MSI Tumor Analysis Implicates Lynch Syndrome in Cancer Types

A new pan-cancer analysis suggests that there may be a benefit to doing germline testing for Lynch syndrome in advanced cancer patients who have high microsatellite instability (MSI) in their tumors.

Lynch syndrome mutations have turned up in the germline of individuals with prostate cancer, sarcoma, mesothelioma, and other cancer types not linked to the condition in the past. Nearly half of the non- colorectal cancer/endometrial cancer cases with Lynch gene mutations and MSI-high (MSI-H) or intermediate/indeterminate (MSI-I) status came from cases that would not meet the current criteria for Lynch syndrome testing.


Scientists at Memorial Sloan-Kettering Cancer Center (New York, NY, USA) carried out a prospective study involving 15,045 cancer patients who had their matched tumor and normal samples analyzed on MSK-IMPACT, an FDA-authorized, next-generation sequencing-based pipeline for detecting MSI as well as mutations in hundreds of tumor-associated genes. After clustering the tumors based on their MSI scores, the team overlaid information on Lynch syndrome gene mutations in the patients' germlines, demonstrating that the autosomal dominant cancer predisposition syndrome appears to be dramatically over-represented in individuals with tumors in the MSI high (MSI-H) and intermediate/indeterminate (MSI-I) group, but rare in individuals with microsatellite stable (MSS) tumors.

The team found that half of the tumors that occurred in the apparent Lynch syndrome individuals with MSI-H or MSI-I tumors were colorectal or endometrial, the cancer types that are best known in Lynch syndrome. The team was also able to determine whether those MSI classifications coincided with the presence of pathogenic or likely pathogenic changes in Lynch syndrome-related mutations in the Lynch syndrome-related DNA repair genes MLH1, MSH2, MSH6, PMS2, and EPCAM. The investigators reported that more than 16% of the 326 tumors classified as MSI-H contained Lynch syndrome-related mutations, as did 1.9% of the 699 tumors designated as MSI-I. In contrast, only 0.3% of the 14,020 MSS tumors contained the telltale Lynch syndrome mutations in MLH1, MSH2, MSH6, PMS2, or EPCAM, on par with the 0.3% Lynch syndrome prevalence rate previously reported in the general population.

Zsofia Kinga Stadler, MD, a medical oncologist and senior author of the study, said, “The result is an increased ability to recognize Lynch syndrome, not only in our cancer patients, but also in at-risk family members who may benefit from genetic testing for Lynch and subsequent enhanced cancer surveillance and risk reduction measures.” The study was presented at the American Society of Clinical Oncology annual meeting held June 1-5, 2018, in Chicago, IL, USA.

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Memorial Sloan-Kettering Cancer Center