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.

Abstract

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<0.001; WT 10.3%, p<0.001) and less frequently dMMR/MSI-H (1.3% vs mLOF 9.7%, p=0.018; WT 7.8%, p=0.036). CMS2 (34.1%) and CMS4 (31.7%) were the most common subtypes in MUTYH bMut, w/similar distributions in mMut (p=0.52) and WT (p=0.84). COSMIC signatures SBS18 (damage by reactive oxygen species) and SBS36 (defective base excision repair) were highly enriched in MUTYH bMut (21% and 17%, respectively, vs 6% and 1% in mMut, and 2% and <1% in WT). APC bMut tumors were less frequently TMB-H (10.1% vs mLOF 13.0%, p=0.67; WT 18.0%, p=0.019), dMMR/MSI-H (6.4% vs mLOF 10.5%, p=0.50; WT 18.7%, p=0.002), and PD-L1+ (4.1% vs mLOF 13.6%, p=0.072; WT 9.6%, p=0.041). APC bMut were enriched with the canonical CMS2 subtype (36.3% vs 18.8% mMut, p=0.17; WT 9.8%, p<0.001) and less frequently CMS1 subtype (9.9% vs 31.3%, p=0.19; WT 37.1%, p<0.001). No SBS signatures were enriched in APC bMut. In pMMR/MSS CRC, MUTYH bMut was associated with similar prognosis as mMut and WT (median OS: 29.3 vs 32.0 and 28.2 months, p=0.57), while the prognosis of APC bMut was superior to mMut WT tumors (median OS: 40.5 vs 34.2 and 21.1 months, p<0.001). Conclusions: The APC-I13017K variant may positively impact prognosis in pts with pMMR/MSS tumors. Tumor differences derived from distinct molecular signatures in MUTYH bMut and APC bMut warrant further investigation as CRC treatment targets.