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© 2000 American Society for Clinical Oncology
Hereditary Nonpolyposis Colorectal Cancer: A Call for AttentionBrigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA HEREDITARY NONPOLYPOSIS colorectal cancer (HNPCC) is the most common hereditary colon cancer syndrome. It is a dominantly inherited disease associated with increased lifetime risks of a range of malignancies, including colorectal and endometrial cancers as well as extracolonic gastrointestinal, genitourinary, ovarian, and brain tumors.1 In 1993, the identification of mismatch repair gene mutations associated with HNPCC revealed a novel mechanism of cancer pathogenesis.2,3 Thus far, HNPCC has been associated with germline mutations in several DNA mismatch repair genes, most commonly, MSH2 and MLH1.4 Tumors of MSH2 and MLH1 mutation carriers exhibit a characteristic phenotype termed microsatellite instability (MSI), characterized by expansion or contraction of short repeat sequences of DNA at multiple loci.5 In this issue of the Journal of Clinical Oncology, Salovaara et al6 examined 535 colorectal cancers and found that 12% showed evidence of MSI. Of the 66 patients with MSI, 12 were found to have germline mutations of MSH2 or MLH1, for an overall mutation rate of 3.4%. This article and previous studies by this research group7 have provided essential data on the contribution of MSH2 and MLH1 mutations to colorectal cancer predisposition. The authors reviewed the clinical features of MSH2 and MLH1 mutation carriers and propose a diagnostic algorithm for large-scale molecular screening of HNPCC. Their discussion of population-based screening for HNPCC raises several interesting issues relevant to hereditary cancer syndromes in general and HNPCC in particular. What constitutes the diagnosis of HNPCC? This is the difficult question and one that has led to the most confusion. HNPCC does not have any specific distinguishing phenotypic characteristics, unlike its much rarer cousin, familial adenomatous polyposis. Familial adenomatous polyposis is also characterized by a high risk of cancer and an available genetic test (for mutations in the adenomatous polyposis coli [APC] gene)8 but is a disease that can usually be easily diagnosed because of its clear phenotype of hundreds to thousands of polyps that carpet the colon. The only way to diagnose HNPCC is by a family history consistent with the disease. Several clinical diagnostic criteria have been proposed to define HNPCC. The classic criteria, known as the Amsterdam criteria,9 have been the most widely used in the research setting, but they have been criticized as being too stringent for use in clinical practice. Several additional diagnostic10-12 criteria have been proposed that attempt to account for small families and extracolonic tumors of HNPCC, and studies like the one by Salovaara et al have also attempted to define clinical predictors that increase the likelihood of an MLH1/MSH2 mutation.13 Rather than attempt to memorize these multiple criteria or algorithms for HNPCC, it is useful to remember some general concepts that are hallmarks of hereditary cancer syndromes: young age of onset of cancer (for colorectal cancer, young is age < 50 years) or colorectal adenomas, multiple family members affected with cancer in multiple generations, the association of certain tumors in an individual or family (ie, colon and endometrial, or colon and other gastrointestinal tumors), and multiple tumors (either synchronous or metachronous) in the same individual. If any of these features is present and early-onset colorectal cancer is one of the cancers, HNPCC should be considered as a possible diagnosis. What are the clinical management implications of a diagnosis of HNPCC? First, there are distinct differences in colorectal cancer surveillance recommendations for at-risk members from HNPCC families compared with the population at average risk (age > 50 years without other risk factors) or moderate risk (for example, those with histories of adenomatous polyps or colorectal cancer) for the development of colorectal cancer. It is recommended that all at-risk individuals from HNPCC families undergo colonoscopic surveillance every 1 to 2 years starting at age 25.14 Surveillance for average-risk and moderate-risk individuals most often does not begin until age 50, and the intervals between screening procedures are increasingly being lengthened to 3 to 5 years.14 HNPCC tumors seem to be biologically different from sporadic cancers, in that they develop more quickly and may have an appearance that, at least at an early stage, may be more difficult to diagnose endoscopically than sporadic tumors.14 Unlike breast cancer surveillance, in which mammography only has the potential to detect earlier-stage lesions, colonoscopy and polypectomy of adenomatous polyps offer true secondary cancer prevention benefit in addition to detection of earlier-stage cancers. Second, endometrial cancer surveillance needs to be addressed in at-risk women.15 The lifetime risk of developing endometrial cancer in affected individuals is 40% to 60% and may be higher than colorectal cancer in some women.16 Therefore, it is recommended that annual pelvic ultrasounds and/or endometrial biopsies be performed in at-risk women, again starting as early as age 25. Third, prophylactic surgery should be discussed as a possible management option for affected individuals.15 Prophylactic colectomy has been advocated, both as an option for the asymptomatic mutation carrier or at the time of a cancer diagnosis to prevent second primary tumors. Prophylactic hysterectomy, particularly for women who have completed childbearing, may be an attractive option considering the lack of data on effectiveness of endometrial cancer screening techniques. Limited prospective data have shown that colon cancer incidence and mortality are decreased by approximately 65% with colorectal cancer surveillance,17 and a decision analysis demonstrated life expectancy gains of 13 to 15 years with surveillance or prophylactic colorectal surgery at varying time points compared with no intervention.18 Thus, there is real benefit in diagnosing HNPCC, and aggressive, appropriate management works, no matter what method the patient and his or her physician choose together. How can genetic testing help? Genetic test results can provide valuable information that has a direct impact on patient management. In families in which a pathogenic mutation is identified, intensive surveillance and consideration of prophylactic surgery can be limited to those individuals who show the family sequence abnormality; family members without the mutation can undergo the same form of surveillance recommended for the general population.19 Individuals who are mutation-negative can be relieved of cancer worry for themselves and their offspring, and those who are found to carry disease-associated mutations can try to be proactive to decrease cancer risk by aggressive surveillance, prophylactic surgery, or, increasingly, chemotherapeutic agents. What is involved in genetic testing? If the individual or family history is suggestive of HNPCC and the patient desires to pursue genetic testing, molecular evaluation is generally first performed on an affected member of a family. Here, there are two options. The first is to start with testing of the tumor for MSI. The second is to go directly to analysis of MSH2 and MLH1, the genes most commonly involved. Both MSI testing and MSH2/MLH1 genetic analysis are now available commercially through several molecular diagnostic laboratories. Although some have advocated MSI testing as an initial screen for all patients,7 an alternative approach is to use a combination of family history and MSI testing in the initial diagnostic evaluation of HNPCC families. Sequencing of MSH2/MLH1 in classic Amsterdam families has an approximately 50% likelihood of finding a disease-associated mutation that can be used for clinical management.19 MSI testing before gene testing can then be reserved for less classic families or patients with young-onset colorectal cancers without family history, for whom the likelihood of finding mutations in MSH2/MLH1 is significantly lower (10% to 20%).19 There are advantages and disadvantages to both approaches. MSI testing is cheaper (at a cost of approximately $300) and can act as an initial screen to increase the probability of finding a mutation in MSH2/MLH1. However, because 10% to 15% of sporadic tumors exhibit MSI, its presence still requires further genetic analysis to determine whether an inherited germline mutation exists that is the cause of the MSI-positive tumor. In addition, recent studies have demonstrated that other mismatch repair genes, such as MSH6, can be associated with low levels of MSI20; therefore, the absence of MSI cannot be used as a sole criterion to exclude the diagnosis of HNPCC. Genetic analysis of MSH2 and MLH1 is relatively more expensive ($1,600 to 1,800) and more labor intensive (there have been no founder mutations in the United States as are present in the Finnish population studied by Salovaara et al) and can yield inconclusive results, such as the presence of missense alterations.19 There is likely no one correct approach to the diagnostic algorithm for molecular analysis in HNPCC. Variations will occur, appropriately, on the basis of test availability to a particular physician, financial considerations, availability of tumor blocks, and other factors. Finally, it is important to review interpretation of genetic test results. Once a disease-associated mutation is identified in a family, then testing for that family mutation becomes almost 100% accurate for other family members. However, the statement by Salovaara et al6 in the Introduction of their article, that "a definitive diagnosis of HNPCC can only be established by demonstrating a germline mutation," may be misleading, as it implies that the absence of a mutation in a family is an indication that HNPCC is not present. Due to the genetic heterogeneity of the syndrome and the fact there are absolutely classic families who have no identifiable mutation in one of the known genes, some families undergoing genetic evaluation will still not have a definitive test result.19 In these situations, medical recommendations should be based primarily on the family history, and members of the family should still be viewed as being at-risk for inheriting the disease. What about the recommendations by Salovaara et al6 advocating population-based molecular detection of all HNPCC families? They point out some of the difficulties of implementing their approach at the current time, including the need for validation of their clinical criteria in other populations and the small but definite likelihood of overlooking families with the syndrome using their proposed guidelines. Although the ideal diagnostic approach to HNPCC is still in evolution, studies like those of Salovaara et al highlight that molecular analysis is increasingly a part of the evaluation and management of cancer patients. The clinical syndrome and the genetics of HNPCC have many similarities with features of hereditary breast cancer, associated with mutations of BRCA1 and BRCA2.21,22 Both syndromes account for approximately 5% of a common cause of cancer mortality in the United States. Both syndromes are highly penetrant, with risks of the primary cancer being estimated to be as high as 60% to 90%. Both syndromes also include elevated risks of cancers of other organs, many for which no effective form of surveillance exists. The underlying genes for both diseases were identified at approximately the same time, and both syndromes have been shown to be genetically heterogenous. Despite the similarities, the evolution of public and health care provider awareness of the syndrome, use of genetic testing, and recognition of the management issues particular to the syndrome have been strikingly different between hereditary breast cancer and HNPCC. The reasons for this are somewhat unclear and are likely multifactorial. Breast cancer, at least until recently, has received far more media and public attention than colorectal cancer, and perceptions of the familial nature of breast cancer are likely overestimated by most. While research in hereditary breast cancer has focused on studying influence of genetic knowledge on disease prognosis and management, much of the discussion on HNPCC has centered around the complexities of diagnosis of the syndrome and of genetic evaluation. In addition, attention in the general medical and oncologic clinical literature has been disproportionately devoted to hereditary breast-ovarian cancer. An informal search of the National Library of Medicine PubMed database revealed five times the number of references related to hereditary breast cancer compared with HNPCC in several widely read clinical journals. There were a total of 76 references with the search terms BRCA1 and BRCA2 in the Journal of Clinical Oncology (n = 25), Journal of the American Medical Association (n = 23), and New England Journal of Medicine (n = 28). The corresponding total number was 16 with the search terms HNPCC, mismatch repair genes, MSH2, MLH1, and MSH6 (n = 5, 6, and 5 references, respectively). Perhaps one of the main reasons that HNPCC has been relatively neglected is that correct diagnosis and management rely on the cooperation of multiple medical subspecialties, including oncologists, gastroenterologists, surgeons, radiation oncologists, and, increasingly, medical geneticists. Oncologists, not only those involved in the treatment of gastrointestinal tumors but also those who treat gynecologic malignancies, genitourinary cancer, and even brain tumors, can play a central role in the identification of HNPCC patients and can advocate for them and their family members for appropriately aggressive surveillance and management. If we can start to think of HNPCC based simply on clinical grounds, then the more lofty goal of population-based molecular identification of all families may soon become more realistic. REFERENCES 1. 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Powell SM, Petersen GM, Krush AJ, et al: Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 329:1982-1987, 1993 9. Vasen HFA, Mecklin J-P, Meera Khan P, et al: The International Collaborative Group on hereditary nonpolyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 34:424-425, 1991[Medline] 10. Bellacosa A, Genuardi M, Anti M, et al: Hereditary nonpolyposis colorectal cancer: Review of clinical, molecular genetics and counseling aspects. Am J Med Genet 62:353-364, 1996[Medline]
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Kolodner RD, Tytell JD, Schmeits JL, et al: Germ-line msh6 mutations in colorectal cancer families. Cancer Res 59:5068-5074, 1999 21. Wooster R, Bignell G, Lancaster J, et al: Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789-792, 1995 (see comments) (published erratum appears in Nature 379:749, 1996)
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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