Profiling tumor characteristics and outcomes in colorectal cancers (CRC) from carriers of the recessive MUTYH founders (G396D/Y179C) and the low-penetrance APC founder APC-I1307K.

32 Background: The clinical significance of CRC risk imparted by prevalent recessive variants MUTYH-G396D and Y179C (Caucasian carrier rate 1/50) and the low-penetrance APC-I1307K variant (Ashkenazi Jewish carrier rate ~1/15) is debated. Evidence supporting differential mutational spectrum, immune biology, and clinical outcomes in tumors that arise in carriers could lend support to their relevance. Here, we compare CRC tumor characteristics and survival of MUTYH-G396D/Y179C and APC-I1307K carriers to pts w/MUTYH or APC wild-type (WT) tumors. Methods: Retrospective review of CRC pt samples (n = 38,622) submitted to a CLIA-certified laboratory (Caris Life Sciences) for NGS of DNA (592-gene or whole exome) and RNA (whole transcriptome). Deficient mismatch repair/microsatellite instability (dMMR/MSI-H) was assessed by IHC/NGS. PD-L1 expression was tested by IHC (SP142; positive (+): ³2+, ³%5). Presumed monoallelic (mMut) and biallelic mutations (bMut) included those with or without, respectively, a second-hit mutation or variant allele frequency ³60%. Statistical significance determined by Fisher’s-Exact/Mann Whitney/X 2 tests. Real-world overall survival was obtained from insurance claims data, w/Kaplan-Meier estimates used for comparison. Results: MUTYH-G396D/Y179C (296 mMut, 88 bMut) and APC-I1307K (23 mMut, 133 bMut) alterations were identified. MUTYH bMut was more frequently TMB-High (³ 10 mutations/Mb: 29.1% vs mLOF 11.6%, p