MSI-High Status and Lynch Syndrome Found in Surprising Variety of Cancers

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In a study that many consider to be practice-changing, Lynch syndrome, a hereditary cancer predisposition syndrome, was found in many persons who would not ordinarily be suspected of having it.1 The study, which was presented at the 2018 ASCO Annual Meeting, has implications for broader testing among the cancer population.

Our study suggests that an MSI-H tumor signature, regardless of tumor type and irrespective of family cancer history, should prompt germline genetic assessment for evaluating Lynch syndrome.
— Zsofia K. Stadler, MD

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The genomic analysis of more than 15,000 tumor samples across more than 50 types of cancer revealed microsatellite instability-high (MSI-H) status in 2.2% of specimens, of whom 16% had a germline mutation in a DNA mismatch repair gene, indicative of Lynch syndrome. Surprisingly, many of these patients had cancers that are not typically associated with MSI-H status or Lynch syndrome.

Among 66 patients with Lynch syndrome and MSI-H or -intermediate (MSI-I) tumors, 33 had malignancies other than colorectal and endometrial cancers. In fact, 18 of the 33 patients had tumors that did not meet the current testing criteria for Lynch syndrome.

Alicia Latham Schwark, MD

Alicia Latham Schwark, MD

“MSI-H is predictive of Lynch syndrome across tumor types and suggests a more heterogeneous phenotype than previously expected,” said Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center (MSK), New York, the study’s senior author. The first author was Alicia Latham Schwark, MD, also of MSK.

“Lynch syndrome was recognized in tumors rarely or not previously associated with Lynch syndrome, including prostate cancer, sarcoma, mesothelioma, adrenocortical carcinoma, and even in a young patient with an ovarian germ cell tumors,” Dr. Stadler said at a press briefing during the 2018 ASCO Annual Meeting.

Dr. Stadler, and other specialists who commented on the findings, agreed on the need to look for MSI-H status and to suspect Lynch syndrome among a broader population than is currently done. “If there is a finding of MSI-H, our data clearly support those patients getting germline genetic testing for Lynch syndrome,” Dr. Stadler told The ASCO Post. “While MSI testing has historically been limited to colorectal and endometrial cancers, the emergence of immunotherapy for advanced MSI-H solid tumors has led to an increase in MSI testing across all tumor types.”

Study Details

The aim of the study was to assess the distribution of germline mutations diagnostic of Lynch syndrome across tumor types and according to MSI status. To do so, Dr. Stadler and her team analyzed 15,045 tumor samples collected from patients with more than 50 different types of cancer using MSK-IMACT, a next-generation sequencing platform. MSI status was determined and scored as stable, intermediate (MSI-I), or high (MSI-H), and patients were also assessed for germline mutations in the DNA mismatch–repair genes: MLH1, MSH2, MSH6, PMS2, and EPCAM. Germline mutations within these genes are indicative of Lynch syndrome.

Of the 15,045 tumors that were tested, 93.2% were microsatellite--stable, 4.6% were MSI-I, and 2.2% were MSI-H. Germline mutations indicative of Lynch syndrome were identified in 0.3% of microsatellite-stable tumors, 1.9% of MSI-I tumors, and 16.3% of MSI-H tumors.


  • In an analysis of 15,045 tumor samples across more than 50 malignancies, MSI-H status was found in 2.2%, of whom 16% had a germline mutation indicative of Lynch syndrome.
  • About 50% of these patients had cancers other than colorectal or endometrial cancer—the malignancies that are most associated with Lynch syndrome.
  • The results suggest that if an MSI-H tumor is identified, germline testing for Lynch syndrome is indicated.

Surprisingly, 50% of patients with Lynch syndrome who had MSI-H/MSI-I tumors had cancers other than colorectal or endometrial—the two malignancies that typically raise suspicion of Lynch syndrome—and almost half these patients did not meet the clinical testing criteria for Lynch syndrome, she reported.

Among the samples, an additional 699 (4.6%) were shown to be MSI-I, and 1.9% had abnormalities that were diagnostic for Lynch syndrome. Interestingly, in the MSI-H and MSI-I subgroups combined, just half of the cancers that harbored Lynch syndrome abnormalities were colorectal or endometrial cancer.

The most common MSI-H tumors were small bowel (25%), endometrial (16%), and colorectal (14%). When MSI-I was combined with MSI-H, adrenocortical tumors topped the list (40%), followed by small bowel (30%), endometrial (23%), colorectal (16%), and gastric (10%).

“Our study suggests that an MSI-H tumor signature, regardless of tumor type and irrespective of family cancer history, should prompt germline genetic assessment for Lynch syndrome,” Dr. Stadler said. “This will increase our ability to recognize Lynch syndrome, not only in our cancer patients but also in family members who may benefit from genetic testing and undergo subsequent enhanced cancer surveillance and risk-reduction measures.” ■

DISCLOSURE: Dr. Stadler reported relevant relationships with Adverum, -Allergan, Genentech/Roche, Optos, and Regeneron. Dr. Schwark reported no conflicts of interest.


1. Schwark AL, Srinivasan P, Kemel Y, et al: Pan-cancer microsatellite instability to predict for presence of Lynch syndrome. 2018 ASCO Annual Meeting. Abstract LBA1509. Presented June 4, 2018.

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