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Originally published as JCO Early Release 10.1200/JCO.2007.10.8597 on October 9 2007 © 2007 American Society of Clinical Oncology. Prospective Determination of Prevalence of Lynch Syndrome in Young Women With Endometrial Cancer
From the Departments of Gynecologic Oncology and Pathology, University of Texas M.D. Anderson Cancer Center, Houston; Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX; and the Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY Address reprint requests to Karen H. Lu, MD, Department of Gynecologic Oncology, Division of Surgery, The University of Texas M.D. Anderson Cancer Center, 1155 Herman Pressler, Unit 1362, Houston, TX 77030-4009; e-mail: khlu{at}mdanderson.org
Purpose Age younger than 50 years at the time of colon cancer diagnosis is often used as a screening criterion for Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). The purpose of this study was to determine the prevalence of MLH1, MSH2, and MSH6 mutations in an unselected cohort of women diagnosed with endometrial cancer at age younger than 50 years. Methods A prospective, multicenter study was performed at three institutions. After written consent was obtained, germline mutation testing by full sequencing and large deletion analysis of the MLH1, MSH2, and MSH6 genes was performed. Tumor studies included immunohistochemistry of MLH1, MSH2, and MSH6; microsatellite instability analysis; and hypermethylation of the MLH1 promoter. Results Of the 100 women, nine (9%; 95% CI, 4.2 to 16.4) carried a deleterious germline mutation: seven women with mutations in MSH2, one woman with a mutation in MLH1, and one woman with a mutation in MSH6. Two additional women had molecular studies consistent with the diagnosis of Lynch syndrome. The mean body mass index (BMI) for the entire cohort was 34.4, which is significantly higher than 29.2, the mean BMI for the mutation carriers. Predictors of finding a germline mutation included having a first-degree relative with a Lynch syndrome–associated cancer, endometrial tumor with loss of MSH2 expression, tumors with high microsatellite instability, and lower BMI. Conclusion In this prospective study of endometrial cancer patients younger than age 50 years, 9% were found to carry germline Lynch syndrome–associated mutations. In addition to young age of onset, family history, BMI, and molecular tumor studies can improve the likelihood of identifying a Lynch syndrome–associated germline mutation in MLH1, MSH2, and MSH6.
Lynch syndrome, or hereditary nonpolyposis colorectal cancer syndrome, is an autosomal dominant inherited cancer susceptibility syndrome. Although individuals with Lynch syndrome are at significant lifetime risk of developing colorectal cancer, recent studies have reported that women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer. In fact, their risk for endometrial cancer may exceed their risk for colon cancer.1,2 The average age of diagnosis of endometrial cancer in women with Lynch syndrome is 48 years, which is substantially younger than age 60 years (the mean age of diagnosis for sporadic endometrial cancer).3 This indicates that early age of onset of endometrial cancer is one possible indicator of Lynch syndrome. Lynch syndrome is due to an inherited defect in one of the DNA mismatch repair genes.4,5 Germline mutations in MLH1, MSH2, and MSH6 account for the majority of families with Lynch syndrome.6 Clinical genetic testing is currently available for all three genes. General hallmarks for hereditary cancer predisposition syndromes include young age of onset, more than one primary cancer in one individual, and multiple family members with the same or related types of cancer. For Lynch syndrome, more specific criteria have been developed to help identify at-risk families. The modified Amsterdam criteria (or Amsterdam II criteria) recognize the importance of extracolonic cancers in identifying Lynch syndrome.7 Although helpful, these criteria may lack sensitivity, particularly in cases of small families or when extensive family history information is not ascertained or is not available. The revised Bethesda criteria were developed in part to help identify Lynch syndrome based primarily on an individual's medical history. In addition, these recommendations are useful in patients whose extended family history is not available. The criteria focus primarily on patients with colon cancer and recommend additional evaluation depending on certain tumor histology and age of onset. Patients with endometrial cancer are not addressed by the revised Bethesda criteria.8 Few studies have been conducted to determine at what age and what other criteria should be used to refer women with endometrial cancer for additional genetic evaluation. Gastroenterologists, surgeons, and medical oncologists traditionally have identified individuals with early-onset colon cancer or a strong family history of colon cancer as potentially having Lynch syndrome. Traditionally, gynecologists and gynecologic oncologists have not played a significant role in identifying women with Lynch syndrome. This is likely due to the relative lack of studies of endometrial cancer and ovarian cancer in Lynch syndrome. Approximately 12% of women with endometrial cancer are diagnosed at younger than age 50 years. In one of our previous retrospective studies,9 we identified 117 women from Amsterdam criteria–positive families with colon cancer and endometrial cancer/ovarian cancer. Interestingly, in one half of these women the gynecologic cancer preceded the development of the colon cancer by an average of 5.5 years (ovarian cancer presenting first) or 11 years (endometrial cancer presenting first), allowing for sufficient time for the development of an adequate colon cancer screening strategy if the woman can be properly identified as being at risk. Thus, it is crucial for physicians who care for young women with cancer to be aware of the possibility of Lynch syndrome. The purpose of this study was to determine the frequency of Lynch syndrome-associated germline mutations in an unselected series of women with endometrial cancer younger than age 50 years. In addition, microsatellite instability (MSI) analysis; immunohistochemistry of MLH1, MSH2, and MSH6; and hypermethylation of the MLH1 promoter were performed to correlate germline mutation results with pertinent molecular markers.
Patient Population and Study Design Women who were younger than age 50 years at the time of diagnosis of endometrial cancer and who had their initial diagnosis after January 2000 were enrolled prospectively at three institutions. Consecutive patients were approached for enrollment in the gynecologic oncology clinics of each institution. Patients were identified by reviewing the weekly surgical and clinic schedules. Institutional review board approval was obtained from all sites. Written informed consent was obtained from each participant. Demographic data and medical, gynecologic, and family history were obtained using a uniform data sheet. Germline mutation testing by full sequencing of the MLH1 and MSH2 genes was performed by Myriad Genetics (Salt Lake City, UT). Germline mutation testing by full sequencing of the MSH6 gene and large deletion testing of MLH1, MSH2, and MSH6 was performed by Baylor Diagnostics Laboratory (Houston, TX). Patients were given the option of obtaining the results of their mutation testing.
Molecular Studies MSI analysis was performed using formalin-fixed, paraffin-embedded sections of endometrial cancer for each patient. Tumor and normal tissues were microdissected with an 18-guage needle under light microscopy. DNA was extracted from each tumor-normal pair. After DNA amplification using fluorescent-labeled primers, a panel of six markers recommended by the National Cancer Institute (BAT25, BAT26, BAT40, D2S123, D5S346, and D173250) was analyzed for allelic shift. Tumors showing allelic shift at two or more markers were classified as MSI-high (MSI-H), whereas those with allelic shift in one marker were classified as MSI-low (MSI-L). Tumors with no allelic shift were classified as microsatellite stable. Analysis of MLH1 promoter hypermethylation was performed in those patients who demonstrated MSI-H tumors and loss of immunohistochemical expression of MLH1. Analysis of MLH1 promoter hypermethylation was also performed for the few patients in whom IHC yielded uncertain results. DNA was isolated from microdissected formalin-fixed, paraffin-embedded sections of endometrial cancer and then treated with bisulfite for the performance of methylation-specific polymerase chain reaction, as described previously.10
Statistical Analysis
One hundred women diagnosed with endometrial cancer younger than age 50 years were enrolled prospectively onto this study. At M.D. Anderson Cancer Center (Houston, TX), 89 women were eligible and 58 enrolled (65%); at University of Texas Southwestern Medical Center (Dallas, TX), 50 women were eligible and 22 enrolled (44%); and at Roswell Park Cancer Institute (Buffalo, NY), 33 women were eligible and 20 women enrolled (61%). The mean age at diagnosis was 41.6 years, with a range of 24 to 49 years (Table 1). Nine (9%) of the 100 women (95% CI, 4.2% to 16.4%) were found by clinical genetic testing to carry deleterious Lynch syndrome mutations: one in MLH1, seven in MSH2, and one in MSH6. Each of these women had MSI-H tumors with IHC loss of the appropriate DNA mismatch repair protein (patients 1 to 9; Table 2).
The median age of the women with a germline Lynch syndrome mutation was 44.0 years (Table 1). The median age of women without a mutation was 43.0 years. The median BMI of women with a germline mutation was 27.6, which is significantly lower than 37.5, the median BMI for women without a germline mutation (Table 1). Twelve of the 100 patients in our entire cohort had multiple cancers (Table 1). Nine patients had synchronous ovarian cancers, but only one of these had a germline Lynch syndrome mutation. Two patients in the entire cohort had a history of colon cancer, and both were found to have an MSH2 germline mutation. Tumor histotype and stage were similar between mutation carriers and those with negative germline testing results (Table 1). Among the women with endometrial cancer diagnosed at age younger than 50 years, 21 had a first-degree relative with a Lynch syndrome–associated cancer (Table 1). All patients with germline Lynch syndrome mutations had a first-degree relative with a Lynch syndrome–associated cancer, whereas 13.2% of women with negative test results had first-degree relatives with a Lynch syndrome–associated cancer. Table 2 summarizes the molecular data for patients with either abnormal germline testing results, abnormal microsatellite findings, or abnormal IHC results. MSI analysis was performed on 95 patients, with the remaining five patients having insufficient tumor tissue for DNA extraction. Among the 25 women who were MSI-H, eight had germline mutations of MLH1, MSH2, or MSH6. The ninth mutation carrier did not have sufficient tumor for MSI analysis but had appropriate loss of expression of protein by IHC. Eleven women had tumors with hypermethylation of the MLH1 promoter (patients 12 to 22; Table 2) and all had loss of expression of MLH1. Nine of these had negative germline MLH1 testing, one had a variant of uncertain significance (VUS) in MLH1, and one had a VUS in MSH2. In addition to these two patients with VUS, there were nine additional VUS in the total cohort: three in MLH1, five in MSH2, and one in MSH6. In these nine patients, the IHC panel was normal and the tumors were microsatellite stable. Among the six patients with MSI-L tumors, none had a germline Lynch syndrome mutation. Five of these women had tumors with intact IHC expression of MLH1, MSH2, and MSH6 (patients 28 to 32; Table 2). The sensitivity, specificity, and positive and negative predictive values for having a germline Lynch syndrome mutation are listed in Table 3. In women who had loss of either MLH1, MSH2, or MSH6 by IHC, the probability of having a germline Lynch syndrome mutation was 38%. Loss of MSH2 IHC expression was highly (64%) predictive of having an MSH2 germline mutation. MSI-H status was associated with a 32% probability of having a germline Lynch syndrome mutation. Having a first-degree relative with a Lynch syndrome–associated cancer was also highly predictive (43%) of having a germline Lynch syndrome mutation. Interestingly, a young woman with endometrial cancer and a BMI greater than 30 is unlikely to have a Lynch syndrome mutation. Finally, the combination of a BMI greater than 30 and a negative family history is highly predictive of not having a Lynch syndrome mutation.
The frequency of identifying a germline MLH1, MSH2, or MSH6 mutation by clinical genetic testing in this cohort of prospectively enrolled women with endometrial cancer diagnosed at younger than age 50 years was 9%. All nine women with germline Lynch syndrome mutations had first-degree relatives with a Lynch syndrome cancer, and seven of nine fulfilled revised Amsterdam criteria for Lynch syndrome. The molecular analysis of their tumors, including MSI and immunohistochemistry, was consistent with their genetic test results. Two additional women had molecular studies consistent with Lynch syndrome, including MSI-H tumors with loss of IHC expression of MSH2 and MSH6, but did not have a germline Lynch syndrome mutation. Neither patient had family histories that were suggestive of Lynch syndrome. However, given the molecular data, we would consider these women to have the clinical diagnosis of Lynch syndrome with an unidentifiable mutation. Current germline testing technologies are not 100% sensitive. The majority of the germline mutations that we identified were in MSH2. We found only one germline MSH6 mutation, which had an associated MSI-H tumor with loss of MSH6 staining. Endometrial tumors in patients with germline MSH6 mutations have been reported commonly to have a MSI-L phenotype, with loss of IHC expression of MSH6 and later age of onset.11-14 In a Dutch study, Berends et al15 reported that 8.6% (five of 58) of women younger than age 50 years with endometrial cancer had a mutation in MLH1, MSH2, or MSH6. Of their five germline mutations, one was in MLH1, three were in MSH2, and one was an MSH6 mutation. Our study, which is larger and includes prospectively enrolled, consecutive women younger than age 50 years presenting for their primary treatment to gynecologic oncology clinics of three institutions, found a similar rate (9%) of germline Lynch syndrome mutations. In a population-based study of women with endometrial cancer, Hampel et al16 identified a subset of 81 women younger than age 50 years and reported a 4.9% (four of 81) rate of germline Lynch syndrome mutations. One of the goals of our study was to determine what additional clinical or molecular data, in addition to young age of onset, would be helpful to clinicians in identifying individuals with Lynch syndrome. In our study, women with a first-degree relative with a Lynch syndrome–associated cancer had a 43% chance of having a germline Lynch mutation as compared with women without an affected first-degree relative. Berends et al15 reported that 23% of women with endometrial cancer younger than age 50 years and a first-degree relative with a Lynch syndrome–associated cancer were found to have a germline Lynch syndrome mutation. Of the 95 tumors in which MSI analysis was performed, 25 were MSI-H and six were MSI-L. If MSI-H status was used as screening criteria, the probability of carrying a germline MLH1, MSH2, or MSH6 mutation was 32% for this cohort of women younger than age 50 years with endometrial cancer. Loss of expression by IHC was also predictive of identifying a germline Lynch syndrome mutation. In particular, loss of MSH2 IHC expression was highly predictive of identifying an MSH2 mutation. In addition to IHC for MLH1, MSH2, and MSH6, a recent study on colon cancer suggested that IHC of PMS2 should also be performed to identify individuals who may have Lynch syndrome. PMS2 dimerizes with MLH1, and loss of PMS2 by IHC identified additional individuals with MLH1 germline mutations. PMS2 germline mutations are rare.17 From a clinical standpoint, molecular analysis with either MSI or IHC can refine further the likelihood of identifying a Lynch syndrome gene mutation in a young woman with endometrial cancer. In most patients, IHC and MSI tumor studies are consistent with the germline test results. However, there are cases in which tumor studies are inconclusive or are not consistent with germline test results. As discussed previously, we would counsel individuals who have negative germline MSH2 results, but have an MSI-H tumor with loss of MSH2 protein by IHC (patients 10 and 11), that current clinical testing for MSH2 is not 100% sensitive, and that they are likely to have Lynch syndrome. In other cases of inconclusive tumor and germline testing (patients 26 and 27), we review the results and discuss the limitations of the molecular and germline testing. In these patients, Lynch syndrome is possible but cannot be diagnosed definitively. Family history of relevant cancers is helpful in these patients. Although a diagnosis of endometrial cancer in patients younger than age 50 years may be a helpful clinical indicator of Lynch syndrome, Lynch syndrome cannot be excluded by later age of diagnosis. In the population-based study of 543 women with endometrial cancer by Hampel et al,16 10 mutation carriers were identified. Four of the 10 women were younger than age 50 years, but six were older than age 50 years. In our previous multi-institutional, retrospective analysis, we found that the mean age of diagnosis for women with Lynch syndrome and endometrial cancer was 46.8 years, with 16 of the 50 women studied older than age 50 years.18 In the revised Bethesda criteria, it is recommended that patients with synchronous Lynch syndrome–related cancers, regardless of age, undergo MSI analysis. A woman with a synchronous or metachronous colon and endometrial cancer has a high likelihood of having Lynch syndrome.19 However, data from our study and others suggest that synchronous endometrial and ovarian cancer in the absence of other family history may not be a strong predictor of Lynch syndrome. Synchronous primary tumors of the ovary and endometrium can be detected in 7% to 29% of women with endometrial cancer.20-23 A large proportion of such women are younger than age 50 years.24,25 In two different retrospective analyses, only 3% and 7% of such synchronous primary cases were attributable to Lynch syndrome.10,26 In the present study, only one of the nine (11%) women with synchronous endometrial and ovarian carcinomas had a positive Lynch syndrome mutation. In addition to increased risk due to a hereditary predisposition, obesity is the strongest risk factor for the development of endometrial cancer.27 For the entire cohort of women younger than age 50 years with endometrial cancer, the mean BMI was 34.4. The women in the lowest age quartile (age < 35 years) had the highest mean weight. The median BMI of nonmutation carriers was significantly higher than the BMI of mutation carriers. From a clinical standpoint, a young woman with endometrial cancer who has a BMI greater than 30 and no first-degree relatives with a Lynch syndrome cancer likely has sporadic endometrial cancer. Although our findings need to be confirmed, we believe that these criteria may be useful for physicians to rule out Lynch syndrome in a young woman with endometrial cancer. Such an association with weight and Lynch syndrome–associated cancer has not been reported previously and will need to be validated in future studies. In conclusion, in this prospective multicenter study, we found a 9% rate of finding an MLH1, MSH2, or MSH6 germline mutation in women diagnosed with endometrial cancer at younger than age 50 years. In women younger than age 50 years with endometrial cancer and a first-degree relative with a Lynch syndrome–associated cancer, the probability of identifying a germline MLH1, MSH2, or MSH6 mutation was 43%. MSI testing of the tumor as well as IHC can assist in accurately identifying young women with Lynch syndrome. Obtaining extended family histories is not absolutely necessary for triage purposes. However, a query of the cancer history in a patient's first-degree relatives and calculation of BMI are simple and effective means of assisting the clinicians in identifying young women with endometrial cancer who should be referred for more detailed genetic evaluation and molecular diagnostic testing. Although larger studies will be needed to confirm these findings, those young endometrial cancer patients without a family history of a Lynch syndrome cancer and who are obese are unlikely to have Lynch syndrome.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Kerry J. Rodabaugh, Myriad Genetics Research Funds: N/A Testimony: N/A Other: N/A
Conception and design: Karen H. Lu, Kerry J. Rodabaugh, Molly S. Daniels, David M. Gershenson, Russell R. Broaddus Financial support: Karen H. Lu Administrative support: Karen H. Lu, David M. Gershenson Provision of study materials or patients: Karen H. Lu, John O. Schorge, Kerry J. Rodabaugh, Molly S. Daniels Collection and assembly of data: Karen H. Lu, John O. Schorge, Kerry J. Rodabaugh, Molly S. Daniels, Charlotte C. Sun, Pamela T. Soliman, Kristin G. White, Rajyalakshmi Luthra, Russell R. Broaddus Data analysis and interpretation: Karen H. Lu, John O. Schorge, Molly S. Daniels, Charlotte C. Sun, Pamela T. Soliman, Kristin G. White, Russell R. Broaddus Manuscript writing: Karen H. Lu, Molly S. Daniels, Pamela T. Soliman, Russell R. Broaddus Final approval of manuscript: Karen H. Lu, John O. Schorge, Kerry J. Rodabaugh, Molly S. Daniels, Charlotte C. Sun, Pamela T. Soliman, Kristin G. White, Rajyalakshmi Luthra, David M. Gershenson, Russell R. Broaddus
We thank Myriad Genetics Laboratories for performing the clinical sequencing analysis of MLH1 and MSH2.
published online ahead of print at www.jco.org on October 9, 2007. Supported in part by funding from the National Cancer Institute Grant No. N01-CN-05127 and Specialized Program of Research Excellence (SPORE) Grant No. NCI-P50CA098258, and the M.D. Anderson Cancer Center Multi-Disciplinary Research Program. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Peltomäki P, Vasen HF: Mutations predisposing to hereditary nonpolyposis colorectal cancer: Database and results of a collaborative study—The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 113:1146-1158, 1997[CrossRef][Medline] 7. 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] 8. 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 9. Lu K, et al: Gynecological malignancy as a "sentinel cancer" for women with HNPCC. Gynecol Oncol 92:421, 2004 10. Soliman PT, Broaddus RR, Schmeler KM, et al: Women with synchronous primary cancers of the endometrium and ovary: Do they have Lynch syndrome? J Clin Oncol 23:9344-9350, 2005 11. Berends MJ, Wu Y, Sijmons RH, et al: Molecular and clinical characteristics of MSH6 variants: An analysis of 25 index carriers of a germline variant. Am J Hum Genet 70:26-37, 2002[CrossRef][Medline] 12. Wijnen J, de Leeuw W, Vasen H, et al: Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet 23:142-144, 1999[CrossRef][Medline] 13. Goodfellow PJ, Buttin BM, Herzog TJ, et al: Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A 100:5908-5913, 2003 14. Vasen HF, Stormorken A, Menko FH, et al: MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: A study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol 19:4074-4080, 2001 15. Berends MJ, Wu Y, Sijmons RH, et al: Toward new strategies to select young endometrial cancer patients for mismatch repair gene mutation analysis. 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Obstet Gynecol 91:349-354, 1998[CrossRef][Medline] 21. Tran BN, Connell PP, Waggoner S, et al: Characteristics and outcome of endometrial carcinoma patients age 45 years and younger. Am J Clin Oncol 23:476-480, 2000[Medline] 22. Gitsch G, Hanzal E, Jensen D, et al: Endometrial cancer in premenopausal women 45 years and younger. Obstet Gynecol 85:504-508, 1995[CrossRef][Medline] 23. Soliman PT, Oh JC, Schmeler KM, et al: Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol 105:575-580, 2005[Medline] 24. Zaino R, Whitney C, Brady MF, et al: Simultaneously detected endometrial and ovarian carcinomas–a prospective clinicopathologic study of 74 cases: A gynecologic oncology group study. Gynecol Oncol 83:355-362, 2001[CrossRef][Medline] 25. Soliman PT, Slomovitz BM, Broaddus RR, et al: Synchronous primary cancers of the endometrium and ovary: A single institution review of 84 cases. Gynecol Oncol 94:456-462, 2004[CrossRef][Medline] 26. Shannon C, Kirk J, Barnetson R, et al: Incidence of microsatellite instability in synchronous tumors of the ovary and endometrium. Clin Cancer Res 9:1387-1392, 2003 27. Brinton LA, Berman ML, Mortel R, et al: Reproductive, menstrual, and medical risk factors for endometrial cancer: Results from a case-control study. Am J Obstet Gynecol 167:1317-1325, 1992[Medline] Submitted January 18, 2007; accepted July 30, 2007.
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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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ABSTRACT
INTRODUCTION
2 and Fisher's exact tests were used to compare differences between groups for categoric variables. P values were two sided and P < .05 was considered significant. Sensitivity, specificity, and predictive values were calculated for immunochemical loss of protein expression, MSI status, and family history (first-degree relative) both with and without body mass index (BMI), versus the results of germline mutation testing. Data were analyzed using SPSS version 14.0 (SPSS Inc, Chicago, IL). 
