Prevalence and clinical characterization of MMR-D/MSI extra-colonic cancers among germline PMS2 mutation carriers.

Abstract

1527 Background: PMS2-associated Lynch syndrome (LS) may have a more modest phenotype than that associated with other mismatch repair (MMR) genes ( MLH1, MSH2, MSH6, EPCAM). Recent studies suggest limited extra-colonic cancers, and modified risk-reducing measures can be provided. Understanding the spectrum of risk is of critical importance as some LS-associated cancers do not have effective screening, requiring risk-reducing surgery (endometrial, ovarian). As MMR-deficiency (MMRD)/ microsatellite instability (MSI) is associated with LS pan-cancer, we sought to characterize PMS2-associated malignancies according to MMR/MSI status. Methods: Review of cancer patients (pts) consented to an IRB-approved protocol of tumor/germline next-generation sequencing (NGS) identified 43 germline heterozygous PMS2 mutation carriers. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via immunohistochemical staining (IHC). Clinical variables were correlated with MMR/MSI status, comparing via Chi-square or standard T-test. Results: There were > 10 tumor types; 69.8% (30/43) were extra-colonic cancers (endometrial (n = 4), ovarian (n = 6), small bowel (n = 3), urothelial (n = 2), pancreas (n = 3), prostate (n = 3), breast (n = 3), brain (n = 3), biliary (n = 1), spindle cell sarcoma (n = 1), and hepatoblastoma (n = 1)). 46.5% (20/43) of tumors were MMRD/MSI. 61.5% (8/13) of colorectal cancers (CRC) were MMRD/MSI, compared to 40% (12/30) of extra-colonic tumors. All endometrial and small bowel cancers were MMRD/MSI. Of 6 ovarian cancers, 3 were clear-cell, 1 endometrioid, and 2 high-grade serous (HGS). The only MMRD/MSI ovary tumor was HGS. 73.9% (17/23) of pts with MMRP/MSS tumors had recurrent/metastatic disease vs 30% (6/20) of pts with MMRD/MSI tumors ( p= 0.004). Mean age at diagnosis did not differ significantly between MMRP/MSS and MMRD/MSI groups (49 vs. 57, respectively, p= 0.146). 11.6% (5/43) of pts had a prior cancer, with only one patient having prior CRC. Pts with extra-colonic tumors were less likely to meet clinical pt and family history LS testing criteria than those with CRC (63.3% (19/30) vs. 7.7% (1/13); p< 0.001). Conclusions: While PMS2-related LS may have a more modest clinical phenotype, in this single-institution study, 60% (12/20) of patients with MMRD/MSI tumors presented with extra-colonic cancers. We caution counseling pts with PMS2-associated LS about reduced extra-colonic risk until more complete information about penetrance, spectrum, and age distribution of cancer is available.