Screening for Lynch Syndrome in Endometrial Cancer

SGO Clinical Practice Statement: Screening for Lynch Syndrome in Endometrial Cancer

March 2014

All women diagnosed with endometrial carcinoma should undergo systematic clinical screening (review of personal and family history) and/or molecular screening for Lynch syndrome, a hereditary cancer syndrome.

Approximately 3-5% of endometrial cancers can be attributed to Lynch syndrome, caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2). Patients with Lynch syndrome have a 40-60% lifetime risk for endometrial and colon cancer [1,2]. The identification of Lynch syndrome in women with endometrial cancer can lead to the prevention of a second cancer in the patient and incident cancers in family members through risk-reducing strategies and heightened surveillance. Lynch syndrome differs from other hereditary cancer syndromes in that tumor tissue can be utilized to aid in the identification of patients at risk for Lynch syndrome and help inform germline genetic testing. Endometrial carcinomas can be screened for Lynch syndrome using immunohistochemistry (IHC) for the four mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), microsatellite instability (MSI) analysis, and MLH1 hypermethylation testing[3].

Assessing for Lynch syndrome in the general endometrial cancer population can be accomplished through two main strategies. First, patients can be identified through a systematic clinical screen, including a focused personal and family history[4]. Patients noted to be at increased risk for Lynch syndrome by clinical criteria then undergo germline testing or molecular tumor testing. However, this method will miss a significant fraction of women with Lynch syndrome who do not have a suggestive family history. A more sensitive strategy is universal molecular tumor testing for either all endometrial cancers or cancers diagnosed at age less than 60, regardless of personal or family cancer history. IHC for MLH1, MSH2, MSH6, and PMS2 expression is the most cost-effective of the tumor studies and is widely available in most pathology laboratories. However, the majority of MLH1 loss is due to MLH1 hypermethylation, a sporadic cause of MLH1 loss. Therefore, MLH1 hypermethylation analysis should be completed on tumors that show loss of MLH1 on IHC to help triage appropriate cases for germline testing[5].

In summary, all women who are diagnosed with endometrial cancer should undergo systematic clinical screening for Lynch syndrome (review of personal and family history) and/or molecular screening. Molecular screening of endometrial cancers for Lynch syndrome is the preferred strategy when resources are available.


[1]        Stoffel E, Mukherjee B, Raymond, VM, Tayob N, Kastrinos F, Sparr J, et al. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome  2009;Gastroenterology, 137 (5), pp. 1621-1627.

[2]        Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999;81(2):214-218.

[3]        Egoavil C, Alenda C, Castillejo A, Artemio Paya, Gloria Peiro, Ana-Beatriz Sánchez-Heras, et al. Prevalence of Lynch syndrome among patients with newly diagnosed endometrial cancers. PLoS ONE 2013;8(11):e79737.

[4]        Daniels MS, Urbauer DL, Zangeneh A, Batte BA, Dempsey KM, Lu KH. Outcomes of screening endometrial cancer patients for Lynch syndrome by patient-administered checklist. Gynecol Oncol 2013;131(3):619-623.

[5]        Salvesen HB, MacDonald N, Ryan A, Iversen OE, Jacobs IJ, Akslen LA, et al. Methylation of hMLH1 in a population-based series of endometrial carcinomas. Clin Cancer Res 2006;6(9):3607-3613.