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Originally published as JCO Early Release 10.1200/JCO.2007.13.4940 on October 9 2007 © 2007 American Society of Clinical Oncology.
How Should Women With Early-Onset Endometrial Cancer Be Evaluated for Lynch Syndrome?
Clinical Genetics Service, Department of Medicine, and Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY In a 1990 meeting in Amsterdam, the Netherlands, the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer established criteria for recruiting families into collaborative studies to identify the genetic causes and elucidate the natural history of hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome.1 These initial so-called Amsterdam criteria required that at least three cases of colorectal cancer occur in first-degree relatives of each other, that the predisposition span at least two generations, and that one of the colorectal cancers occurs at younger than age 50 years. Although these guidelines were useful to identify families for participation in research studies, it became evident that these criteria were overly restrictive for clinical use and did not reflect the fact that HNPCC/Lynch syndrome was actually a multiorgan-system disease in which extracolonic malignancies account for a great proportion of the total cancer burden. In 1999, recognizing these limitations, the International Collaborative Group on HNPCC revised the Amsterdam criteria to include extracolonic cancers, especially endometrial cancer. These Amsterdam II criteria are listed in Table 1.2
Although the revised criteria are quite specific, only 13% to 36% of patients with molecularly confirmed Lynch-associated colorectal cancer meet these criteria.3,4 To better identify individuals who could be at risk for Lynch syndrome and to reflect the emerging understanding that this syndrome was due to defects in the mismatch repair pathway, the Early Detection Branch of the National Cancer Institute convened a conference in Bethesda in 1996 to identify clinicopathologic criteria that could lead to the identification of patients with Lynch syndrome who were not identified by the original Amsterdam criteria.5 The guidelines that emerged from this conference, which have become known as the Bethesda criteria, identified individuals with colorectal or endometrial cancer whose tumor should undergo evaluation for mismatch repair defects by microsatellite instability (MSI) testing. These criteria specifically included a recommendation that tumors from individuals with endometrial cancer diagnosed at younger than age 45 years be tested for MSI. In the subsequent 5 years, it became apparent that the sensitivity and specificity of the original Bethesda guideline could be improved, and a follow-up conference in 2002 created the Revised Bethesda guidelines (listed in Table 2) 6 that have become the standard for offering testing for mismatch repair defects in colorectal cancer. However, the revised criteria do not provide guidelines for which endometrial tumors should undergo mismatch repair defect evaluation, despite a 40% to 60% lifetime risk of endometrial cancer in women with a mismatch repair mutation associated with Lynch syndrome.7,8
In the current issue of Journal of Clinical Oncology (JCO), Lu et al9 attempt to provide some guidance for which women with endometrial cancer younger than age 50 years should be offered genetic risk assessment to consider the possibility of HNPCC. In this series, women with endometrial cancer diagnosed at younger than age 50 years were identified prospectively at one of three centers. Participants underwent germline testing for mutations in MLH1, MSH2, and MSH6 as well as immunohistochemical (IHC) analysis of mismatch repair protein expression and MSI testing. Patients with loss of MLH1 protein expression in which no germline MLH1 mutation was identified also underwent methylation analysis of the MLH1 promoter. In this series of 100 patients, nine patients had clearly identified deleterious mutations. Four additional patients had MSI, IHC, or methylation results suggestive of the possibility of a germline mutation, though no additional mutations were identified on screening. The authors then correlated clinical information with mutation status and found that having either a low body mass index (BMI) or a first-degree relative with a Lynch syndrome–associated cancer were highly associated with the presence of a germline mutation. The authors go on to conclude that women with endometrial cancer diagnosed at younger than age 50 years in combination with a BMI greater than 30 and no first-degree relative with a Lynch syndrome–associated cancer are unlikely to have Lynch syndrome. While the results of the current study are provocative and are in general agreement with results from a smaller study by Berends et al10 published in JCO in 2003, it is reasonable to ask if the study design led to a self-fulfilling conclusion with regard to the impact of family history. Only 58% of the 172 patients with endometrial cancer diagnosed at younger than age 50 years at the three study sites chose to participate in the study protocol. Of these 100 participants, two had metachronous colon cancers; nine had synchronous ovarian cancers; 16 had a parent with colon, uterine, or ovarian cancer; and 10 had a sibling with a colon, uterine, or ovarian cancer. In this cohort, which appears to be over-represented for Lynch syndrome–associated malignancies in the probands and their first-degree relatives, the possibility of a bias leading to the preferential enrollment of individuals with personal or familial features of Lynch syndrome must be considered. It is possible that individuals who had isolated endometrial cancer and a germline mutation were less likely to be included in the study cohort. One reason that an individual would have an apparently isolated Lynch syndrome–associated endometrial cancer could be that there is paucity of relatives in an at-risk lineage who reach an age old enough to manifest a component tumor. The impact that such uninformative lineages could have on predictive models was reported recently in the setting of the hereditary breast-ovarian cancer syndrome.11 An accompanying editorial suggested that the decisions regarding genetic testing need to reflect variables that current risk assessment models do not fully assess, including the informativeness of the family history, pathologic and immunohistochemical features of the tumors, and the presence of other less common cancers that may be part of the inherited cancer spectrum.12 Similarly, although Lu et al9 show that low BMI is associated with risk of having a deleterious mismatch repair mutation, the converse is not necessarily true. The patients with germline mutations spanned the spectrum of body habitus, and at least one of the patients with a mismatch repair mutation was morbidly obese, with a BMI of 41.2. In addition, given that Lynch syndrome–associated endometrial cancers share many pathologic and molecular features with sporadic type I endometrial cancers, it is possible that risk factors for type I endometrial cancer, including obesity or other hyperestrogenic states, could be contributing factors to the development of Lynch syndrome–associated endometrial cancer. Given these concerns, conclusions about inclusion of BMI in criteria for HNPCC genetic testing should await confirmation from future population-based studies. Acknowledging these possibilities and limitations, how do we best use these data? Even if no additional germline mutations were identified in the 72 participants who elected not to participate in the study, the minimal rate of detectable germline mismatch repair defects in endometrial cancer diagnosed at younger than age 50 years would be 5.2%. In two other studies that have examined unselected endometrial cancer diagnosed in this age range, the rate of detectable germline mutations was 4.9% to 8.6%.10,13 These mutation prevalence rates seem similar to the 5.6% to 7.0% prevalence rates of mismatch repair mutations seen in patients diagnosed with colorectal cancer at younger than age 503,4 (Table 3). Given that the prevalence of detectable germline mutations in both early-onset colon cancer and early-onset endometrial cancer are quite comparable, a strong argument can be made that the revised Bethesda criteria should be modified to include endometrial cancer at younger than age 50 years as an indication for offering evaluation of mismatch repair defects.
The study by Lu et al9 also provides some guidance regarding which methods may be appropriate to triage patients with possible Lynch syndrome–associated endometrial cancer. In this series, both MSI testing and IHC evaluation of the mismatch repair proteins showed comparable sensitivity and specificity for detection of mismatch repair mutations. These results are in agreement with several other studies that have suggested that IHC assessment of the four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) is an efficient method to identify microsatellite-unstable endometrial cancer.13,14 Given the substantially wider availability of IHC compared with MSI testing, and the ability of IHC to direct sequencing efforts or the need for MLH1 promoter methylation studies, it appears that IHC evaluation of mismatch repair protein expression should be used as the primary technical method for triage of Lynch-associated endometrial cancer, as has been suggested for colorectal cancer.15,16 Of the 40,000 cases of endometrial cancer that will be diagnosed in the United States this year, 1,200 to 2,000 will be due to inherited defects in the mismatch repair genes. The study by Lu et al9 provides important information regarding the identification of these Lynch syndrome–associated malignancies. Although the majority of these individuals will be cured of their endometrial cancer, both the patient and their relatives will be at risk for other potentially life-threatening and, importantly, preventable cancers. Recognition of these individuals will allow the opportunity to take advantage of proven cancer prevention strategies,17,18 and it is an opportunity our patients cannot afford to have us miss. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES published online ahead of print at www.jco.org on October 9, 2007 REFERENCES 1. Vasen HF, Mecklin JP, Khan PM, et al: The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34:424-425, 1991[CrossRef][Medline] 2. Vasen HF, Watson P, Mecklin JP, et al: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116:1453-1456, 1999[CrossRef][Medline] 3. Piçnol V, Castells A, Andreu M, et al: Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA 293:1986-1994, 2005 4. Hampel H, Frankel WL, Martin E, et al: Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352:1851-1860, 2005 5. Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al: A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: Meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89:1758-1762, 1997 6. Umar A, Boland CR, Terdiman JP, et al: Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261-268, 2004 7. Dunlop MG, Farrington SM, Carothers AD, et al: Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 6:105-110, 1997 8. Aarnio M, Sankila R, Pukkala E, et al: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81:214-218, 1999[CrossRef][Medline] 9. Lu KH, Schorge JO, Rodabaugh KJ, et al: Prospective determination of prevalence of Lynch syndrome in young women with endometrial cancer. J Clin Oncol 25:5158-5164, 2007 10. Berends MJ, Wu Y, Sijmons RH, et al: Toward new strategies to select young endometrial cancer patients for mismatch repair gene mutation analysis. J Clin Oncol 21:4364-4370, 2003 11. Weitzel JN, Lagos VI, Cullinane CA, et al: Limited family structure and BRCA gene mutation status in single cases of breast cancer. JAMA 297:2587-2595, 2007 12. Kauff ND, Offit K: Modeling genetic risk of breast cancer. JAMA 297:2637-2639, 2007 13. Hampel H, Frankel W, Panescu J, et al: Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res 66:7810-7817, 2006 14. Modica I, Soslow RA, Black D, et al: Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma. Am J Surg Pathol 31:744-751, 2007[CrossRef][Medline] 15. Stormorken AT, Bowitz-Lothe IM, Noren T, et al: Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer. J Clin Oncol 23:4705-4712, 2005 16. Southey MC, Jenkins MA, Mead L, et al: Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol 23:6524-6532, 2005 17. Järvinen HJ, Aarnio M, Mustonen H, et al: Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118:829-834, 2000[CrossRef][Medline] 18. Schmeler KM, Lynch HT, Chen LM, et al: Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 354:261-269, 2006
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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