Lynch Syndrome More Prevalent Than Previously Thought

Microsatellite instability and or mismatch repair deficiency found predictive of LS across a broader tumor spectrum than previously thought.

Microsatellite instability (MSI) and or mismatch repair deficiency (MMR-D) was predictive of hereditary Lynch syndrome (LS) across a broader spectrum of solid tumors than previously thought, according to a recent study. Traditionally associated with colorectal cancer or endometrial cancer, the study found that half of patients with MSI-high or -intermediate tumors had cancers other than colorectal or endometrial.

“The FDA’s recent tissue site-agnostic approval of pembrolizumab for advanced MSI-H/MMR-D solid tumors and the increasing availability of tumor NGS platforms that simultaneously report MSI status are expected to increase routine MSI testing across a broad spectrum of cancers,” wrote Alicia Latham Schwark, MD, of Memorial Sloan Kettering Cancer Center and colleagues. “Our results support that all MSI-H/MMR-D tumors should undergo germline assessment for LS, with cascade testing of at-risk relatives, given clinical implications for increased cancer surveillance and potential risk-reducing surgeries that may be warranted.”

The study used next-generation sequencing via MSK-IMPACT to classify tumors as MSI-high (2.2%), MSI-intermediate (4.6%), or microsatellite stable (93.2%) in 15,045 patients with more than 50 cancer types. In addition, the researchers used matched germline DNA to look for mutations in Lynch syndrome-associated mismatch repair genes. The data were presented at the 2018 ASCO Annual Meeting and published in Journal of Clinical Oncology.

Of the included patients, Lynch Syndrome was found in 16.3% of tumors with MSI-high status, 1.9% with MSI-intermediate status, and 0.3% in microsatellite stable tumors (P < .001). Among patients with MSI-high tumors, 50% had a tumor type other than colorectal or endometrial. Germline MMR mutations were found in people with MSI-high or -intermediate mesothelioma, melanoma, soft tissue sarcoma, adrenocortical, prostate, pancreatic, small bowel, glioma, and ovarian germ cell tumors. Lynch syndrome was not found in the 6.3% of MSI-high or -intermediate breast tumors, or in an ovarian tumors.

About one-fourth of patients identified as having Lynch syndrome had a history of a prior malignancy.

The researchers noted that although most patients found to have Lynch syndrome had MSI-high/intermediate tumors, 36% had microsatellite stable tumors, the majority of which were not colorectal or endometrial cancers.

“We considered that these patients harbored mutations in the lower-penetrance MMR genes, they had low tumor purity that confounds the ability to detect MSI, or tumors were driven by mechanisms other than the MMR mutations,” the researchers wrote. “Indeed, although 71.2% (47 of 66) of germline

mutations in the Lynch syndrome-positive MSI-H/I tumors were in MLH1, MSH2, or EPCAM, 78.4% (29 of 37) of germline mutations in the LS-positive MSS tumors were in the lower-penetrance PMS2 or MSH6 genes.”

The researchers also noted that of the patients identified as having Lynch syndrome, almost half (45%) did not meet the clinical criteria for Lynch syndrome genetic testing on the basis of their personal or family history.

“This study establishes the prevalence of LS in a pan-cancer analysis on the basis of MSI status and demonstrates that once an MSI-H/MMR-D tumor phenotype is established, germline genetic assessment for LS is necessary, regardless of tumor type and family history,” the researchers wrote.

Commenting on the results of the study, Albert de la Chapelle, MD, PhD, distinguished university professor in the human cancer genetics program at the Comprehensive Cancer Center at The Ohio State University, told Cancer Network,

"The paper in the Journal of Clinical Oncology is the result of a study of 15,045 patients, conducted by Zsofia Stadler and colleagues at the Memorial Sloan Kettering Cancer Center in New York. The answer to the above question is, yes, indeed microsatellite instability occurs in subsets of almost all solid cancers. The identification of individuals at risk is straightforward as outlined in the paper." 

"It is a bit too early to assess how well patients with cancer in the different organs will respond. However, already it seems that testing for Lynch syndrome or variants thereof may be called for in most cancers. We shall soon know more because numerous clinical trials are underway. So far this sounds like a major success story," said Chapelle.

Half of diagnosed cases occurred in non-colorectal or endometrial cancers.