Originally published as JCO Early Release 10.1200/JCO.2007.10.8597 on October 9 2007

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Prospective Determination of Prevalence of Lynch Syndrome in Young Women With Endometrial Cancer

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

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.

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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• How Should Women With Early-Onset Endometrial Cancer Be Evaluated for Lynch Syndrome?
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