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Prevalence of Lynch Syndrome in Solid Tumors According to Microsatellite Instability Status

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Key Points

  • Half of patients with Lynch syndrome had tumors other than CRC or endometrial cancer.
  • Of these, nearly half did not meet Lynch syndrome genetic testing criteria.

In a study reported in the Journal of Clinical Oncology, Latham et al found that microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) is predictive of Lynch syndrome across a greater than heretofore recognized breadth of the solid tumor spectrum.

As noted by the investigators, MSI/MMR-D testing has been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome–associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors supports testing for MSI in all advanced solid tumors. The investigators therefore attempted to determine the extent to which Lynch syndrome accounts for MSI-H across heterogeneous tumor types.

Study Details

The study involved data from 15,045 patients with cancer, including > 50 cancer types, at Memorial Sloan Kettering Cancer Center. MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate (MSI-I), or microsatellite-stable. Matched germline DNA was assessed for mutations in Lynch syndrome–associated mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). Immunohistochemical staining for MMR-D was performed in patients with Lynch syndrome with MSI-H/I tumors.

Prevalence of Lynch Syndrome Across Tumors

Among the 15,045 patients, Lynch syndrome was identified in 53 (16.3%) of 326 with MSI-H, 13 (1.9%) of 699 with MSI-I, and 37 (0.3%) of 14,020 patients with microsatellite-stable tumors (P < .001). Among the 66 patients with Lynch syndrome with MSI-H/I tumors, 33 (50%) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. Among the 33 with non-CRC/EC tumors, 15 (45%) did not meet Lynch syndrome genetic testing criteria on the basis of personal/family history. MMR-D status was found on immunohistochemical staining of Lynch syndrome–positive MSI-H/I tumors in 56 (98.2%) of 57 of available cases.

The investigators concluded, “MSI-H/MMR-D is predictive of [Lynch syndrome] across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for [Lynch syndrome] for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.”

The study was funded by the Romeo Milio Lynch Syndrome Foundation, Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Robert and Kate Niehaus Center for Inherited Cancer Genomics, Fieldstone Family Fund, a Stand Up to Cancer Colorectal Cancer Dream Team Translational Research grant, American Association for Cancer Research, and National Cancer Institute.

Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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