Germline and somatic MUTYH mutations: Clinicopathologic and mutational analysis in a pan-cancer cohort.

10590 Background: MUTYH is a tumor suppressor gene involved in the base-excision DNA repair pathway. Biallelic pathogenic or likely pathogenic germline variants (gPV) in MUTYH are associated with MUTYH-associated polyposis (MAP), inclusive of colorectal carcinoma (CRC) and additional cancer risks. While monoallelic MUTYH gPV carriers do not have the same cancer risk as those with biallelic MAP, further work is needed to fully characterize secondary somatic events, including allelic imbalances. Methods: Using the MSK-IMPACT targeted NGS to detect both MUTYH gPVs and MUTYH somatic variants in patients (pts) with a solid tumor diagnosis, we analyzed clinicopathologic characteristics at cancer diagnosis, ancestry label as defined per cBioPortal, genomic biomarkers, as well as allele-specific copy number estimates using FACETS annotation. Results: Out of 38,907 samples with germline testing available, 587 pts with a solid tumor and presence of MUTYH gPV were identified. Of these, 15 pts had ≥2 MUTYH gPVs, including 4 pts with homozygous MUTYHgPVs (G396D, T179C, p.G480* and c.389-1G>C) and 11 pts with compound heterozygous MUTYHgPVs. In pts of European ancestry (n=403), the MUTYH G396D and T179C variants were predominant, present in 56% and 19% of cases, respectively. All patients with the R241W variant were listed as being of South Asian ancestry (n=6). Concurrent gPV in other genes were observed in 12% (n=69), with high/moderate-penetrance gPVs in 4% (n=24) including BRCA2 (n=6), BRCA1 (n=5), ATM (n=4) and PALB2 (n=3). Among all pts with MUTYH gPVs, 254/587 pts had concurrent tumor samples with FACETS results. Among pts with monoallelic MUTYH gPVs and FACETS annotation available, 24% of evaluable tumors exhibited biallelic MUTYH inactivation due to loss of heterozygosity (LOH). CRC (29% vs 13%; p=0.004) and cholangiocarcinoma (11% vs. 2%; p=0.04) were enriched in the biallelic MUTYH inactivation cohort vs. the cohort of pts with monoallelic MUTYH gPVs. Co-alterations in KRAS G12C and APC were enriched in the biallelic as compared to the monoallelic cohort (9% vs. 3%, p=0.04 and 27% vs. 12%, p=0.005, respectively). In addition, we identified 244 pts for whom FACETS annotation was available without MUTYH gPVs, but with somatic variants at MUTYH. Of these 244 pts, 117 pts had biallelic MUTYH inactivation either from homozygous deletions (n=87), somatic hit + LOH (n=27) or ≥2 somatic hits (n=3). The predominant cancer types with biallelic somatic MUTYH inactivation were breast cancer (16%), non-small cell lung cancer (14%) and CRC (11%). Conclusions: This study represents the largest cohort of pts with MUTYH gPVs and FACETS analysis on concurrent tumor samples, confirming a high prevalence of LOH in pts with monoallelic MUTYH gPVs and enrichment in KRAS G12Cin pts with MUTYH gPVs and biallelic MUTYH inactivation.