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  • Review Article
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Searching for the hereditary causes of renal-cell carcinoma

Key Points

  • A predisposition to renal cancer has been identified in several autosomal-dominant inherited cancer syndromes.

  • von Hippel–Lindau (VHL) disease, associated with conventional (clear-cell) renal-cell carcinomas and multi-organ neoplasia, is caused by germline mutations in the VHL tumour-suppressor gene and loss of the wild-type VHL allele.

  • Patients with hereditary papillary renal carcinoma (HPRC) harbour germline-activating mutations in the MET proto-oncogene, which can cause renal cancers with papillary type-1 histology.

  • Papillary type-2 renal carcinomas and cutaneous and uterine smooth-muscle tumours are associated with the syndrome of hereditary leiomyomatosis and renal-cell cancer (HLRCC), which is caused by germline loss-of-function mutations in the fumarate-hydratase (FH) gene.

  • The Birt–Hogg–Dubé syndrome (BHD) predisposes to cutaneous nodules (benign tumours of the hair follicle), spontaneous pneumothorax and an increased risk for renal cancers of various histological types, such as chromophobe renal-cell carcinoma and oncocytic hybrid renal tumour. BHD is caused by germline mutations in a newly discovered tumour-suppressor gene, BHD.

  • Hyperparathyroidism-jaw tumour syndrome (HPT-JT) is associated with parathyroid adenomas, fibro-osseous tumours of the jaw, and unusual renal tumours containing a mixture of epithelial and stromal elements. This syndrome is caused by germline mutations in HRPT2.

  • The identification of non-VHL families affected with clear-cell renal carcinomas, termed familial clear-cell renal carcinoma (FCRC), indicates that additional renal-cancer-predisposing genes remain to be identified.

  • Diagnosis and appropriate treatment of these hereditary renal-cancer-associated syndromes relies on an understanding of their clinical spectrum, accurate histological evaluation of renal tumours from patients and on genetic testing for predisposing genes.

Abstract

Families with hereditary predispositions to cancer continue to provide a unique opportunity for the identification and characterization of genes involved in carcinogenesis. A surprising number of genetic syndromes predispose to the development of renal-cell carcinoma, and already genes associated with five of these syndromes have been identified — VHL, MET, FH, BHD and HRPT2. These very different genes and the biochemical pathways in which they participate raise interesting questions about the development of renal cancers and could lead to new therapeutic approaches in the near future. So, what is known about hereditary renal cancer at present?

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Figure 1: Dysregulation of HIF-1α by VHL inactivation leads to clear-cell renal tumours in patients with von Hippel–Lindau disease.
Figure 2: Activating missense mutations in MET lead to papillary renal carcinoma.
Figure 3: Fumarate-hydratase-inactivating mutations in hereditary leiomyomatosis renal-cell carcinoma lead to papillary type-2 renal-cell carcinoma.
Figure 4: Possible targets for VHL-related therapeutics.

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Acknowledgements

This publication has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health. The content of this publication does not reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the United States Government.

Correction: The DOI number given for this article in the May 2004 print issue of Nature Reviews Cancer was wrong. The correct DOI number is: doi:10.1038/nrc1364.

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Related links

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DATABASES

Cancer.gov

colon cancer

renal-cell carcinoma

Locuslink

BHD

CBP

CUL2

CXCR4

cyclin D1

DIRC1

DIRC2

DIRC3

elongin B

elongin C

EPO

FH

FHIT

FIH-1

HGF

HIF-1α

HIF-1β

HIF-2α

HIF-3α

HRPT2

LSAMP

MET

NORE1

p300

PTCH

RASSF1A

TGF-α

TRC8

VEGF

VHL

OMIM

Birt–Hogg–Dubé syndrome

familial papillary thyroid carcinoma

hereditary leiomyomatosis and renal-cell cancer

hereditary papillary renal carcinoma

hyperparathyroidism-jaw tumour syndrome

multiple cutaneous and uterine leiomyomatosis

tuberous sclerosis

Wilms' tumour

FURTHER INFORMATION

GeneTests web site

National Society Of Genetic Counselors

Glossary

KREBS CYCLE

Also known as tricarboxylic-acid cycle. A series of enzymatic reactions that break down pyruvate to carbon dioxide and hydrogen atoms, which are in turn transferred to specific coenzymes for the oxidative generation of ATP in the mitochondria.

GENODERMATOSIS

An inherited syndrome involving a dermatological phenotype and possibly other phenotypes.

ONCOCYTOMA

Large tumour cells with poorly defined borders, granular eosinophilic cytoplasm and large, basophilic nuclei.

PENETRANCE

The frequency with which individuals who carry a given gene mutation will show the manifestations associated with the gene syndrome. If penetrance of a disease allele is 100%, then all individuals carrying that allele will express the associated phenotype.

LOSS OF HETEROZYGOSITY

(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with a high frequency of LOH are believed to harbour tumour-suppressor genes.

HYPERMETHYLATION

Methylation of a CpG island in a promoter of a gene usually prevents expression of the gene and can be used to regulate gene expression in a tissue-specific manner. Tumour-suppressor genes might be inactivated by mutation or hypermethylation of promoter regions.

KNUDSON TWO-HIT HYPOTHESIS

In 1971, Alfred Knudson proposed that two successive genetic 'hits' are required to turn a normal cell into a tumour cell and that, in familial cancers, one 'hit' was inherited.

PHEOCHROMOCYTOMA

A neuroendocrine tumour that typically arises in the adrenal medulla. These tumours can be benign or malignant. Symptoms often relate to the ability of these tumours to secrete catecholamines.

CRE/LOX RECOMBINATION

A method in which the Cre recombinase enzyme catalyses recombination between loxP sequences. If the loxP sequences are arranged as a direct repeat, recombination will delete the DNA between the sites.

EPITHELIAL–MESENCHYMAL TRANSITION

Conversion from an epithelial to a mesenchymal phenotype, which is a normal component of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

MOSAICISM

Postzygotic mutations resulting in some, but not all, of a patient's tissues being affected by gene mutation. Patients with mosaicism represent de novo cases of a disease within the family. The patient might be asymptomatic or have less severe disease than offspring and might test negative for a germline mutation, making them difficult to diagnose.

NONSENSE MUTATION

A sequence alteration in the DNA that changes a codon specific for one amino acid to a chain termination codon, that is, TAA, TAG or TGA. Termination codons produce premature truncated proteins that are likely to abolish protein function.

CUTANEOUS LEIOMYOMAS

Benign smooth-muscle tumours of the skin presenting as firm, skin-coloured papules and nodules.

UTERINE LEIOMYOMAS

Also known as a 'fibroids', benign smooth-muscle tumours of the uterus, the most common gynaecological tumours in women of reproductive age. Fibroids can interfere with child-bearing.

FUMARASE DEFICIENCY

An autosomal-recessive disorder in which biallelic FH mutations cause gross developmental delay and death in the first decade.

FIBROFOLLICULOMAS

Benign hamartomas of the hair follicle, characterized by anastomozing (branching) strands of proliferating epithelial cells extending from a central hair follicle encapsulated by loose, mucin-rich connective-tissue stroma.

SPONTANEOUS PNEUMOTHORAX

A sudden rupture of lung tissue, resulting in air escaping from the lung into the pleural cavity.

CHROMOPHOBE RCC

Tumour with well-defined cell borders, fluffy eosinophillic cytoplasm, pyknotic nuclei and perinuclear halos.

ONCOCYTIC HYBRID TUMOUR

Hybrid tumours contain zones classic for more than one type of tumour histology. Oncocytic hybrid tumours contain areas with cells histologically consistent with oncocytoma, areas consistent with chromophobe RCC and mixed areas.

SYNTENY

In this context, this term is used to refer to gene loci in different organisms that are located on a chromosomal region of common evolutionary ancestry.

MICROSATELLITE INSTABILITY

Describes diploid tumours in which genetic instability is due to a high mutation rate, primarily in short nucleotide repeats. Cancers with the microsatellite instability phenotype are associated with defects in DNA mismatch-repair genes.

HAMARTOMAS

Tumours comprising cells of more than one histological type.

ODDS RATIO

The odds ratio is a way of comparing whether the probability of a certain event is the same for two groups, and is calculated using a 2 × 2 table. An odds ratio of one implies that an event is equally likely in both groups. An odds ratio greater than one implies that an event is more likely in the first group. An odds ratio less than one implies that the event is less likely in the first group.

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Pavlovich, C., Schmidt, L. Searching for the hereditary causes of renal-cell carcinoma. Nat Rev Cancer 4, 381–393 (2004). https://doi.org/10.1038/nrc1364

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