Testing Reveals Extent of Lynch Syndrome

Alicia Latham Schwark, MD

Alicia Latham Schwark, MD

The presence of Lynch syndrome (LS) correlates with microsatellite-instability (MSI) status and DNA mismatch-repair deficiency (dMMR) across a variety of tumor types, according to a prospective study of 15,045 tumor samples that were analyzed with MSK-IMPACT next-generation sequencing and MSI testing. Tumors with MSI-high (MSI-H) and MSI-indeterminate (MSI-I) scores were most commonly associated with small bowel, endometrial, colorectal, and gastric cancers, according to the findings. A high proportion of MSI-H and MSI-I tumors exhibited dMMR signatures. The results also suggest that LS-associated cancers may be more heterogeneous than previously thought.

For the study, investigators employed the multiplex panel test MSK-IMPACT, which was authorized for tumor profiling by the FDA last year. The multiplex panel incorporates MSI assessment using a bioinformatics tool called an MSI sensor. The tool generates a report that designates a score of ≥10 as MSI-H, a score between 3 and 10 as MSI-I, and scores <3 as microsatellite stable (MSS).

Lead author Alicia Latham Schwark, MD, a medical genetics fellow at Memorial Sloan Kettering Cancer Center in New York, New York, and colleagues demonstrated that among the noncolorectal/nonendometrial tumor samples, which spanned more than 50 cancer types, 50% of patients (33/66) with LS had either MSI-H or MSI-I tumors that were not previously associated with the syndrome. Findings were reported during the 2018 American Society of Clinical Oncology Annual Meeting, held June 1-5 in Chicago, Illinois.

The presence of MSI indicates a defect in the DNA mismatch repair system. It has been established that this finding is characteristic of LS-associated cancers, primarily colorectal and endometrial. Testing for MSI is routinely performed in all colorectal and endometrial cancers as an initial screening for LS. However, the prevalence of LS in other cancers has not been documented.

The study had 2 objectives: to determine the overall LS prevalence in all patients who underwent MSK-IMPACT testing, according to tumor MSI status, and to characterize germline findings into causative versus incidental through immunohistochemical (IHC) concordance rates and tumor mutational signatures across MSS, MSI-I, and MSI-H groups.

Five mismatch repair genes were assessed: MLH1, MSH2, MSH6, PMS2 (single nucleotide variations and deletion [del]/duplication), and EPCAM (del only). In patients with LS with MSI-H and MSI-I tumors, IHC staining for MMR protein expression was performed. Breast cancer made up the largest group (16%) of tumor types, followed by lung cancer (13%). Overall, colorectal and endometrial cancer tumors made up 5% and 3.5% of the group, respectively. Because of its gene type, LS is often hard to detect when it is not associated with cancer, Schwark said. When tumors are categorized by MSI status, the distributions change, Schwark said.

“Small bowel cancer had the highest rate of MSI-H tumors at 25%. This was followed by endometrial, colorectal, and gastric cancers, which were previously associated with LS. When including the indeterminate prevalence, adrenocortical had the highest rate at over 40%.” Across the 3 groups, the prevalence of LS in patients with MSI-H tumors was 16.3%, the MSI-I group had a 1.9% LS prevalence, and the prevalence of LS in patients in the MSS group was 0.3% (Figure).

“This 0.3% is in line with current general population prevalence estimates,” Schwark said. “Looking at the MSI-H cohort, 43% of patients with LS had cancers other than colorectal and endometrial.”

When reviewing the distribution of germline mismatched repair mutations by gene and MSI status, the investigators found that the majority of germline mutations in the MSI-H and MSI-I groups were MLH1 and MSH2. The majority of mutations in the MSS group were MSH6 and PMS2 (P <.001).

“This is notable, as it has been previously demonstrated that MSH6 and PMS2 are lower penetrance genes that are found more commonly in the general population, suggesting that these may be incidental findings,” Schwark said.

Tumor mutational signatures identified patients with LS. Overall, 88% of high and indeterminate tumors from patients with LS exhibited dMMR tumor signatures, while 89% of MSS tumors from patients with LS did not.

Patients with LS who had MSI high or indeterminate tumors had tumors that were likely caused by LS. In the case of MSS tumors, LS was probably not the cause, Schwark said.

Figure. Distribution of MSI Status Across Tumor Types

Schwark added that about 45% of patients with LS who had either MSI-H or MSI-I noncolorectal or nonendometrial tumors did not meet clinical criteria for genetic testing. This suggests that these types of tumors, regardless of cancer type, should prompt LS testing.

The researchers concluded that overall prevalence of LS varied significantly across the cohorts, although MSI-H tumors showed significantly greater prevalence of LS. Half of the patients with LS, with either MSI-H or MSI-I tumors, had cancers other than colorectal or endometrial. Concordant IHC indicated that their cancer was caused by their LS. The overall concordance rate for IHC and MSI-H/I, which includes not-previously LS-associated tumor types was 98% (56/57). Moreover, patients with other cancers were less likely to meet clinical testing criteria.

Schwark AL, Srinivasan P, Kemel Y, et al. Pan-cancer microsatellite instability to predict for presence of Lynch syndrome. Presented at: 2018 ASCO Annual Meeting, June 4, 2018. J Clin Oncol. 2018;36 (suppl; abstr LBA1509).