Abstract 5789: A novel role of APC-partnering mutations in the sidedness of colorectal cancer survival

Left-sided colorectal cancer (CRC) tumors have been reported to be more favorably associated with better survival than right-sided tumors. A molecular basis of the laterality of prognosis, however, is still poorly understood. We have recently developed a multi-gene mutation classification system from targeted exome sequencing of 1,321 cancer-related genes on 468 CRC tumor specimens (Schell et al, Nat Commun, 2016). We found that among 17 significantly mutated genes, four (BRAF, APC, KRAS, TP53) demonstrated pairwise, statistically significant, correlations, with APC-partnering mutations playing a central role in predicting overall survival. APC might assume 0, 1, or 2 identified truncating mutations, each with a striking differential impact on survival. Tumors lacking any APC mutation carried a worse prognosis than single mutation tumors, but the triply-mutated tumors (APC, KRAS, TP53) with two APC mutations conferred substantially worse survival. Thus, we hypothesized that APC-partnering mutations might also have a significant role in the sidedness effect on CRC outcome. We carried out various Left (L) vs Right (R) survival analyses on 464 tumors that had the primary tumor location data. When individual driver mutations (BRAF, APC, KRAS, TP53) were analyzed separately, although a statistically significant association with overall survival was seen in left-sided tumors for APC mutations and BRAF (V600E) for all patients and for MSS patients, no significant survival difference was observed when each of four driver mutations was (left vs right) compared. However, when APC-partnering mutations (i.e. APC WT; APC only; APC/KRAS; APC/TP53; APC/KRAS/TP53) were analyzed, left-sided APC/KRAS tumors were found to be associated with dramatically better survival than their right-sided counterparts (HR=0.37 (0.17-0.82), logrank p=0.0078 for all patients; HR=0.059 (0.021-0.162), logrank p=0.0001 for MSS patients). Analysis of APC hit mutation (0-hit, 1-hit, 2-hit) groups reveals that left-sided APC 2-hit tumors had significantly better survival than right-sided counterparts in all patients and MSS patients. However, surprisingly, we also identified that several mutation subgroups conferred better survival in right-sided tumors than left-sided tumors. For example, APC-only mutation tumors were associated with better survival than their left-sided counterparts (logrank p=0.030) in MSS patients (n=403); Right-sided all wild-type (BRAF, APC, KRAS, TP53) tumors conferred much better survival (HR=0.12 (0.038-0.368), logrank p=0.0135) in APC WT tumors (n=35). In conclusion, our findings identified a novel role of APC-partnering mutation subgroups associated with the sidedness effect, suggesting that routine clinical APC and TP53 mutation assessment, in addition to BRAF and KRAS, may refine and improve predicting outcomes in left vs right-sided CRC patients. Citation Format: Mingli Yang, Michael Schell, Andrey Loboda, Michael Nebozhyn, W. Jack Pledger, Timothy Yeatman. A novel role of APC-partnering mutations in the sidedness of colorectal cancer survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5789.