Abstract A005: Genomic profiling identifies differences in the distribution of APC mutations in non-Hispanic black and non-Hispanic white patients with colorectal cancer

Abstract

Abstract Intro: We compared molecular profiles of a large cohort of colorectal cancer patients treated at a single tertiary center to better understand the role of genomic factors for explaining differences in clinical outcomes of non-Hispanic black (NHB) vs. non-Hispanic white (NHW) patients. Methods: We analyzed targeted DNA sequencing data from 4,322 colorectal adenocarcinoma patients treated at Memorial Sloan Kettering Cancer Center, including 366 patients self-identified as NHB and 3,956 patients who self-identified as NHW. Tumors were sequenced using the MSK-IMPACT assay, a targeted sequencing platform that identifies somatic mutations, copy number changes, and gene fusions in a selected panel of 341-505 genes in tumor tissue compared to a matched normal blood sample. Genetic ancestry was estimated using reference populations from the 1000 Genomes Project, including European (EUR), African (AFR), East Asian (EAS), South Asian (SAS), and Native American (NAM). Patients were assigned specific ancestry labels when the corresponding ancestry fraction was above 80%. Results: Self-reported race and genetic ancestry were highly concordant, with 225/235, 95.7% of AFR patients self-reporting as NHB and 3215/3216, 99.96% of EUR patients self-reporting as NHW. While tumors from AFR patients were more often located in the right colon (43.27% vs. 30.56%, p<0.001), they were also found to be less frequently microsatellite-instable (MSI) when compared to tumors from EUR patients (5.96% vs. 11.1%, p=0.026). Among right-sided cases, MSI tumors accounted only for 7.8% of AFR patients vs. 26.4% in EUR cases (p<0.0001). Among MSS cases, tumors from AFR patients had a higher frequency of KRAS (59.1% vs. 44.7%, p<0.0001) and SMAD2 (7.72% vs. 3.59%, p=0.006) mutations, as well as a lower frequency of BRAF mutations (3.18% vs. 7.22%, p=0.019). While the frequency of APC mutations was similar in both groups (77.45% vs. 72.98%, p=0.147), APC mutations in tumors from AFR patients were more frequently located within the C-terminal part of the protein (i.e., beyond the first 1400 amino acids), both when all tumors were analyzed together (50.0% vs. 38.5%, p=0.003) and when the analysis was restricted to non-hypermutated, microsatellite-stable (MSS) cases (48.0% vs. 35.5%, p=0.001). This higher frequency of C-terminal side mutations was also seen in self-reported Black/African American MSS colorectal cancer patients from AACR Project GENIE (58.9% vs 41.3%, p < 0.001) and The Cancer Genome Atlas (61.1% vs 40%, p = 0.026). This type of distal APC mutations, which are considered “weak activators” of Wnt signaling, have been linked to more aggressive tumors due to concurrent activation of alternative mitogenic pathways such as ERK or PI3K. Conclusion: Some of the genomic differences between NHB and NHW patients that we had previously identified based on self-reported race were confirmed using analyses of genetic ancestry. We also present preliminary data demonstrating racial differences in the distribution of inactivating somatic mutations within the APC gene. Citation Format: Henry Walch, Anisha Luthra, Walid Chatila, Kanika Arora, Samantha Chin, Michele Waters, Jesse J. Smith, Nikolaus Schultz, Michael F. Berger, Karuna Ganesh, Julio Garcia-Aguilar, Rona Yaeger, Francisco Sanchez-Vega. Genomic profiling identifies differences in the distribution of APC mutations in non-Hispanic black and non-Hispanic white patients with colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A005.