New Issues in Genetic Counseling of Hereditary Colon Cancer Patrick M

New Issues in Genetic Counseling of Hereditary Colon Cancer Patrick M. Lynch

Abstract Clinicians face significant challenges in the diagnosis and management of familial colorectal cancer predisposition. Many of the challenges concern the rarity of individual conditions and their unfamiliarity to most clinicians, even those in the subspecialty areas of gastroenterology, colorectal surgery, and medical oncology. Because the World Wide Web now offers a wealth of information, familiarity with available online resources should be a minimal expectation of clinicians. Notably, these same resources are available to the lay public, so a more informed group of patients can be expected and is already being encountered.The web sites noted throughout this article are merely early examples of what should become an opportunity for instant access to the most up-to-date knowledge of rare familial colorectal cancers and their clinical features, molecular diagnostics, and clinical management and prevention. Many professional organizations have pro- duced guidelines (in print and online) for use by practitioners in various specialties.The consisten- cy, growing evidence base, and ready availability of these guidelines to providers and patients alike will likely foster greater recognition of the need to be in compliance with them. Finally, as investigators make progress with the genetics of these rare diseases, one can anticipate a ‘‘cooperative group’’approach to clinical trials.

Identification of inherited susceptibility to colon cancer is now protein expression, which is followed by mutational testing readily possible, with genes identified for familial adenomatous when MSI and/or immunohistochemical screens are informa- polyposis (FAP) and its variants (1–3), hereditary nonpoly- tive. Alternatively, models to refine a priori risk predictions posis colorectal cancer (HNPCC; refs. 4, 5), Peutz-Jeghers without resorting to MSI and immunohistochemistry have been syndrome (6, 7), and juvenile polyposis (8, 9). Yet, the process developed as strategies (11–14) and are similar to models of identifying genetic susceptibility is complicated, due to the commonly used to predict risk of BRCA mutations in familial presence of clinical phenotypes whose appearances overlap breast cancer. with normal variation and other genetic syndromes. Multiple In addition to the technical intricacies of conducting genetic genes may need to be evaluated, and the sensitivity of available predisposition testing, numerous logistic challenges to the mutational tests is limited (60-80%). Suboptimal sensitivity is delivery of effective genetic counseling and testing also exist. compounded by the potential for detecting gene sequence Many insurance companies do not reimburse for the very labor- variants that are simply polymorphisms or variants of uncertain intensive genetic counseling that is delivered by genetic significance. The International Human Variome Project has counselors. Tremendous variability exists regarding the circum- been initiated in an effort to properly catalogue and curate such stances in which insurers will reimburse for the expensive variants, including the use of existing mutation databases (10). testing itself, which often exceeds $2,000. Because mutations in the APC gene and the mismatch repair Notwithstanding the challenges described, clinicians are (MMR) genes of HNPCC could be due to the deletion of part or increasingly expected to be familiar with disease conditions, all of the whole exon, no single test for sequence variants (end- the genetic testing process, and clinical applications, as to-end sequencing or single-strand conformation analysis) is witnessed by a recent proliferation of clinical practice guide- sufficient in all cases. In the case of HNPCC, a two-tiered lines (Table 1). Current approaches to testing and counseling approach can involve initial screening of tumors for evidence of issues, using applicable practice guidelines and their short- microsatellite instability (MSI) or corresponding immunohis- comings as a template for analysis, are presented here. tochemical evaluation to detect loss of MMR gene-associated What are the key issues in providing appropriate genetic counseling, genetic testing, and clinical management in patients and families with inherited colorectal cancer susceptibility? The challenges fall into several broad, overlapping areas: (a) Author’s Affiliation: Department of Gastroenterology, Hepatology, & Nutrition, educating and ‘‘marketing’’ to providers and consumers; (b) The University of Texas M. D. Anderson Cancer Center, Houston,Texas routing of patients to specialists able to carry out effective Received 5/8/07; revised 9/6/07; accepted 9/24/07. Presented at a symposium NewApproaches to Assessing and Treating Early-Stage genetic counseling/testing; (c) developing optimal decision Colon and Rectal Cancers held January 12-13, 2007, in Santa Monica, California. matrices for determining who is (and is not) a proper candidate Requests for reprints: Patrick M. Lynch, Department of Gastroenterology, for genetic testing; (d) delivering and interpreting state-of-the- Hepatology, & Nutrition, The University of Texas M. D. Anderson Cancer Center, art genetic testing; (e) providing preventive health services, P.O. Box 301402, Houston, TX 77230-1402. Phone: 713-794-5073; Fax: 713- including endoscopic and other surveillance; and (f) develop- 563-4398; E-mail: [email protected]. F 2007 American Association for Cancer Research. ing chemoprevention strategies, including new clinical trials. doi:10.1158/1078-0432.CCR-07-1124 Each of these areas is discussed in turn here.

www.aacrjournals.org 6857s Clin Cancer Res 2007;13(22 Suppl) November 15, 2007 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2007 American Association for Cancer Research. Developing Optimal Decision Matrices for scope of most clinical practices, the perceived need for such Determining Who Is and Who Is Not a Proper work may constitute an additional argument in favor of referral to a ‘‘full-service’’ genetic counseling program. Candidate for Genetic Testing In all likelihood, the most controversial questions have to do All decision-making begins with the selection of subjects who with HNPCC, specifically, where to set the cut-point for are clinically affected, usually but not always straightforward. consideration of performance of at least MSI and/or immuno- Difficult cases include those with a phenotype mildly suggestive histochemical testing of tumor tissue, as opposed to ‘‘merely’’ of attenuated FAP, such as patients undergoing screening recommending more intensive clinical surveillance, as for colonoscopy and found to have 10 to 20 adenomas. If no ‘‘positive family history, not otherwise specified.’’ The Bethesda family history is present, such a presentation might indicate the guidelines actually do a good job of this, although such liberal presence of MYH-associated polyposis or ‘‘MAP’’ in which case criteria for MSI, such as age below 50, are likely not acted on evaluating the MYH gene will be more informative than testing with any regularity in clinical practice. Considerably greater the APC gene. Cases without any appreciable polyp burden awareness of both the liberality of these guidelines and the generally point to HNPCC and are characterized by early onset ready availability of appropriate testing is warranted. Once a and/or right-sided colorectal cancer, commonly with mucin- decision has been made to consider such testing, the key, ous, poorly differentiated histology and ‘‘tumor-infiltrating incompletely resolved issue is whether to do sequential or lymphocytes’’ or ‘‘Crohn’s’’ reaction, multiple primary cancers parallel MSI/immunohistochemistry or, in selected cases involving colon or selected associated sites (endometrium, (unequivocal Amsterdam Criteria family), skip these and go other gastrointestinal tract, sebaceous skin tumors, uroepithe- straight to mutational testing. The National Comprehensive lial tumors). A family history of similar features greatly Cancer Network guidelines recommend the use of either MSI or strengthens the likelihood of HNPCC and of a MMR mutation immunohistochemistry of all four commonly involved MMR being detectable. In practice, the presence of the much more genes (hMLH1, hMSH2, hMSH6, hPMS2) when tumor tissue is liberal Bethesda guidelines provide a threshold for testing that available. When evaluable tissue is not available, direct increases the sensitivity of the next screening measures, but at mutation testing is regarded as an appropriate alternative, but the cost of lowered specificity. only if Amsterdam Criteria are met. The National Comprehen- Whether FAP, one of its variants, or HNPCC is being sive Cancer Network does not address the issue of whether considered, it is always helpful to have access to and to review there might be circumstances in which mutational testing may as much family history information as possible. Although the be considered, notwithstanding normal results of immunohis- presenting clinical features for a particular patient may be tochemistry, MSI, or both. Pathologic mutations are rare in compelling, properly targeted decision-making can only benefit these situations and decision-making in such a circumstance from the opportunity to assess the presence or absence of must certainly be tailored individually and upon the advice of patterns of disease expression within the family. Obtaining a truly expert consultation. detailed family history at the time of initial interview helps In the case of HNPCC, it is known from population studies establish the presence or absence of a pattern. Depending on that even the rather broad Bethesda guidelines do not identify the nuance of this history, a case may or may not be made for every case of colorectal cancer in which MSI is present and a taking the additional step of trying to retrieve records from pathologic germ line mutation is found (15, 16). However, additional relatives. Because such an undertaking is beyond the because it is probably not practical to conduct MSI or

Table 1. Relevant colorectal cancer screening practice guidelines

Society Guidelines American Cancer Society Guidelines on screening/surveillance National Society of Genetic Counselors Genetic cancer risk assessment and counseling American Gastroenterology Association Hereditary colorectal cancer and genetic counseling New Zealand Guidelines Group Surveillance and management of groups at increased risk of colorectal cancer American Society of Colon and Rectal Surgeons Practice parameters FAP/HNPCC Institute for Clinical Systems Improvement Colorectal cancer screening U.S. Preventive Services Task Force Screening for colorectal cancer: recommendations and rationale

Several other sources representing interest groups and organizations with published practice guidelines (some labeled as such and others not) National Comprehensive Cancer Network Clinical Clinical practice guidelines Practice guidelines (see http://www.nccn.org) American College of Medical Genetics/American Society Genetic testing for colon cancer of Human Genetics American Society of Clinical Oncology Policy update—genetic testing of cancer susceptibility Ethical/Legal/Social Implications Follow-up care in HNPCC (28)

NOTE: Available at the National Guideline Clearinghouse web site (http://www.guideline.gov/); for additional information, search on ‘‘colon cancer’’.

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Table 2. Selected web sites with information on hereditary colorectal cancer, genetic testing, and counseling

Web site Information http://www.guideline.gov/ Lists annotated practice guidelines http://www.CGAICC.com Collaborative Group of the Americas on Inherited Colorectal Cancer http://www.nsgc.org National Society of Genetic Counselors http://www.insight-group.org International Society for Gastrointestinal Hereditary Tumors http://www.genetests.org Lists available tests, laboratories, and disease-specific clinical and testing updates http://www.cancer.gov/cancertopics/ Updated synthesis of current literature on inherited colon cancer pdq/genetics/colorectal/healthprofessional immunohistochemical studies on every case of colorectal cancer, prised of members of the American Gastroenterology Associa- good clinical judgment must be called upon to determine who tion, American College of Gastroenterology, and American should be considered for mutational testing (17). Society of Gastrointestinal Endoscopy. Similar guidelines have been promulgated by the National Comprehensive Cancer Educating and Marketing to Providers and Network (19), American Cancer Society (20), American Society Consumers of Clinical Oncology (21), and American Society of Colorectal Surgery (22). However effective it may be to follow an algorithm for As an example of the content of clinical practice guidelines, selecting and testing patients for inherited colorectal cancer consider those of the National Comprehensive Cancer Net- susceptibility, the patient must present for such evaluation. This work.2 Among the various cancer management guidelines is a may be the single greatest challenge in accomplishing the goal set that pertains to colorectal cancer screening, including details of genetic diagnosis in all who would benefit from such testing. for approaching patients with known or suspected inherited HNPCC, FAP, Peutz-Jeghers syndrome, and juvenile polyposis susceptibility to colorectal cancer. These guidelines are more syndrome are all rare diseases. In the case of classic FAP, Peutz- detailed than many other organization guidelines and are most Jeghers syndrome, and juvenile polyposis syndrome, clinical familiar to the current author, who served on the screening presentation is most often diagnostic. In such cases, the guideline development committee. In general, these guidelines diagnosing clinician should have no trouble determining very much mirror our approach to any given patient in the the clinical diagnosis, even if the patient has no grasp of the clinic. One begins with the presenting circumstance, whether significance of the condition or its straightforward genetic basis. colorectal cancer (typically early onset) or adenomas (typically The challenge to the clinician is the need to extend manage- multiple). One then tries to identify the patient’s goal in ment beyond the individual patient and to provide for genetic seeking counseling and to collect additional background counseling and testing. Strictly speaking, genetic counseling information (e.g., status of affected and unaffected relatives). and testing are not required for disease management. Rather, A provisional clinical diagnosis and recommendation for genetic counseling and testing provide the basis for identifying consideration of a formal genetic counseling session is made. family members at risk, accomplishing genetic diagnosis in A genetic counselor, usually with the assistance of a clinician these individuals, and arranging proper surveillance. Tremen- having an interest in such disorders, obtains additional dous barriers exist, even in the most straightforward of information and makes a recommendation for or against situations. Because the diseases are rare, the individual genetic testing, influenced by the patient’s wishes. Algorithms practitioner will rarely know which laboratory performs what exist for FAP, attenuated FAP, and HNPCC. Due to the rarity of diagnostic test. Referral to a specialty center with genetic Peutz-Jeghers and juvenile polyposis syndromes, no algorithm counselors who routinely deal with such patients will generally is provided; referral to a specialty center is recommended. suffice, but the clinician must first be willing and able to make the referral. For this process to work, the patient and family Delivering and Interpreting State-of-the-Art must appreciate the importance of submitting to such an Genetic Testing evaluation. A genetics evaluation may be necessary for making an appropriate diagnosis in individuals with suspicious, yet After a patient has been identified as definitely or possibly subtle features, as in attenuated FAP and in HNPCC. The World having polyposis or HNPCC susceptibility, referral for genetic Wide Web could be instrumental in providing guidance to both counseling can be properly initiated. Identifying a gastroenter- providers and patients (Table 2). For example, the National ologist, colorectal surgeon, medical oncologist, or medical Guideline Clearinghouse1 offers a well-indexed and curated list geneticist in one’s region who has a specific interest in these of guidelines for diseases, including familial colorectal cancer. conditions is challenging; thus it may be convenient to identify Detailed recommendations for management (extending from genetic counselors. The National Society of Genetic Counselors’ recognition of suggestive clinical pictures, through genetic web site3 enables a simple search within a specified radius of a counseling and testing, to clinical surveillance) have been zip code of interest and is narrowed by area of specialization, in provided by a Gastrointestinal Consortium Panel (18) com- this case ‘‘cancer.’’ A search beginning with the Google entry

2 http://www.nccn.org/ 1http://www.guideline.gov/ 3 http://www.nsgc.org

www.aacrjournals.org 6859s Clin Cancer Res 2007;13(22 Suppl) November 15, 2007 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2007 American Association for Cancer Research. ‘‘National Society of Genetic Counselors’’ quickly generated a endoscopic mucosal resection. Once invasive cancer is reason- list of 12 cancer genetic counselors in the Los Angeles area, all ably excluded, the pros and cons of both surgical and with e-mail addresses and phone numbers listed. Once a colonoscopic approaches can be presented, with second counselor is identified, a query regarding services provided, opinions encouraged. Even if the lesion can be safely and ideally directed by a thumbnail sketch of the case under completely removed at colonoscopy, it is important that a consideration, generally leads to an appropriate referral. Other surgeon familiar with HNPCC be ‘‘on the case.’’ The patient is web sites that can lead to resources for colon cancer genetic reminded that adenomas are commonly very flat and rapidly services include the Collaborative Group of the Americas for progress to cancer, leading to the problem of interval cancer Inherited Colorectal Cancer,4 with 15 affiliated centers in the (i.e., missed cancers occurring between even frequently United States and one center in Canada, and the International schedule colonoscopies). Society of Gastrointestinal Hereditary Tumors.5 The National The issue of ‘‘pure prophylaxis’’ is even more vexing (24). The Cancer Institute also has a helpful listing, which can be found possibility of missed or interval cancer must be weighed against at its web site.6 Finally, the American College of Medical the risks and long-term adverse effects of colectomy, as well as Genetics provides a list of geneticists, accessible at the ACMG the fact that as many as 20% to 30% of HNPCC mutation web site.7 carriers will not develop colorectal cancer, perhaps even without the benefit of screening and polypectomy. Providing Preventive Health Services, Including Endoscopic and Other Surveillance Developing Chemoprevention Strategies, Including New Clinical Trials It is widely accepted that intensive endoscopic surveillance is appropriate for the familial colorectal cancer syndromes. Key Rightly or not, FAP has come to serve as a common proving- decision points involve the point at which, short of invasive ground for the clinical evaluation of agents believed to have cancer, prophylactic surgery should take place. The threshold promise in the prevention of colorectal adenomas. Virtually for prophylactic colectomy differs dramatically in FAP, the every trial whose aim has been the reduction in recurrence of hamartomatous polyposes, and HNPCC. In FAP, even a sporadic adenomas had a predecessor trial in FAP. This has minimal rectal adenoma burden may warrant early prophylac- been the case with the use of nutritional supplements (fiber, tic colectomy. Proctectomy and ileal pouch construction may vitamins, calcium), as well as pharmacologic agents, most be warranted at the same surgery, depending on rectal adenoma notably nonsteroidal anti-inflammatory drugs, including aspi- burden. However, many surgeons are willing to wait until there rin. A nonselective nonsteroidal anti-inflammatory drug (sulin- is more frank colonoscopic evidence of adenoma progression, dac) and two selective cyclooxygenase-2 inhibitors (celecoxib with a trial of sulindac or celecoxib in the meantime (see and rofecoxib) have shown efficacy, with celecoxib receiving below). In the case of Peutz-Jeghers and juvenile polyposis U.S. Food and Drug Administration approval for adjunctive use syndromes, management must be even more individualized, as in FAP. An excellent review has been provided by Hawk et al. the polyp burden is much more variable, and the risk of (25). FAP has been a good model because, despite its rarity, a dysplasia and cancer in the hamartoma considerably lower given patient can be easily and quickly evaluated for than in FAP. Many such patients can be managed indefinitely quantitative evidence of adenoma regression. A few similar with colonoscopic and enteroscopic (due to risk of small bowel trials have been conducted in HNPCC, but its rarity and the polyps) polypectomy. relative infrequency of adenomas (compared with FAP) have The issues are even more complicated in HNPCC. If cancer is required larger samples. diagnosed, one controversy is whether a standard segmental Future studies in FAP can be expected to follow the pattern of resection or subtotal colectomy should be done. Surgical previous trials: an agent showing preclinical promise and opinion is divided. One view is to favor the smallest resection preliminary safety in phase I or other human experience is possible, along with careful endoscopic follow-up. The other offered for use in FAP. A sample of 40 to 80 patients with FAP is view is to favor abdominal colectomy and ileorectal anasto- chosen, as this is the number of patients generally required to mosis, as the rate of second primaries is high, and colonoscopic show a z20% reduction in adenoma burden, compared with miss rates can reach 10%. placebo, over an interval of 6 to 12 months, in patients with In the case of patients without previous cancer resection, measurable residual adenoma burden. Trials could involve adenomas found in the course of surveillance pose another patients with prior colectomy with ileorectal anastomosis, intact challenge. The endoscopist’s bias is to aggressively tackle any colons, and/or duodenal adenomas. Again, adenoma regression adenoma that is found. With advances in endoscopic mucosal is the usual end point. Trials involving true prevention in FAP resection techniques, this could include large, flat, right-sided would, of necessity, involve children and take much longer to adenomas that would until recently have required surgical conduct, as the end point (i.e., time to adenoma formation) is resection (23). It is very important that the patient understand quite variable and may take years, even without intervention, in the issues and options in such cases. One approach (mine) is to a given patient (26). Trial designs can involve prevention of merely sample large polyps that would otherwise require adenoma ‘‘recurrence’’, but ablation and ‘‘clearance’’ of polyps in an anatomic segment that has historically shown evidence of high polyp formation are required (27). Recruitment of eligible patients for clinical chemoprevention 4 http://www.CGAICC.com 5 http://www.insight-group.org trials poses the greatest logistic challenge, due to the infre- 6 http://www.cancer.gov/search/geneticsservices/ quency of disease and the need for a requisite adenoma burden. 7 http://www.acmg.net/ Most early trials were single institution studies, but more

Clin Cancer Res 2007;13(22 Suppl) November 15, 2007 6860s www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2007 American Association for Cancer Research. Genetic Counseling in Colon Cancer recently, multicenter trials have been reported. To quickly carry set of guidelines attempt to summarize a minimal acceptable out trials according to the rather generic designs described practice or enunciate the ideal level of practice that is achievable above, studies will need to be conducted on a multicenter basis with existing technology? Whether limited to genetic counsel- and/or marketed directly to patients. A ‘‘cooperative group’’ ing and testing, as dealt with here, or more broadly to staging, approach holds the greatest promise. surgery, and chemotherapy for early-stage colorectal cancer, the sense seems to be that existing standards are set fairly high, on Conclusion the one hand, but that practice in both the community and academia fall short of such standards. Our challenge therefore Numerous sets of practice guidelines focus on the diagnosis is to identify the key elements of practice that must be upgraded and management of inherited cancer susceptibility, and the and to develop measures for enabling such standards to be met. algorithms that have been developed are quite consistent. The Because this is a new field, knowledge of existing practice(s) in Santa Monica Consensus Development Group on Early-Stage genetic counseling for colorectal cancer is lacking, but would be Colorectal Cancer has often broached the issue of whether a a good place to start. Subsequent attention could then be drawn given practice guideline is considered a ‘‘floor’’ or a ‘‘ceiling.’’ In to measures for educating practitioners and setting benchmarks other words, in codifying a standard of care, does a particular for performance.

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Patrick M. Lynch

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