Screening for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) among Endometrial Cancer Patients

Abstract

Endometrial cancer is the most common cancer in women with Lynch syndrome. The identification of individuals with Lynch syndrome is desirable because they can benefit from increased cancer surveillance. The purpose of this study was to determine the feasibility and desirability of molecular screening for Lynch syndrome in all endometrial cancer patients. Unselected endometrial cancer patients (N = 543) were studied. All tumors underwent microsatellite instability (MSI) testing. Patients with MSI-positive tumors underwent testing for germ line mutations in MLH1, MSH2, MSH6, and PMS2. Of 543 tumors studied, 118 (21.7%) were MSI positive (98 of 118 MSI high and 20 of 118 MSI low). All 118 patients with MSI-positive tumors had mutation testing, and nine of them had deleterious germ line mutations (one MLH1, three MSH2, and five MSH6). In addition, one case with an MSI-negative tumor had abnormal MSH6 immunohistochemical staining and was subsequently found to have a mutation in MSH6. Immunohistochemical staining was consistent with the mutation result in all seven truncating mutation-positive cases but was not consistent in two of the three missense mutation cases. We conclude that in central Ohio, at least 1.8% (95% confidence interval, 0.9-3.5%) of newly diagnosed endometrial cancer patients had Lynch syndrome. Seven of the 10 Lynch syndrome patients did not meet any published criteria for hereditary nonpolyposis colorectal cancer, and six of them were diagnosed at age >50. Studying all endometrial cancer patients for Lynch syndrome using a combination of MSI and immunohistochemistry for molecular prescreening followed by gene sequencing and deletion analysis is feasible and may be desirable. (Cancer Res 2006; 66(15): 7810-7)

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

“…In a previous populationbased study of colorectal and endometrial cancers, we found that 6 of 44 (13.7%) probands with LS had PMS2 mutations (these 6 mutation carriers are included in this analysis). 1,2 In the current study, we found deleterious PMS2 gene mutations in 62% of probands selected on the criterion that their tumors showed isolated loss of PMS2 protein by IHC. In addition, we found 10 probands with variants of uncertain significance in PMS2 that could be deleterious.…”

“…In a population based study, 7 of 10 (70%) of endometrial cancer patients and 5 of 23 (22%) of colorectal cancer patients who had LS did not meet either set of published criteria. 1,2 In a population-based series of colorectal cancer patients diagnosed under age 45, 50% of LS cases would have been missed using Amsterdam criteria alone. 22 The argument could be made that given the low penetrance in monoallelic PMS2 mutation carriers, identification of probands without a family history of LS-associated tumors is not of great importance.…”

“…[1][2][3] Mutations in one of four mismatch repair genes: MLH1, MSH2, MSH6, and PMS2 cause LS and studies suggest that there may be differences in cancer risks for mutation carriers depending on the gene that is mutated. 4,5 Most recent valid estimates of cancer risks to age 70 suggest that individuals with LS have an increased risk of colorectal cancer (22-74%), endometrial cancer (32-42%), and a number of other cancers (such as those of the stomach, ovary, small intestine, biliary tract, and urinary tract).…”

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

“…4 MLH1 inactivating mutations lead to an approximately 20-fold increased risk of cancer development and account for 50% of Lynch syndrome cases. 5,6 However, several germline missense alterations have been identified in MLH1 whose role in the pathogenesis of colonic epithelial neoplasia is less clear.…”

Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair

“…The term Lynch syndrome emphasizes the hereditary predisposition of malignancy that is due to germline mutation in one of the DMMR genes. Extra-colonic malignancies are especially prevalent in women with Lynch syndrome as they have a higher risk of endometrial cancer than CRC (7). The identification of Lynch syndrome families is of paramount importance as these individuals may benefit from genetic counseling, genetic testing, and more intense cancer surveillance (8).…”