1998) and one of its major roles may be as an inducer of apoptosis. Recent work by Karuman et al. (2001) showed that LKB1 is upregulated in normal mucosa, while in the intestinal polyps of PJS there is a noticeable reduction in the number of apoptotic cells. p53 and LKB1 were also found to interact functionally such that overexpression of LKB1 induces apoptosis only in cells with wild-type TP53 (Karuman et al., 2001). In the epithelial cells of the small intestine, LKB1 is normally expressed in the nucleus and cytoplasm (Karuman et al., 2001). Transfection of mouse Lkb1 cDNAs into COS cells demonstrates that endogenous expression occurs predominantly in the nucleus although LKB1 also functionally interacts with LIP1, a cytoplasmic-based protein in mammalian cells (Smith et al., 2001). When coexpressed, LIP1 becomes the cytoplasmic anchor for LKB1, thus regulating its subcellular localization and allowing for phosphorylation of cytoplasmic as well as nuclear substrates (Smith et al., 2001). In this fashion, LKB1 might induce apoptosis following redistribution to the cytoplasm, with subsequent phosphorylation of p53 or other apoptotic pathway regulators. In that LKB1 has been shown to translocate to the mitochondria in the presence of p53 (Karuman et al., 2001), and many types of signals converge upon the mitochondria to initiate apoptosis (Gross et al., 1999), this remains a possibility. Even more intriguing is the evidence that LIP1 co-precipitates SMAD4. Together with LKB1, they form a ternary complex, which, as such, implies a role in regulating TGFbeta–SMAD superfamily signalling (Smith et al., 2001). In point of fact, LIP1 may very well be the missing link that could explain some similar phenotypic features of PJS and JPS.

LKB1 was recently found to be the major upstream kinase of AMP-activated protein kinase (AMPK), which is part of a protein kinase cascade that plays a pivotal role in energy homeostasis (Woods et al., 2003). How phosphorylation (or lack thereof) of AMPK relates to the phenotype of PJS in unclear, but recent evidence has shown that the beta1-subunit of AMPK may act as a p53-independent stress-responsive protein that inhibits tumour growth and that AMPK may be linked to cellular senescence. Furthermore, tuberin, encoded by TSC2, which is one of the susceptibility genes for tuberous sclerosis complex, is downstream of AMPK (Inoki et al., 2003). Interestingly, activated Akt downregulates tuberin (Manning et al., 2002) and, theoretically, dysregulated PTEN can activate Akt, which should in turn downregulate tuberin signalling. This interplay of signalling pathways may begin to explain some of the common phenotypic features, for example, hamartomatous gastrointestinal polyps, shared by CS/Bannayan–Riley–Ruvalcaba syndrome (BRRS) (see below), PJS, and tuberous sclerosis complex.

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Hereditary breast ovarian cancer

Hereditary breast ovarian cancer (HBOC, MIM 113705) syndrome is the most common form of inherited breast cancer and is caused by germline mutations in BRCA1 on 17q11 and BRCA2 on 13q12–q13 (Miki et al., 1994; Wooster et al., 1995). The prevalence of BRCA mutations in the general population is estimated to be between 1 in 500 and 1 in 1000 (Claus et al., 1991; Ford et al., 1995), although this is much higher in certain founder populations, such as the Ashkenazi Jewish and Icelandic populations (see Table 5) (Roa et al., 1996; Struewing et al., 1997). The proportion of HBOC attributable to BRCA1/2 mutations is poorly defined and estimates depend upon the population studied, the number of breast and ovarian cancer cases in the family, and the mutation detection technique utilized. In families with greater than or equal to2 cases of breast cancer (<50 years) and at least one case of ovarian cancer, >90% will carry a deleterious mutation. In families with site-specific breast cancer, these figures are lower and range from 30 to 81% (Ford et al., 1998). In addition, a significant proportion of young breast cancer cases unselected for family history will carry a BRCA1 or BRCA2 mutation. This proportion is as high as 20% in women of Ashkenazi Jewish ancestry diagnosed before the age of 40 (Neuhausen et al., 1996; Offit et al., 1996).


Along with early-onset breast and ovarian cancer, other cancers seen more commonly in BRCA mutation carriers include fallopian tube cancer, pancreatic cancer, stomach cancer, and laryngeal cancer (Consortium, 1999; Brose et al., 2002). The lifetime relative risk of these cancers is on the order of two- to fourfold, with the exception of fallopian tube cancer (RR=120) (Brose et al., 2002). Male BRCA mutation carriers have an increased risk of developing prostate cancer (16% risk by age 70) and male breast cancer (5–10% lifetime risk in BRCA2 carriers) (Struewing et al., 1997). Identification of high-risk individuals and families can lead to earlier and increased cancer surveillance, particularly for breast and ovarian cancer, and the option of chemoprevention and/or prophylactic surgery to reduce cancer risk.

Penetrance estimates for BRCA1 and BRCA2 vary widely depending on the population studied, and are generally higher in studies of multiple-case families (Easton et al., 1993; Ford et al., 1998) as compared to those based on unselected series of patients (Thorlacius et al., 1998; Hopper et al., 1999). This wide range in risk is most likely due to several factors including allelic risk heterogeneity (i.e. different mutations causing different cancer risks) as well as modifying influences, both genetic and environmental. Based on studies of multiple-case families presenting to high-risk clinics, the risk of developing female breast cancer in BRCA1 and BRCA2 mutation carriers is between 70 and 85% by age 70. The risk of ovarian cancer differs slightly between BRCA1 and BRCA2 carriers, with BRCA1 carriers having a 44–63% lifetime risk and BRCA2 carriers a 27–31% lifetime risk (Easton et al., 1993; Struewing et al., 1997). Recently, cumulative risks for breast and ovarian cancer were estimated by pooling pedigree data from 22 studies of 8139 index cases unselected for family history (Antoniou et al., 2003). BRCA1 mutation carriers had a cumulative risk of developing breast or ovarian cancer by age 70 of 65 and 39%, respectively. For BRCA2 mutation carriers, the risks were 45% for breast cancer and 11% for ovarian cancer (Antoniou et al., 2003). The authors concluded that both mutation status and family history should be taken into account when counselling high-risk families.

BRCA1, identified in 1994 by positional cloning methods, encodes a 1863-amino-acid polypeptide (Miki et al., 1994). The N-terminus contains a zinc-finger domain that interacts both directly and indirectly with DNA (Miki et al., 1994). Exon 11 of BRCA1 encodes over 60% of the protein, contains two nuclear localization signals, and interacts with RAD-51 (Scully et al., 1997b), p53 (Zhang et al., 1998), RB (Aprelikova et al., 1999) and c-Myc (Wang et al., 1998). The C-terminus contains a transcription activation domain and interacts with RNA polymerase II (Scully et al., 1997a) and BRCA2 (Chen et al., 1998), as well as other proteins. BRCA1 has been shown to play a role in a multitude of cellular processes, including but not limited to DNA transcription, cell cycle regulation, DNA damage repair, and apoptosis (Somasundaram, 2003). It is thought to act as a tumour suppressor, which is supported by the fact that many BRCA1-associated tumours show LOH of the wild-type allele (Smith et al., 1992; Cornelis et al., 1995).

The BRCA2 protein has also been implicated in DNA repair and has recently been shown to regulate the activity of RAD-51, which is required for homologous recombination leading to double-stranded DNA repair (Jasin, 2002). Interestingly, biallelic inactivating mutations in BRCA2 were recently identified in patients with Fanconi anaemia, group D1 (FANC-D1) (Howlett et al., 2002), linking two seemingly unrelated syndromes to a common DNA damage response pathway.

To date, over 750 different mutations in BRCA1 and 400 in BRCA2 have been identified (http://research.nhgri.nih.gov/
bic/
). The majority of these are frameshift or nonsense mutations that lead to premature truncation and loss of function, consistent with the tumour suppressor model. Less than 10% of BRCA mutations are missense mutations. Some of these are deleterious and others are classified as variants of uncertain significance. Evidence for genotype–phenotype correlations exists. Mutations in and around exon 11 of BRCA2, which is often referred to as the ovarian cancer cluster region (OCCR), confer a higher ovarian cancer risk and lower breast cancer than mutations in other areas of the gene (Gayther et al., 1997b; Thompson et al., 2001). BRCA1 mutations that lie 3' of nucleotides 4200–4400 confer a lower ovarian cancer risk than mutations 5' of this region (Gayther et al., 1995). Lastly, BRCA1 mutations in and around exon 11 confer a lower risk of breast cancer than mutations in the 5' and 3' regions of the gene (Thompson and Easton, 2002).

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Cowden syndrome

CS (MIM 158350) is an autosomal dominant disorder and part of the PTEN hamartoma tumour syndrome (PHTS), which also includes Bannayan-Riley-Ruvalcaba Syndrome (BRRS), Proteus syndrome, and Proteus-like syndrome (Zhou et al., 2001b; Waite and Eng, 2002). Before the identification of the gene for CS, incidence estimates were on the order of 1/1 000 000 (Nelen et al., 1996). However, since that time, the gene for CS has been identified (see below) and molecular-based estimates of the incidence are approx1/200 000 (Nelen et al., 1997, 1999). Because many of the features of CS are common in the general population (e.g. fibrocystic breast disease, uterine fibroids), this condition is underdiagnosed and therefore the incidence may be even higher.

The most commonly reported manifestations of CS include mucocutaneous lesions (90–100%), fibrocystic breast disease (76% of affected females), thyroid abnormalities (50–67%), multiple uterine leiomyoma, gastrointestinal polyps (usually hamartomas, 40%), and macrocephaly (38%). Trichilemmomas and papillomatous papules are considered pathognomonic for the disease (Eng, 1997, 2000b). Affected individuals also have an increased risk for several malignancies, including breast cancer (25–50% lifetime risk), thyroid cancer, typically follicular-type (3–10% lifetime risk), and endometrial cancer (lifetime risk unknown) (Starink et al., 1986; Longy and Lacombe, 1996; Marsh et al., 1998b; Eng, 1997, 2000b) By age 30, approx99% of affected individuals will have developed at least the mucocutaneous signs of CS. Consensus diagnostic criteria for CS were developed in 1996 by the International Cowden Consortium (ICC) and have recently been revised (Table 6) (Eng, 2000b).


The CS susceptibility locus was mapped to 10q22–q23 (Nelen et al., 1996). Subsequently, germline mutations in PTEN, localized to 10q23.3, were found in CS (Liaw et al., 1997). PTEN, comprising nine exons, encodes a 403-amino–acid, almost ubiquitously expressed, dual-specificity phosphatase with lipid and protein phosphatase activities (Li and Sun, 1997; Li et al., 1997; Steck et al., 1997; Weng et al., 2001a, 2002). PTEN is the major lipid phosphatase that signals down the phosphoinositol-3-kinase (PI3K)/Akt pathway resulting in G1 cell cycle arrest and/or apoptosis, depending on the tissue type (Myers et al., 1997, 1998; Furnari et al., 1998; Maehama and Dixon, 1998; Stambolic et al., 1998; Weng et al., 1999, 2001a, 2001b, 2001c, 2001d, 2002).

Germline intragenic mutations in PTEN are found in 80% of individuals meeting the ICC criteria (Marsh et al., 1998). Among CS probands found not to have PCR-detectable intragenic mutations, approximately 10% have germline mutations in the PTEN promoter, which have been shown to activate Akt (Zhou et al., 2003). In a series of 37 CS probands, almost 70% of mutations were found in exons 5, 7, and 8, and included nonsense mutations, frameshift insertions and deletions, missense mutations, and splice-site mutations (Marsh et al., 1998). Approximately 40% of all mutations are localized to exon 5, which includes the phosphatase core motif, although exon 5 only represents 20% of the coding sequence (reviewed in Marsh et al., 1998; Eng, 2003). The clustering of mutations in exon 5 likely reflects the importance of the core of the phosphatase domain. Indeed, the majority of missense mutations occur in the core motif (reviewed in Eng, 2003). Similarly, mutations in exons 7 and 8 not only disrupt phosphatase function but also are thought to disrupt phosphorylation sites. Genotype–phenotype analyses revealed an association between the presence of PTEN mutation and risk of breast cancer (Marsh et al., 1998). Further, mutations within the phosphatase core motif and 5' of it, as well as missense mutations, appear to be associated with multiorgan involvement.

BRRS (MIM 153480) and CS were originally thought to be distinct clinical entities, but the discovery of PTEN mutations in approximately 60% of patients with BRRS shows that these represent different phenotypic expressions of the same genotype (Marsh et al., 1997). Of those without intragenic PCR-detectable mutations, approximately 10% have large deletions (Zhou et al., 2003). Hallmark features of BRRS include pigmented macules of the glans penis, haemangioma, lipomatosis, mental retardation, and developmental delay. Genotype–phenotype analyses in a series of 43 BRRS probands revealed an overlap in mutational spectra between BRRS and CS, thus formally demonstrating allelism (Marsh et al., 1999), although CS-associated mutations tended to occur in the 5' five exons and BRRS-associated mutations tend towards the 3' exons (reviewed in Eng, 2003). Further, the presence of a mutation in an individual with BRRS increased the risk for breast tumour formation (Marsh et al., 1999). Thus, in a syndrome not previously thought to be associated with malignancy, the presence of a germline PTEN mutation in BRRS would suggest an increased risk of neoplasia, perhaps similar to CS. There exist families with features of both CS and BRRS as well. To date, >95% of such overlap families have been found to have germline PTEN mutations (Marsh et al., 1998, 1999; Eng, 2003) (C Eng et al., unpublished data).

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Li–Fraumeni syndrome

Li–Fraumeni syndrome (LFS, MIM 151623) was first described in 1969 in four families with a clustering of soft-tissue sarcomas, early-onset breast cancer, and other malignancies in young children and adults (Li and Fraumeni, 1969). In 1990, germline mutations in the TP53 tumour suppressor gene (also known as p53) were identified in six LFS families (Malkin et al., 1990; Srivastava et al., 1990), and since that time, approximately 185 families have been reported in the literature worldwide (reviewed in Nichols et al., 2001). The major component cancers of LFS are sarcomas, breast cancer, brain tumours, adrenocortical carcinoma, and acute leukaemias (Lynch et al., 1978; Tomlinson and Bullimore, 1987; Li et al., 1988). Other associated cancers may include Wilms' tumour, cancers of the colon, stomach, lung, and pancreas, as well as melanoma and gonadal germ cell tumours (Strong et al., 1987; Li et al., 1988; Hartley et al., 1993; Varley et al., 1997; Birch et al., 2001; Nichols et al., 2001), although some of these are isolated observations in a single family and thus their exact frequency in mutation carriers is unknown.

Penetrance in LFS is almost complete and appears to be gender-dependent. In a recent study, the lifetime penetrance for a first cancer was 12, 35, 52, and 80% by ages 20, 30, 40, and 50 years, respectively (Hwang et al., 2003). When analysed by gender, females in this cohort had a higher lifetime risk of developing cancer (93 vs 68% by age 50) and an earlier age at first-cancer diagnosis (mean age at diagnosis, 29 vs 40 years). The risk of multiple primary cancers is also increased (Strong et al., 1987; Garber et al., 1991; Hisada et al., 1998). According to one study of 24 LFS families, of 200 individuals with a primary cancer diagnosis, 30 (15%) developed a second cancer, 8 (4%) developed a third cancer, and 4 (2%) developed a fourth (Hisada et al., 1998). Clinical criteria for LFS and its variant form, Li–Fraumeni-like syndrome (LFL, also called variant-LFS), have been developed and are listed in Table 7a and b (Li et al., 1988; Birch et al., 1994; Eeles, 1995).


The TP53 gene at chromosome 17p13.1 contains 11 exons and encodes a 53 kDa protein (p53). p53 is upregulated in response to cellular stress (e.g. DNA damage, viral infection), which in turn causes cell cycle arrest at the G1 phase, allowing for DNA repair or apoptosis. In large part, p53 function is mediated through direct transcriptional regulation of downstream target genes. However, p53 has also been shown to contribute directly to differentiation (Rotter et al., 1994), senescence (Vojta and Barrett, 1995; Wynford-Thomas, 1999), and angiogenesis (Bouck, 1996). Tight control of p53 expression, activation, and stability is critical and has been shown to occur at the level of transcription, translation, and post-translational modification by a number of proteins. For example, MDM2 mediates p53 degradation through an auto-feedback loop. Kinases such as ATM and CHEK2 (also known as hCHK2) can phosphorylate and thus stabilize the p53 protein (reviewed in Ashcroft and Vousden, 1999). As a significant proportion of families with LFS and LFL do not carry mutations in the TP53 gene, these genes and others in the pathway are obvious candidates. Such possibilities are being investigated, especially after the discovery of both missense and frameshift mutations in the CHEK2 gene in a small number of LFS and LFL families, as well as site-specific breast cancer families (Consortium, 2002; Sodha et al., 2002; Meijers-Heijboer et al., 2003; Schutte et al., 2003). However, further studies are needed to determine the clinical significance of these findings.

Germline TP53 mutations have been identified throughout the coding region, with the majority (approx75%) occurring in exons 5–8 (Frebourg et al., 1995; Varley et al., 1997). In contrast to other cancer syndromes, missense mutations are the most common variety in LFS (Varley, 2003). The mutation frequency in families meeting the standard clinical criteria for LFS is 70–80% in most clinical laboratories (Varley et al., 1997; Varley, 2003). In families meeting the LFL criteria the frequency is lower: 8% using the Eeles criteria and 22–40% using the Birch criteria (Varley et al., 1997; Bougeard et al., 2001; Varley, 2003) (Table 7a and b).

Genotype–phenotype correlations have been observed in some studies but not in others. For example, in one study, families with missense mutations in the core DNA-binding domain tended to have an overall higher cancer incidence (particularly of breast and CNS tumours) with an earlier age at onset, as compared to families with protein-truncating or -inactivating mutations, or families with no mutation at all (Birch et al., 1998). In contrast, a study of 56 TP53 mutation-positive individuals from 107 kindreds ascertained through cases of childhood soft-tissue sarcoma reported no difference in phenotype between patients with missense mutations vs truncating mutations (Hwang et al., 2003). Similarly, Olivier et al. (2003) found no differences in phenotype between mutation type (missense vs truncating), but did find significant differences depending on the location of the mutation, specifically for brain tumours and adrenocortical tumours. Brain tumours were more likely to be associated with mutations in loops 1 and 2 of the p53 protein, which together form a complex with zinc that then binds to the minor groove of its target DNA. Adrenocortical tumours were more strongly associated with mutations in the non-DNA-binding domain vs the DNA-binding domain. Differences in patient accrual, study design, and mutation site classification may have contributed to these disparate findings, and thus more studies are needed to clarify this issue.

The frequency of germline TP53 mutations in patients with multiple primary cancers unselected for family history (Malkin et al., 1992; McIntyre et al., 1994), as well as those with 'isolated' LFS component tumours, has been extensively studied. While only 1% of isolated early-onset breast cancer cases will harbour a germline TP53 mutation (Borresen et al., 1992; Sidransky et al., 1992; Lalloo et al., 2003), the frequency is higher in sporadic osteosarcomas (2–3%) (McIntyre et al., 1994), rhabdomyosarcoma (9%) (Diller et al., 1995), and brain tumours (2–10%) (Felix et al., 1995; Li et al., 1995). Perhaps the most striking association occurs in cases of childhood adrenocortical carcinoma (ACC). In a series of 14 ACC patients unselected for family history, 11 (82%) families carried a germline TP53 mutation. Interestingly, the same two mutations (at codons 152 and 158) were present in 9 of the 11 mutation-positive cases. In another series of 36 cases of childhood ACC in southern Brazil, 35 carried an identical R337H mutation (Ribeiro et al., 2001). There was no evidence of a founder effect in either study and the cancer family history in mutation-positive cases was not striking, suggesting a low-penetrance and possibly tissue-specific mutation at these positions.

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Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN 1, MIM 131100) is an autosomal dominant syndrome with an estimated incidence in the general population on the order of 1–2/100 000 (Chandrasekharappa and Teh, 2001). The major endocrine features of MEN 1 are parathyroid adenomas, entero-pancreatic endocrine tumours, and pituitary tumours. As defined by the consensus diagnostic criteria, a diagnosis of MEN 1 is made in a person with two of the three major endocrine tumours. Familial MEN 1 is defined as at least one MEN 1 case plus at least one first-degree relative with one of these three tumours (Trump et al., 1996; Chandrasekharappa et al., 1997; Brandi et al., 2001).

The age-related penetrance of MEN 1 is 45% at age 30 years, 82% at age 50 years, and 96% at age 70 years (Trump et al., 1996; Carty et al., 1998). Primary hyperparathyroidism (HPT) is the most common, and often the earliest manifestation, occurring in 80–100% of patients by age 50 (Benson et al., 1987; Brandi et al., 1987; Thakker, 1995; Trump et al., 1996). These tumours are typically multiglandular and often hyperplastic, in contrast to the solitary adenoma seen in sporadic primary HPT (Chandrasekharappa and Teh, 2001). In addition, the average age at onset of HPT is 30 years earlier in patients with MEN 1 than in the general population (20–25 vs 50 years). Parathyroid carcinoma is not known to be associated with MEN 1.

Pancreatic islet cell tumours, usually gastrinomas and insulinomas, and less commonly VIPomas (vasoactive intestinal peptide), glucagonomas and somatistatinomas, are the second most common endocrine manifestation, occurring in up to 30–80% of patients by age 40 (Thakker, 1995; Trump et al., 1996). These are usually multicentric and can arise in the pancreas or, more commonly, as small (<0.5 cm) foci throughout the duodenum (Pipeleers-Marichal et al., 1990). Gastrinomas represent 50% of the pancreatic islet cell tumours in MEN 1 and are the major cause of morbidity and mortality in MEN 1 patients (Trump et al., 1996; Norton et al., 1999). Most result in peptic ulcer disease (Zollinger–Ellison syndrome) and half are malignant at the time of diagnosis (Pipeleers-Marichal et al., 1990; Weber et al., 1995; Norton et al., 1999). Nonfunctional tumours of the entero-pancreas, some of which produce pancreatic polypeptide, are seen in 20% of patients (Skosgeid et al., 1994; Marx, 2002).

Approximately 15–50% of MEN 1 patients will develop a pituitary tumour (Thakker, 1995; Trump et al., 1996). Two-thirds are microadenomas (<1.0 cm in diameter) and the majority are prolactin-secreting (Corbetta et al., 1997). Other manifestations include carcinoids of the foregut (typically bronchial or thymic) (Teh et al., 1998), skin tumours including lipomas (30%), facial angiomas (85%), and collagenomas (70%) (Thakker, 1995; Darling et al., 1997; Marx, 2002) and adrenal cortical lesions, including cortical adenomas, diffuse or nodular hyperplasia or rarely carcinoma. These adrenal lesions do not show LOH for the MEN 1 locus and might represent a secondary phenomenon (Skogseid et al., 1992; Burgess et al., 1996). Thyroid adenomas, phaeochromocytoma (PC) (usually unilateral), spinal ependymoma, and leiomyoma have also been reported but their frequency is not known (Ballard et al., 1964; Dackiw et al., 1999).

The prevalence of MEN 1 among patients with apparently sporadic component tumours varies but is quite high for some tumour types. Approximately one-third of patients with Zollinger–Ellison syndrome will have a clinical diagnosis of MEN 1 (Bardram and Stage, 1985; Roy et al., 2000). Only 2–3% of patients with primary HPT have MEN 1 (Uchino et al., 2000), although familial isolated hyperparathyroidism (FIHP) is allelic to MEN 1, with 20% of probands harbouring a germline MEN1 mutation (see below) (Pannett et al., 2003). Lastly, among patients with pituitary tumours, the prevalence of MEN 1 is 2.5–5% (Scheithauer et al., 1987; Corbetta et al., 1997), but is as high as 14% in patients with prolactinoma (Corbetta et al., 1997). These results underscore the importance of collecting a thorough medical and family history in patients with a diagnosis of an MEN 1-associated endocrine tumour.

Germline mutations in MEN1, on 11q13 and encoding menin, have been found in 60–70% of MEN 1 probands (Larsson et al., 1988; Chandrasekharappa et al., 1997). Loss of the wild-type allele in many familial and sporadic MEN 1-associated tumours, as well as the fact that most mutations result in protein truncation, suggests that MEN1 is a tumour suppressor gene. The exact role of menin is not currently known, but its localization to the nucleus and its interactions with proteins such as JunD, NF-kappaB, Smad3, and RelA, among others, suggest that it may play a role in transcription regulation (reviewed in Poisson et al., 2003). A recent study suggests that in murine embryonic fibroblasts, wild-type menin may promote apoptosis through the caspase-mediated cascade by upregulating transcription of procaspase 8 (Schnepp et al., 2003). It is also possible that it plays a role in other regulatory pathways that lead to the control of cell growth and/or genomic integrity, but this remains to be seen.

Over 300 MEN1 mutations have been identified to date and these are scattered across the entire coding region. The majority of these are nonsense or frameshift mutations and the remainder are missense or in-frame deletions that lead to expression of an altered protein. There is currently no evidence of genotype–phenotype correlations and inter- and intrafamilial variability is the rule (Giraud et al., 1998; Wautot et al., 2002). Identification of the familial mutation can be used for predictive testing of at-risk family members. Since many of the tumours in MEN 1 are under- or misdiagnosed, identifying mutation carriers within an MEN 1 family can allow for early detection and treatment. In addition, genetic testing for MEN1 mutations can be used to distinguish between it and other forms of hereditary HPT, such as FIHP (MIM 145000) and hyperparathyroidism–jaw tumour syndrome (HPT–JT, MIM 145001). HPT–JT, which is caused by germline mutations in the HRPT2 gene, is associated with primary HPT, ossifying lesions of the maxilla and mandible, and renal lesions, usually bilateral renal cysts, hamartomas and, in some cases, Wilms' tumour (Teh et al., 1996; Carpten et al., 2002). Unlike MEN1, HPT–JT is associated with an increased risk of parathyroid carcinoma (Marx, 2000). On the other hand, as its name suggests, FIHP is characterized by isolated primary HPT with no additional endocrine features, and in some families, FIHP is the initial diagnosis of what later develops into MEN 1. While 20% of families with a clinical diagnosis of FIHP carry germline MEN1 mutations (Miedlich et al., 2001), the recent identification of germline HRPT2 mutations in other FIHP families is of interest (Carpten et al., 2002). Given the differential risks between these three conditions as well as the increased risk of parathyroid carcinoma in HPT–JT, genetic diagnosis in a patient presenting with early-onset primary HPT may play a larger role in the management of these patients and their families.

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Multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant cancer syndrome characterized by medullary thyroid cancer (MTC), PC, and/or HPT. Historically, MEN 2 has been divided into three subtypes depending on clinical features: MEN 2A (MIM 171400), MEN 2B (MIM 162300), and familial medullary thyroid carcinoma (FMTC, MIM 155240). MEN 2A classically comprises MTC in 100% of affected individuals, PC in 50%, and HPT in 15–30% (reviewed by Gimm, 2001). MEN 2B is similar to MEN 2A except that the average age of tumour onset is 10 years younger than that for MEN 2A, that HPT is not clinically manifest and that other features such as marfanoid habitus and mucosal neuromatosis are present (Gorlin et al., 1968). FMTC is operationally defined as the presence of MTC in the absence of PC and HPT (Farndon et al., 1986). All three subtypes have been mapped to chromosome sub-band 10q11.2 by linkage analyses, and are caused by germline mutations of the RET (REarranged during Transfection) proto-oncogene (Mathew et al., 1987; Simpson et al., 1987; Gardner et al., 1993; Mulligan et al., 1993). RET was the first proto-oncogene to be implicated in an inherited cancer susceptibility syndrome.

Before identification of RET as the MEN 2 susceptibility gene, the clinical penetrance of MEN 2A was said to be 70% by the age of 70 years (Ponder et al., 1988). After the putative susceptibility locus was found, the biochemically induced penetrance of MEN 2A was found to be 100% by the age of 70 years (Easton et al., 1989). Likewise, original epidemiology studies suggested that approximately 25% of all MTC presentations were due to MEN 2. After RET was identified, several series examined the frequency of unexpected germline RET mutations in apparently sporadic MTC. When individuals with MTC were tested without taking a good family history or excluding syndromic features, the mutation frequency was approximately 25% (Decker et al., 1995). However, several other series accruing MTC cases with no family history and no syndromic features reveal that the unexpected germline RET mutation frequency ranges from 5 to 10% (Eng et al., 1995a; Wohlik et al., 1996; Schuffenecker et al., 1997; Wiench et al., 2001). A population-based series of apparently sporadic PC, defined as no family history and no syndromic features, suggests an approx5% occult germline RET mutation frequency (Neumann et al., 2002).

The RET gene is comprised of 21 exons and encodes a transmembrane receptor tyrosine kinase expressed in tissues and tumours derived mainly from the neural crest (Takahashi et al., 1985, 1988; Takahashi and Cooper, 1987; Pachnis et al., 1993; Nakamura et al., 1994; Tsuzuki et al., 1995). The structure of the RET receptor is like that of most receptor tyrosine kinases with a large extracellular domain, comprising a cysteine-rich domain and a cadherin-like domain, a transmembrane domain, and an intracellular tyrosine kinase domain (Pasini et al., 1995; Eng, 1999). However, the RET receptor is unique in that it requires a multicomponent complex to trigger activation. RET has to bind one of four GFRalpha family of GPI-linked coreceptors before binding one of four members of the glial cell line-derived neurotrophic factor family of ligands (GDNF, neurturin, persephin, and artemin) in a heterohexameric complex (Durbec et al., 1996; Jing et al., 1996; Kotzbauer et al., 1996; Treanor et al., 1996; Trupp et al., 1996; Vega et al., 1996; Baloh et al., 1997; Buj-Bello et al., 1997; Klein et al., 1997). When RET is activated, it autophosphorylates and phosphorylates such downstream molecules as Shc (Borrello et al., 1994; van Weering et al., 1995). RET signals down a number of well-characterized signal transduction pathways, including the MAP kinase–RAS–RAF and phosphoinositide 3-kinase pathways (van Weering and Bos, 1998; Besset et al., 2000). MEN 2A- and FMTC-related mutations affecting cysteine codons result in disulphide bond-mediated inter-receptor binding and thus constitutive activation (Borrello et al., 1995; Santoro et al., 1995). Interestingly, colony forming assays revealed that the C634R mutation had a higher transformation rate and/or signal activation than exon 10 cysteine mutations, for example, C620R (Santoro et al., 1995; Carlomagno et al., 1997; Ito et al., 1997). The MEN 2B-related M918T mutation alters a highly conserved residue in the catalytic core of the tyrosine kinase domain by altering substrate specificity (Songyang et al., 1995). Mutations in codon 768 likely affect substrate specificity and perhaps ATP binding (Eng et al., 1995b).

Germline RET mutations have been identified in approximately 95% of all MEN 2, with 98% of MEN 2A probands found to have a mutation, 97% in MEN 2B and 85% in FMTC (Eng et al., 1996; Gimm et al., 1997; Smith et al., 1997) (Figure 3). The characteristic mutational spectrum found in MEN 2A includes missense mutations in one of cysteine codons 609, 611, 618, 620 (exon 10), or 634 (exon 11) (Mulligan et al., 1994b; Eng et al., 1996). Approximately 85% of MEN 2A individuals carry a codon 634 mutation (Eng et al., 1996). Genotype–phenotype analyses reveal that codon 634 mutations are associated with the presence of PC and HPT (Eng et al., 1996). In particular, the C634R mutation is likely associated with the development of HPT (Mulligan et al., 1994b; Eng et al., 1996; Schuffenecker et al., 1998). Rare 'one of' missense mutations seen in MEN 2A include those involving codons 630 and 790 (Eng et al., 1996; Eng, 1999). FMTC-associated mutations occur at the same cysteine codons as those in MEN 2A, although mutations at codons 609–620 are more proportionately frequent in FMTC than MEN 2A (Figure 3). Consistent with the C634R–HPT association, FMTC families have not been found to have C634R mutations, but C634Y and other 634 mutations (Eng et al., 1996). Germline mutations probably unique to FMTC include E768D (exon 13), V804L and V804M (exon 14), although one family segregating V804L has been described with older-onset unilateral PC in two members (Eng et al., 1996; Nilsson et al., 1999).

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Relative frequency and distribution of germline RET mutations in MEN 2, comprising MEN 2A, MEN 2B, and FMTC

Full figure and legend (50K)

Germline M918T and A883F mutations occur in 95% and approx2%, respectively, of MEN 2B patients (Eng et al., 1996; Gimm et al., 1997; Smith et al., 1997). These two mutations are unique to MEN 2B and have never been observed in MEN 2A or FMTC. Interestingly, at least one MEN 2B family appears to carry a V804M mutation in the presence of a RET variant of unknown significance (Miyauchi et al., 1999).

Discovering that RET is the susceptibility gene for MEN 2 also led to the realization that variable penetrance characterized various genotypes. For example, it has now become obvious that RET codons 918, 883, and 634 mutations have the highest penetrance, predisposing to MEN 2B and MEN 2A with MTC, PC, and HPT involvement (Eng et al., 1995a; Eng, 2000a). In contrast, germline V804M mutations and perhaps cysteine codon 609 mutations have the lowest penetrance and the older ages of onset (Eng et al., 1996; Shannon et al., 1999). Mutations at codons 611–620 have a broad range of penetrance and expressivity. Taken together, these data suggest that each of the component organs has a different threshold for transformation to neoplasia, with the highest threshold in the parathyroid glands and the lowest in the C-cells of the thyroid, the precursor cells of MTC.

Although gain-of-function RET mutations cause MEN 2, studies have shown that loss-of-function RET mutations result in Hirschsprung disease (HSCR, MIM 142623). Hirschsprung disease is a frequent (1 in 5000 live births) congenital intestinal malformation characterized by the absence of enteric innervation in the hindgut, resulting in functional intestinal obstruction. Highly selected series of HSCR cases have yielded a 30–50% germline RET mutation frequency in familial cases and a 15–30% frequency in sporadic HSCR (reviewed by Eng, 1999). However, population-based series suggest that 10–30% of familial HSCR are due to germline loss-of-function RET mutations and perhaps 3% of sporadic cases have such mutations as well. Although these mutations are generally scattered throughout the gene, a number of kindreds have been described with germline RET mutation in codons 609, 618, and 620, with co-segregation of both MEN 2A/FMTC and HSCR disease phenotypes (Mulligan et al., 1994a). There are other families with HSCR as the only manifestation, although these families have nucleotide substitutions in the cysteine 609 and 620 codons only (Mulligan et al., 1994a).

Functional data have supplied some clues in an attempt to explain this apparent contradiction. For one, it has been shown that missense mutations of the more 5' codons, such as 609, 611, 618, and 620, result in less migration of these mutant receptors to the cell surface (Ito et al., 1997; Eng, 2001a). Studies have also shown that the exon 10 Cys mutations have a three- to fivefold lower transforming activity in transfection studies of NIH 3T3 cells than the C634R mutant (Carlomagno et al., 1997; Ito et al., 1997). Taken together, this suggests that the MEN 2A/FMTC phenotype may be a direct consequence of the differences in penetrance of each mutation type. In this scenario, the codon 634 mutations will more often result in full manifestation of the classic MEN 2A phenotype (MTC, PC, and HPT) due to the greater availability of mature, albeit mutant, receptors on the cell surface. In contrast, the exon 10 mutations allow a lesser amount of available receptors on the cell surface, so less RET dimerization, activation, and transformation, leading to a less severe phenotype. This 'threshold' effect on disease phenotype would be invariably dependent on the tissue involved, and the particular stage of development (Eng, 2001a). For those families with both MEN 2/FMTC and HSCR, which have exon 10 alteration, it is plausible to speculate that the developing enteric ganglia require a certain number of receptors, while it is sufficient for the presence of constitutively active receptor, whatever the levels, for neoplasia to occur. Clearly, however, the actual levels of available receptor seem to affect penetrance and expressivity.

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von Hippel–Lindau disease

von Hippel–Lindau disease (VHL, MIM 193300) is an inherited multisystem disease predisposing to retinal and central nervous system haemangioblastomas, renal cell carcinoma, PC, pancreatic islet cell tumours, and endolymphatic sac tumours. It has an estimated birth incidence of 1 in 36 000 per year (Maher et al., 1991) and is inherited in an autosomal dominant manner with a high degree of inter- and intrafamilial variability (Neumann and Wiestler, 1991). The penetrance is age-dependent, but reaches 95–100% by age 65 (Maher et al., 1991).

Two large studies comprising approximately 700 patients with VHL, including one six-generation kindred with 43 affected family members, reviewed the frequencies and age of onset of each of the associated lesions (Lamiell et al., 1989; Maddock et al., 1996). The most common manifestations of VHL are retinal haemangiomas (49–57%), haemangioblastomas of the cerebellum (35–59%) and spinal cord (approx14%), clear cell renal carcinoma (24–47%), and PC (7–19%). Pancreatic cysts and tumours (16%), endolymphatic sac tumours (11%), and papillary cystadenoma of the epididymis (15%) have also been described (Neumann, 1987; Maher et al., 1990; Megerian et al., 1995). In general, these lesions occur much earlier than in the general population. For example, the mean age at diagnosis of cerebellar haemangioblastoma is 29plusminus10 years and for renal cell carcinoma is 44.0plusminusyears (Lamiell et al., 1989; Maher et al., 1991), tumours which typically occur in the fourth or fifth decades of life (Murphy et al., 1995). In addition to presenting at an earlier age, these tumours tend to be bilateral and/or multifocal. The clinical criteria for VHL are outlined in Table 8 (Maher et al., 1990).


The VHL susceptibility gene, VHL on chromosome sub-band 3p26, (Latif et al., 1993), is a tumour suppressor gene that comprises three exons and encodes two isoforms: a 24–30 kDa protein and an 18–20 kDa protein, which is the result of a second start codon at amino-acid position 54 within the open reading frame (Iliopoulos et al., 1998; Schoenfeld et al., 1998). These two isoforms are collectively referred to as pVHL. Both are biologically active, although differentially expressed, and inactivation of both is required for tumour formation, as demonstrated through in vitro studies (Iliopoulos et al., 1998; Schoenfeld et al., 1998). In support of these data are the interesting observations that all disease-associated mutations map carboxy-terminal to the second start codon (Maher and Kaelin, 1997) and the highest degree of amino-acid conservation across species occurs in this region (Latif et al., 1993; Duan et al., 1995). Approximately 28% of mutations in the VHL gene are partial or complete deletions (Stolle et al., 1998). The remaining 72% are small deletions/insertions or point mutations. Therefore, genetic testing for VHL should include a combination of quantitative Southern blot analysis and DNA sequencing. The sensitivity of this combined approach is nearly 100% when performed on patients with a clinical diagnosis of VHL (Stolle et al., 1998).

Clear genotype–phenotype correlations have been described for VHL. VHL families are categorized into two subtypes based on a low (type 1) or high (type 2) risk of PC (Table 9). VHL type 2 has been further divided based upon a low risk (type 2A) or high risk (type 2B) of renal cell carcinoma (Maher et al., 1990). In a third subtype, VHL 2C, PC is the only manifestation. Of those with VHL type 1, 50% will have large deletions or truncating mutations, while the majority (approx95%) of patients with VHL type 2 (with PC) have missense mutations (Chen et al., 1995; Kaelin and Maher, 1998). Interestingly, in a population-based study of families fitting the VHL type 2C description (isolated PC with no other syndromic features), 11% had a germline VHL mutation (Neumann et al., 2002). Some have suggested that missense mutations in VHL may result in a 'gain of function' or that the development of PC is the result of partial loss of pVHL function, rather than complete loss.


The VHL protein (pVHL) has been implicated in a variety of cellular functions including extracellular matrix formation and cell cycle exit (Gnarra et al., 1994; Ohh et al., 1998; Pause et al., 1998). Perhaps its most well-characterized role is the regulation of hypoxia-inducible factor 1 (HIF1). HIF1 is a heterodimer (with alpha- and beta-subunits), which in hypoxic conditions binds DNA and activates transcription of a number of downstream genes that are involved in energy metabolism, angiogenesis, and apoptosis. These include vascular endothelial growth factor (VEGF) and platelet-derived growth factor B chain (PDGF B), among many others. When complexed with elongin B, elongin C, and Cul2, pVHL has been shown to bind directly HIF1alpha and target this for ubiquitylation and degradation by the 26S proteosome (Maxwell et al., 1999). Cells lacking pVHL are unable to degrade HIF1alpha, which leads to the constitutive overexpression of hypoxia-inducible mRNAs such as VEGF and PDGF B (Iliopoulos et al., 1996; Levy et al., 1996). When wild-type VHL is transfected back into VHL-/- cells in the presence of oxygen, this overexpression is suppressed.

Several recent lines of evidence indicate that pVHL may act in a tissue-specific manner and that it is not only mutation type (i.e. deletion vs missense) but its differential effects on various pVHL-dependent pathways that determine the tumour phenotype (Clifford et al., 2001; Hoffman et al., 2001). For example, mutations in families with VHL type 2C (PC only) retain the ability to regulate HIF1, but lose the ability to bind fibronectin, which may in turn dysregulate extracellular matrix formation. In contrast, mutations that cause haemangioblastoma and renal cell carcinoma (types 1, 2A, and 2B) are deficient in HIF1 degradation (Table 9). These studies suggest that loss of HIF1 function may lead to an increased risk of the vascularized tumours typically seen in VHL, while the underlying mechanism of PC formation in VHL occurs through a different pathway, possibly fibronectin–matrix assembly.

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Conclusions

The discoveries generated by the investigation of inherited cancer syndromes, some of which are highlighted here, transcend the field of cancer genetics. First, although highly penetrant cancer susceptibility alleles are rare in the general population, the information gained through the discovery and characterization of genes such as RET, APC, PTEN, and TP53 can be (and is being) applied to the study of sporadic tumours as well. Second, while genotype–phenotype correlations will continue to assist clinicians in counselling at-risk families, they will also shed light on the molecular pathogenesis and tissue specificity of such mutations. In addition, some of the aforementioned molecular pathways have been implicated in other disease processes (e.g. HIF1 in ischaemic heart disease and type II BMP receptors in primary pulmonary hypertension) and therefore these discoveries will no doubt have a broader impact on the practice of medicine. And lastly, these studies may allow for the development of targeted molecular-based interventions, which, in theory, may serve as therapeutic adjuncts not only in cancer but also other multifactorial conditions such as diabetes and heart disease.

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Notes

Note added in proof

Recently, it was reported that among seven unrelated cases of JPS individuals with germline MADH4 mutations, all were found to have hereditary haemorrhagic telangectasia (HHT) (Gallione et al., 2004).Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJJ and Marchuk DA. (2004) Lancet, 363, 852–859.

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Acknowledgements

We are grateful to Doreen Agnese, Carrie Drovdlic, Heather Hampel, Rob Pilarski, and Leigha Senter for critical review of this manuscript. We thank Ross Waite for his assistance with electronic artwork. CE is the recipient of a Doris Duke Distinguished Clinical Scientist Award and is supported in part by the American Cancer Society, Department of Defense US Army Breast and Prostate Cancer Research Programs, Susan G Komen Breast Cancer Research Foundation, National Cancer Institute, National Institutes of Health, State of Ohio Biomedical Research and Technology Transfer Fund and V Foundation.

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