ASCO Annual Meeting

ASCO Annual Meeting

June 02, 2018
4 min read

Genomic marker linked to Lynch syndrome across cancer types

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CHICAGO — Microsatellite instability-high tumors predicted occurrence of Lynch syndrome across various cancer types, not just cancers commonly known to be associated with the disease, according to study results presented at ASCO Annual Meeting.

“Our study suggests a microsatellite instability-high tumor signature, regardless of cancer subtype and irrespective of family cancer history, should prompt germline genetic assessment for the evaluation of Lynch syndrome,” Zsofia K. Stadler, MD, medical oncologist and clinical director of Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, and senior author of the study, said during a press conference. “This will result in an increased ability to recognize Lynch syndrome not only in our cancer patients, but also in family members who may benefit from genetic testing for Lynch syndrome and subsequently enhance cancer surveillance and risk-reduction measures.”

Lynch syndrome is commonly associated with colorectal and endometrial cancers. Lynch syndrome-associated tumors are classified via high microsatellite instability (MSI-H), a genomic marker associated with a high number of mutations in the tumor.

“MSI-high is the hallmark of Lynch syndrome-associated tumors,” Stadler said. “Traditionally, MSI analysis has been performed in colorectal and endometrial cancers as screening test for Lynch syndrome. In addition to MSI-high being a marker for Lynch syndrome, more recently, MSI-high has been implicated as a marker in response to immunotherapy.”

In 2017, FDA approved pembrolizumab (Keytruda, Merck) for use in MSI-high advanced solid tumors.

“[This led] to a surge in MSI testing in metastatic cancers outside of the traditional endometrial and colon cancers assessed for Lynch syndrome,” Stadler said.

The classification of Lynch syndrome among heterogeneous MSI-H and mismatch repair-deficiency tumors was previously unknown.

Stadler and colleagues used Memorial Sloan Kettering Cancer Center’s targeted tumor sequencing test, MSK-IMPACT, to measure MSI status via MSIsensor — a C++ program for automatic detection of somatic and germline variants at microsatellite regions — in 15,045 samples from various tumor types.

Researchers classified microsatellite status as stable (MSS; 93.2%), indeterminate (MSI-I; 4.6%) or MSI-H (4.2%).

Researchers assessed germline mutations in MLH1, MSH2, MSH6, PMS2 and EPCAM, and they used immunohistochemical staining for mismatch repair deficiency and tumor characteristics among patients with Lynch syndrome.

“The goal of our study was to determine the prevalence of germline mutations in the DNA mismatched repair genes diagnostic of Lynch syndrome across all MSI-high tumors, irrespective of cancer type,” Stadler said.

Researchers identified germline mutations indicative of Lynch syndrome in 0.3% of MSS samples, 1.9% of MSI-I samples and 16.3% of MSI-H samples (P < .001).


Among the 1,025 MSI-H or MSI-I tumors, 57% with MSI-H and 23% with MSI-I had colorectal or endometrial cancers.

However, 50% of patients with Lynch syndrome had MSI-I or MSI-H tumors not common or previously associated with the syndrome, including mesothelioma, sarcoma, adrenocortical carcinoma, melanoma and ovarian germ cell tumor.

Patients with Lynch syndrome and MSI-I or MSI-H tumors that were not colorectal or endometrial cancer met testing criteria in 63.6% of cases. These patients also had lower MSI sensor scores and had a greater likelihood of MSI-I tumors than patients with colorectal or endometrial cancer (30.3% vs. 9.1%; P = .03).

Because 45% of patients with Lynch syndrome with MSI-H tumors or mismatch repair deficiency not associated with colorectal or endometrial cancers did not meet criteria for genetic testing, MSI-H/mismatch repair deficiency tumors, regardless of cancer type or family history, should prompt germline testing for the evaluation of Lynch syndrome, according to the researchers.

Researchers observed 78% of patients with Lynch syndrome and MSS tumors had MSH6 or PMS2 mutations, yet 71% of patients with MSI-I or MSI-H tumors had MLH1, MSH2 or EPCAM mutations (P < .001).

Of the patients with MSS tumors, 89% had nonmismatch repair-deficiency signatures.

“Our study supports that MSI-H is predictive of Lynch syndrome across tumor types,” Stadler said. “Our study also supports that the spectrum of cancers associated with Lynch syndrome seems to be much broader than previously thought.” – by Melinda Stevens


Schwark AL, et al. Abstract LBA1509. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.

Disclosures: Stadler reports an immediate family member has consultant/advisory roles with Adverum Biotechnologies, Allergan, Genentech/Roche, Optos and Regeneron. Please see the abstract for all other authors’ relevant financial disclosures.