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Learning objectives

Upon completion of this activity, participants should be able to:

1. Describe the gastroenterologist's role in caring for patients and families at risk for hereditary gastrointestinal cancer.
2. Describe surveillance and treatment for patients with Lynch syndrome.
3. Identify the best candidates for genetic testing for hereditary gastrointestinal cancer.
4. Describe the process of genetic counseling and testing for gastrointestinal cancer.

Competing interests

The authors and the Journal Editor N Wood declared no competing interests. The CME questions author CP Vega declared that he has served as an advisor or consultant to Novartis, Inc.

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Recognition and referral

Numerous publications and position statements address genetic testing for hereditary gastrointestinal cancer syndromes.^{3, 4, 5, 6, 7, 8} The National Comprehensive Cancer Network's Clinical Practice Guidelines in Oncology for colorectal cancer screening provide one of the more complete schemata when considering referral for genetic counseling referral and detail several management pathways for high-risk patients.⁹ These guidelines do not, however, address the hamartomatous polyp syndromes. Moreover, very few guidelines specify when a referral should be made for patients who do not meet established criteria. It is, therefore, important to understand the features of hereditary cancer syndromes and where to set the threshold for referral.

Typical features of hereditary cancer syndromes include cancer in two or more first-degree relatives and/or second-degree relatives within the same lineage, early age of onset (50 years), multiple or bilateral tumors, rare neoplasms, constellations of specific malignancies traveling in the same family (e.g. colon and endometrial cancer) and evidence of autosomal dominant or autosomal recessive inheritance. The same features apply to hereditary gastrointestinal cancer syndromes with the additional need to take into account the presence (or absence), number, and histologic subtypes of colonic and extracolonic polyps. It is important to note that while current American Gastroenterological Association guidelines recommend genetic testing for attenuated familial adenomatous polyposis (AFAP) for individuals with 20 or more adenomas, there is a growing movement to lower this threshold to 10 or more adenomas.^{2, 10, 11}

With the exception of Lynch syndrome, most hereditary gastrointestinal cancer syndromes are associated with benign neoplasms and other features that serve as clues as to the existence of a syndrome and the identity of the specific syndrome(s) in the differential diagnosis (Tables 1, 2 and 3 [a full-length version of Table 3 is available as Supplementary Table 1 online]). The genetic workup of Lynch syndrome is unique in its incorporation of tumor studies. Schemata outlining points for consideration before referring a patient to a genetic counselor are provided in Figures 1 and 2.

Figure 1 Referral schema used for patients with gastrointestinal cancers at the Evanston Northwestern Healthcare Center for Medical Genetics, Evanston, IL.

Figure created using information from multiple references.^{4, 6, 8, 11, 13, 14a}Recommendation based on clinical judgment; consider reviewing the case with a genetic counselor. ^bIf fundic gland polyps are identified, consider whether the lesions are secondary to proton pump inhibitor use and review the case with a genetic counselor. Abbreviations: AD, adenoma; FDR, first-degree relative; HA, hamartoma; HP, hyperplastic polyp; IHC, immunohistochemistry; MMR, mismatch repair; MSI, microsatellite instability; SDR, second-degree relative.

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Figure 2 Referral schema used for patients with gastrointestinal polyps found on endoscopy at the Evanston Northwestern Healthcare Center for Medical Genetics, Evanston, IL.

Figure created using information from multiple references.^{4, 6, 8, 11, 13, 14a}Recommendation based on clinical judgment; consider reviewing the case with a genetic counselor. Abbreviations: AD, adenoma; EGD, esophagogastroduodenoscopy; FDR, first-degree relative; HA, hamartoma; SDR, second-degree relative.

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Table 3 Other hereditary cancer syndromes with some gastrointestinal involvement.⁶⁰

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Assisting the genetic workup

Before endoscopy

Before a patient undergoes endoscopy, questions should be posed regarding whether there is a history of cancer, gastrointestinal polyps or other benign neoplasms in the patient and their first-degree and second-degree relatives. The answers to these questions should alert the gastroenterologist to the likelihood of identifying benign or malignant neoplasms during the procedure.¹²

During endoscopy: counting multiple polyps

If multiple polyps are identified during endoscopy, taking as many biopsy samples as possible and counting (rather than estimating) the polyp number will greatly help to narrow the differential diagnosis, which relies heavily on the total polyp count (over the course of time), and pathological polyp subtypes. Of course, if profuse polyposis is identified, counting the number of polyps is not feasible and estimation is acceptable, but taking a large number of biopsies is still desirable. If the polyps are all of one pathological type, the differential diagnosis is limited and genetic testing should generally be straightforward. However, if a mix of polyps is identified—for example hyperplastic polyps and hamartomas—the differential diagnosis will be quite large (Tables 2 and 3 [a full-length version of Table 3 is available as Supplementary Table 1 online]). In this situation, a genetics professional might be required to perform a dysmorphology exam and prompt additional imaging tests and/or laboratory tests to the narrow the differential diagnosis for genetic testing.

If genetic testing is inconclusive or not pursued, the counting of polyps is particularly important for making appropriate surveillance recommendations.^{9, 13} For example, to make a clinical diagnosis of juvenile polyposis syndrome (JPS), AFAP, familial adenomatous polyposis (FAP) or hyperplastic polyposis syndrome, documentation of the presence of more than 5, 20, 100 or 30 polyps, respectively, can be required.^{14, 15, 16} For practical purposes, insurance companies in the US require documentation of polyp burden before genetic testing is deemed medically necessary, although the approximate polyp number can be provided as a notation in the endoscopy report, even if not all polyps were biopsied. For example, most US insurers require that a patient has at least 20 adenomas for them to be covered for APC gene testing if they do not have a first-degree relative with FAP or AFAP.

During endoscopy: malignancy

If a CRC is identified during endoscopy, and the patient meets the revised Bethesda Guidelines¹⁷ or has a family history that meets or approaches the Amsterdam Criteria (Box 2),^{18, 19} the presence of Lynch syndrome should be considered. In this situation, the gastroenterologist should take additional biopsies of the CRC for tumor studies, such as microsatellite instability (MSI) testing or immunohistochemical (IHC) staining of the protein products of the mismatch repair genes.^{17, 20}

A section of normal mucosa (or a blood sample) is needed as a control sample for MSI. Taking multiple biopsies is critical for MSI and IHC studies of rectal cancers as MSI testing and IHC staining are unreliable after chemoradiation, and rectal cancer treatment schemata often involve neoadjuvant therapy.²¹ If MSI and IHC studies are performed in-house, the gastroenterologist requesting the MSI and/or IHC test on the CRC should alert the pathologist to the personal and family history of the patient, so the pathologist can decide whether the patient meets the Bethesda Guidelines. This information is of importance as the personal and family history of the patient make up three of the five criteria in the Bethesda Guidelines. Another option would be to refer the patient to a genetic counselor who can coordinate MSI and IHC testing. Referral to a genetic counselor is the recommended option if MSI and/or IHC studies are not performed in-house.

If the MSI and/or IHC results are suggestive of Lynch syndrome, referral for genetic counseling before genetic testing is mandatory.^{5, 6, 7, 8, 9} If MSI and/or IHC results are inconclusive or not suggestive of Lynch syndrome, referral might still be warranted depending on the family history or if the patient was found to have multiple polyps in addition to cancer. For Lynch syndrome, various computer software programs have been developed to predict the probability of detecting a germline mutation in a mismatch repair gene, including the PREMM1,2 model, which has now been validated.²²

The NIH consensus MSI marker panel has been optimized for CRCs,²³ but tumor studies can also be performed on endometrial cancers^{24, 25, 26} and skin tumors from patients with Muir–Torre syndrome.²⁷ Although detection of high MSI in an adenoma has utility, MSI analysis demonstrates lower sensitivity for adenomas than for CRC and negative results must be interpreted with caution. Although the initial Bethesda Guidelines recommended performing MSI testing on adenomas found in individuals younger than 40 years of age, this recommendation was removed from the revised guidelines because "the value of MSI and IHC assays in identifying MSI in early adenomatous lesions is not firmly established".¹⁷

Post-endoscopy

Gastroenterologists should strongly consider scoping other parts of the gastrointestinal tract in patients deemed to be candidates for referral for genetic counseling, as most hereditary gastrointestinal cancer syndromes can involve the entire gastrointestinal tract (i.e. if a colonoscopy was done, an esophagogastroduodenoscopy should be performed and vice versa). The genetic counselor can then take into account the results of both the upper and the lower endoscopies when they perform their consultation. The use of more-sensitive imaging techniques such as chromoendoscopy or narrow band imaging can also be considered; however, data regarding the clinical utility of these techniques in the diagnosis of hereditary CRC syndromes are sparse and use of these techniques should ideally be within the context of a research study.

Confirming the diagnosis of a hereditary gastrointestinal cancer syndrome before a definitive surgical procedure is performed can alter the recommended surgical procedure (e.g. a subtotal colectomy might be performed instead of a hemi-colectomy), thus preventing secondary cancers and lessening the challenges of future surveillance.²⁸ The gastroenterologist should be cognizant that they can request an urgent genetic consultation in some situations, for example when surgical management might be altered by genetic information and/or genetic counseling could assist in the patient's decision making.

Informing surgical treatment decisions for patients with Lynch syndrome who have newly diagnosed CRC

Elucidation of genetic status before surgery is critical for patients with CRC or advanced adenomas given that CRC is often associated with Lynch syndrome; in fact, the rate of metachronous CRC in patients with Lynch syndrome is estimated at 45%.²⁸ One surgical approach for patients with Lynch syndrome is subtotal colectomy with ileorectal anastomosis, following which annual rectal surveillance is mandatory. Another surgical approach is total proctocolectomy, which has higher long-term morbidity than subtotal colectomy and might leave patients affected by frequent daily bowel movements. For young patients and those with early-stage incident CRC, gains in life expectancy after subtotal colectomy as compared with hemicolectomy or segmental resection are in the order of 2–3 years.²⁹

Pathologic staging before definitive resection can be imprecise, which means that patients who have more-advanced disease will benefit less from surgery than will those with early-stage disease. A crucial part of the decision-making process comprises considering quality of life after prophylactic extended resection and this factor can mitigate against an overall benefit for particular patients.³⁰ On the other hand, fear of cancer can be lessened after subtotal colectomy, and surveillance is far easier, with rectoscopy replacing frequent colonoscopy. For young noncompliant patients, the gain in life expectancy after prophylactic colectomy is projected to be in the order of 15 years.³⁰ The possibility of large gains in life expectancy after resection is an important reason to confirm the genetic diagnosis before embarking on a definitive surgical procedure for CRC.

Women with Lynch syndrome have a 40–60% lifetime risk of endometrial cancer and a 10–12% lifetime risk of ovarian cancer.³¹ Prophylactic hysterectomy with bilateral salpingo-oophorectomy is effective in women with Lynch syndrome³¹ and a survival advantage is predicted in such patients.³² The current consensus is that this procedure should be offered at the time of colon surgery if the patient is postmenopausal, if she does not want to have any further children, or if she is undergoing surgery for another indication.^{9, 28}

It is clear that male and female patients coping with a new diagnosis of CRC face additional challenges when they are confronted with information about the possibility of developing other cancers in the future. Genetic counseling during this uniquely stressful period can clarify the risks and help the patient navigate complex decisions regarding treatments and outcomes.

Assisting the gastroenterologist in making a genetic diagnosis

Taking family history

The genetic counselor begins the counseling process by taking a patient's medical history and reviewing the data provided by the gastroenterologist and pathologist. Next, a three to four generation pedigree is constructed, mapping out the details of living and deceased relatives including ages, affected and unaffected status with regard to cancer, polyps, and other syndromic features, age at diagnosis of cancer and/or polyps, and any results of genetic testing and/or tumor studies.³⁶ The family history is a vital tool for delineating constellations of cancer that are suggestive of particular syndromes, indicating a mode of inheritance, guiding the genetic workup strategy, and exploring social relationships and family communication.

A psychosocial assessment is also performed by the genetic counselor, including an evaluation of the patient's risk perception. The patient is educated in the basic principles of inheritance and cancer etiology, as well as management issues once these are determined. A thorough assessment of possible extracolonic features is also conducted in the patient and their family (e.g. sebaceous gland carcinomas in the Muir–Torre variant of Lynch syndrome; lobular breast cancer in hereditary diffuse gastric cancer; arteriovenous malformations, epistaxis, and mucocutaneous telangiectasias in the hereditary hemorrhagic variant of JPS; non-Hodgkin's lymphoma, acute leukemia, severe growth deficiency and butterfly rash in Bloom syndrome, etc.), as nongastrointestinal features can provide important clues about the individual's syndrome (Tables 1, 2 and 3 [a full-length version of Table 3 is available as Supplementary Table 1 online]).

Certain aspects of a family history are worth noting. Several syndromes can occur de novo (e.g. FAP and JPS), and, therefore, a negative family history for such a disorder does not rule out a heritable syndrome that can be transmitted to the patient's children. Consanguinity can indicate the presence of autosomal recessive conditions (e.g. MAP and CoLoN;³⁷Tables 1 and 2). In addition, a small family size (or the presence of early noncancer deaths) can mask a heritable syndrome such that the family history does not meet diagnostic criteria.

Elucidation of a family history involves very detailed questioning, and some patients are unable to report accurately information beyond that regarding their first-degree relatives.³⁸ Clinical overlap between syndromes (e.g. Lynch syndrome and AFAP), and borderline family histories (especially with respect to age of cancer onset and degree of relationship), can make it difficult to know how stringent to be when considering making a genetics referral. One advantage of developing a professional partnership between the gastroenterologist and the genetic counselor is the ability to discuss such nuances before referral.⁸

Given all these considerations, a case can be made for using clinical judgment to modify the threshold for genetic testing³⁹ and for a population-based approach to MSI and IHC tumor studies.^{40, 41} However, the limitations of a population-based screening approach for CRC patients include a low yield in patients over the age of 55 years, a high rate of MLH1 silencing in older patients through somatic (noninherited) modification of the gene, and overall cost.⁴² An additional problem is that IHC loss of MSH2 is so closely tied with germline mutation of MSH2 that some consider this to be a genetic test meriting pre-test counseling. We concur with Lynch et al.⁴² that these issues would need to be addressed before population-based screening is implemented. Hospitals that perform MSI and IHC studies have the ability to develop regional approaches and ideally should contribute their experiences to the literature.

Reviewing the medical records of a patient and their relatives

Given the specific polyps or cancers associated with different syndromes, extensive data gathering is typically needed to confirm the pathological variant. This data gathering includes obtaining affected family members' colonoscopy reports to count polyps, pathology reports to confirm polyp or cancer type and location (e.g. ascending versus descending colon), death certificates or, if available, genetic test results.^{38, 43} On occasion it might be necessary to collect slides for review by a pathologist who has expertise in identifying and differentiating gastrointestinal neoplasms, particularly polyp types.¹² Ultimately, the differential diagnosis can generally be narrowed to one or two syndromes.

Choosing the proband wisely

The proper selection of an initial individual (proband), for genetic counseling and testing has far-reaching implications within families.⁴⁴ A prevalent assumption among patients and physicians is that a negative genetic test result for an individual who has not had cancer is sufficiently informative. This is not the case. The fact that alterations in risk status cannot be made without first identifying a mutation in the family cannot be overemphasized. Even in ideal circumstances, such as when families meet diagnostic criteria, the sensitivity of genetic testing is only 60–80%.^{10, 45, 46, 47} Some families will, therefore, have mutations that are not detectable with currently available technology. Until a relative with an identifiable mutation is found, it is not possible to distinguish families for whom informative genetic testing is possible from families for whom genetic testing cannot currently be effectively used. Once a mutation is detected in a particular family, testing is fully informative in subsequent relatives, with sensitivity and specificity approaching 100%. Relatives with a 'true negative' status can follow routine surveillance guidelines (bar those with additional familial or hereditary risks).

Genetic counselors strive, therefore, to outline a testing strategy that can efficiently identify the familial mutation. They achieve this by first testing affected family members or obligate carriers, if possible, based on their position in the family. Genetic testing is avoided in those who are unaffected or who might have sporadic cancers (phenocopies).

Variants of uncertain significance, typically missense sequence variants, are particularly vexing.⁸ During pre-test counseling, patients should be informed about this category of results.^{8, 39} In addition, management should be tailored to address the family history and not the variant,³⁹ and further evaluation of the variant through family studies should be pursued on a research basis.⁴⁸

Performing an efficient, cost-effective genetic workup

Genetic counselors work closely with patients to gather information on their relatives necessary to make a genetic diagnosis. Genetic counselors also outline the costs associated with genetic testing and tumor studies and assist with obtaining insurance preauthorization. Until the familial mutation is identified, testing is expensive (for every relative), because one or more genes must be tested in their entirety owing to the hundreds of possible mutations that are present in most cancer predisposing genes. Not infrequently, the best strategy involves testing an individual who might have little to gain themselves from the information generated, or who is not interested in the information. Once the mutation in a particular family is identified, testing can be accomplished at 20% of the initial cost by focusing on the familial mutation, with highly informative results.

Procuring informed consent for genetic testing

Genetic testing for hereditary cancer syndromes mandates full pre-test and post-test informed patient consent,⁷ which includes several basic elements that must be reviewed.⁴⁹ In addition to having features suggestive of a heritable condition and having interpretable tests available, the indications for genetic testing emphasize that testing should be used when the results will aid in diagnosis or influence the medical or surgical management of the patient or at-risk family members. A family-centered approach is important not only on ethical grounds, but also for accurate risk assessment and for many logistical reasons such as obtaining informative genetic test results.

Mediating family communication

Another vital service performed by genetic counselors is the facilitation of risk communication within families so that genetic testing and heightened cancer surveillance can be accomplished. It has been shown for Lynch syndrome that genetic screening and lifelong cancer screening are very cost-effective, particularly when patients with cancer are considered along with their children and siblings.⁵⁰

Physicians have a medicolegal responsibility to their patients' relatives known as the 'duty to warn', which entails alerting a relative about a genetically inherited disease even if the clinician has no patient–physician relationship with this individual.⁵¹ For example, in the case of Safer v Estate of Pack, the plaintiff developed FAP and CRC at 36 years of age and won a unanimous ruling against the estate of the physician who had treated the plaintiff's father for FAP in 1964, when the plaintiff was aged 10 years.⁵¹

Although health professionals cannot directly contact relatives with whom they have no prior relationship, genetic counselors enlist the help of their patients by explaining the health implications associated with a heritable cancer syndrome and devising workable strategies for the patient to disseminate information in the family.⁸ Many centers will provide a patient with a family letter that provides them with information on the genetic syndrome, the mode of inheritance, and broad management implications. The family letter also notes the specific familial mutation that is present and provides information on how to find genetic counselors in the region, but stops short of stating who in the family was tested and what medical problems they have faced. The patient can then send the letter to their relatives, with guidance from the genetic counselor regarding who is at risk.

Genetic discrimination: reality versus myth

In the US, national legislation called the Genetic Information Nondiscrimination Act (GINA) has been signed into law by President George W Bush.^{52, 53} GINA, which includes provisions for violation penalties, will take effect 21 May 2009 for health plans and 21 November 2009 for employers. Until this bill was passed, legislation in the US has involved a patchwork of federal and state laws, including the Health Insurance Portability and Accountability Act (HIPAA) of 1996.⁵⁴

GINA requires that genetic information be treated as "protected health information" under HIPAA, bars the use of genetic information for health plan eligibility, premium adjustment or underwriting, prohibits the requirement of genetic testing by group health plans or insurers, and protects workers from the use of genetic information in hiring, termination of employment, and promotion decisions. Under GINA, there will be no exception for small group health plans, as occurs now under HIPAA. More than 30 states in the US already ban or limit genetic discrimination for employment purposes and all but a few have adopted laws prohibiting genetic discrimination for health insurance purposes. It has been difficult to document actual cases of genetic discrimination, and early reports of alleged discrimination were based on actual disease rather than predisposition.⁵⁴

Despite the safeguards of GINA and other legislation, the fear of genetic discrimination is palpable and could discourage patients from seeking information through genetic counseling and from undergoing genetic testing. Genetic counseling is separate to genetic testing, and the risk of genetic discrimination as a result of a counseling session is slim to none. Physicians should also be aware that according to the experiences of the very large number of people who have undergone genetic testing, the actual risk of discrimination is low. The possible risk of genetic discrimination, which will be lessened under GINA, should be balanced against the documented lifesaving potential of genetic risk management.

Genetic privacy

Genetic information is managed with close attention to privacy, and patients often maintain a high level of control over dissemination of such information. Risks and protection are reviewed by genetic counselors as part of patients' decisions about whether or not to undergo genetic testing. Ultimately, the information is intended to help guide management and thus communication between the genetic counselor and the referring physician is paramount. The provision of insurance coverage for high-risk surveillance or prophylactic surgery can usually be justified on the basis of a patient's medical history (e.g. polyposis) or family history rather than by invoking a genetic test result.

Management issues

Optimization of cancer surveillance is one of the key management issues affecting patients who have a heightened susceptibility to gastrointestinal malignancies. For patients who have a confirmed gene mutation, surveillance follows established guidelines that have been detailed elsewhere.^{9, 13, 55} Put into context, a decision analysis found that high-risk surveillance of a young patient with Lynch syndrome led to an expected gain in life expectancy of 13.5 years.³⁰ Tailoring surveillance to the patient's specific situation and counseling the patient on the importance of long-term compliance are critically important.

The role of the genetic counselor is to gauge the level of gastrointestinal cancer risk, consider the full spectrum of malignancies for which the patient faces a heightened risk, and discuss a long-term surveillance strategy. Although genetic counselors typically stop short of making medical recommendations, they generally work under the supervision of a physician. In any event, genetic counselors should be able to cite the most up-to-date surveillance recommendations on the basis of their familiarity with the literature, attendance at cancer genetics meetings, and networking through professional alliances and the internet.³⁴ In our experience, opinions are often elicited from other genetic counselors working directly with expert clinician-researchers.

Cancer genetic counseling arose before genetic testing was available. Accordingly, genetic testing is used to guide management, but risk assessment can be performed in the absence of genetic testing, either when the causative gene is not yet known or when testing is not practicable for a particular family. Banking DNA from an affected family member provides options when the causative gene is discovered at a later date. Families with as yet unidentified syndromes can avail themselves of gene discovery research. In addition, mutation carriers can potentially take part in surveillance studies, if available. Genetic counselors can provide a gateway to participation in these research studies.