Somatic tumor profiling of DNA mismatch repair (MMR) deficient endometrial cancers (EC).

e17121 Background: Approximately 20% of EC have loss of MMR ( MSH2, MSH6, MLH1, PMS2) protein expression by immunohistochemistry (IHC). The majority have somatic MLH1/PMS2 loss, driven by MLH1 promoter hypermethylation. For the remaining patients (pts), germline testing for Lynch Syndrome (LS) is recommended. However, half do not have a corresponding germline mut. This is considered “Lynch-like syndrome” (LLS) & clinical management is challenging. We sought to determine if tumor profiling could identify somatic mut potentially underpinning loss of protein expression. Methods: Per institutional standard, all EC, regardless of age or family history undergo reflex LS screening with IHC for MMR protein expression. Pts consented to IRB approved protocols. Tumor-normal sequencing was performed via custom next-generation sequencing panel (MSK-IMPACT). Electronic medical records were reviewed. Results: 16 pt have completed tumor sequencing, median age 53 (35-83), 6 (38%) < 50 yrs at diagnosis. 2 had personal history of additional cancer (DCIS, ovary), none had first degree relative with colon or EC. A mix of EC histologies was represented: 10 endometrioid (all grades), 2 clear cell, 4 mixed. There were no serous cancers. There were median 58 mut (9-546), 14 (88%) had hyper or ultra mutated EC. 5 EC were driven by somatic POLE mut (3 known hotspot, 1 likely pathogenic), all ultra-mutated phenotype, resulting in multiple somatic MSH6 muts with isolated IHC MSH6 loss. 4 EC had MSH2/MSH6 IHC loss with corresponding double somatic mut in MSH2. 5 had one somatic mut corresponding to the MMR protein loss, assessment of LOH in these cases is pending. Two cases are unexplained: 40 yo with IHC MLH1 loss, 47mut; 69 yo, IHC MSH6 loss, 12 mut. In this cohort of LLS, somatic muts were frequently observed in ARID1A (13,81%), PTEN (10,63%) & PIK3CA(9,56%), in keeping with non serous histologies. Conclusions: In line with our prior report that pt with LLS had benign personal & family cancer histories compared with LS pts, we have identified that in 56% of LLS EC either POLE mut or double somatic MMR mut likely underpins the MMR IHC loss. As such, in these LLS EC cases, somatic tumor profiling may help to rule out LS. Further testing is ongoing to increase cohort size.