Microsatellite Instability Status Links to Lynch Syndrome in Broad Array of Cancers

Zsofia Kinga Stadler, MD

Microsatellite instability-high (MSI-H) tumors are more likely to be associated with the presence of Lynch syndrome, which, in turn, means that all patients with MSI-H tumors should be tested for the hereditary condition. Yet, 45% of patients with cancers not typically identified with Lynch syndrome actually qualified for germline genetic testing criteria, according to large genomic study results presented at the 2018 ASCO Annual Meeting.

MSI is a genomic marker that indicates a defect in a tumor cell’s ability to repair damaged DNA, which results in the accumulation of mutations, and in turn, is a hallmark of Lynch syndrome—associated cancers. Lynch syndromewhich accounts for approximately 3% of all colorectal and endometrial cancersis an autosomal dominant inherited cancer predisposition syndrome caused by germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2, and EPCAM.

MSI testing is recommended for patients with colorectal and endometrial cancers as an initial screening test to identify whether they are at risk for having Lynch syndrome; however, the characterization of Lynch syndrome across heterogeneous MSI-H and MMR-deficient tumors is unknown.

Therefore, the researchers analyzed 15,045 tumor samples collected from patients with more than 50 different types of advanced cancer using MSI analysis with MSIsensor plus a comprehensive genomic test called MSK-IMPACT. With the sequencing platform, scores of <3, ≥3 to < 10, or ≥10 designated microsatellite stable (MSS), MSI-indeterminate (MSI-I), or MSI-H status, respectively.

“The goal of our study was to determine the prevalence of germline mutations in the DNA mismatch repair genes diagnostic of Lynch syndrome, across MSI-H tumors,” said senior study author Zsofia Kinga Stadler, MD, clinic director, Clinical Genetics Service, and medical oncologist, Memorial Sloan Kettering Cancer Center.

Overall, the majority of tumors were found to be MSS (93.2%; n = 14,020), while 4.6% (n = 699) were MSI-I, and 2.2% (n = 326) were MSI-H. Analyses identified Lynch syndrome in 0.3%, 1.9%, and 16.3% in the MSS, MSI-I, and MSI-H groups, respectively (P <.001).

MSI-H status was identified in small bowel (25%), endometrial (16%), colorectal (14%), and gastric (6%) cancers. However, nearly 50% of patients with MSI-H/MSI-I tumors who were identified as having Lynch syndrome had cancer types not previously, or rarely, linked to the syndrome, including mesothelioma (n = 165), sarcoma (n = 785), adrenocortical cancer (n = 44), melanoma (n = 573), prostate (n = 1048), and ovarian germ cell cancer (n = 348).

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

Among the patients with cancers not typically linked to Lynch syndrome, 45% did not meet germline genetic testing criteria based on family or personal cancer history. In addition, these patients had lower MSIsensor scores, and their tumors were more likely to test positive for MSI-I status (non-colorectal/endometrial cancers, 30.3% vs. colorectal/endometrial cancers 9.1%; P = .03).

Lastly, immunohistochemistry (IHC) testing was completed in 86.4% (n = 57) of MSI-I/MSI-H tumor samples for abnormal DNA repair proteins, for which MMR-deficiency was found in nearly all (98.3%) of those tumors.

Among patients with Lynch syndrome and MSS tumors, 78% had MSH6/PMS2 mutations; meanwhile 71% of patients with Lynch syndrome and MSI-H/MSI-I tumors had MLH1/MSH2/EPCAM mutations (P <.001). In addition, 89% of patients with Lynch syndrome and MSS tumors had non—MMR-deficiency signatures.

“Our study suggests that MSI-high signature, regardless of tumor type and irrespective of the family history should prompt germline genetic assessment for the evaluation of Lynch syndrome,” Stadler said. “This will result in 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 surveillance and risk reduction measures.”

ASCO expert Shannon Westin, MD, agreed, saying physicians are only testing “the tip of the iceberg patients that are affected by Lynch syndrome.”

“What we learned is that MSI not only has therapeutic implications, but also has cancer prevention implications,” she added. “And we now know that under the surface there is a larger number of patients with specific cancer types that should be tested for Lynch syndrome.”

Westin added that increased testing is not only needed, but can be easily put into practice as well. “This is a straight forward testing strategy that can be immediately implemented to impact not only the patients themselves and their risk for cancer, but also their family members,” she added. “The impact of that cannot be overstated.”

Schwark AL, Srinivasan P, Kemel Y, et al. Pan-cancer microsatellite instability to predict for presence of Lynch syndrome. J Clin Oncol. 2018;36(suppl; abstr LBA1509).

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