Abstract 5364: Somatic mutations in African American and non-Hispanic White young-onset colorectal cancers

Abstract

Abstract The proportion of colorectal cancers (CRCs) diagnosed at age <50 years is two-fold higher among African-Americans (AAs) compared to non-Hispanic Whites (NHW). Additionally, despite the rising incidence of young-onset CRC, little is known about the molecular characteristics of these as only 23 young-onset tumors were profiled in the TCGA cohort. Studies of CRC diagnosed in older individuals (age >50) demonstrate that CRC tumors in AAs are more often right-sided and MMR proficient, with higher prevalence of KRAS mutations. Risk of death from CRC among AAs with MMR proficient tumors is 73% higher than for NHW, after adjusting for treatment and known prognostic factors. We analyzed archival FFPE CRC tumors diagnosed in individuals age <50 (NHW enrolled in the UM Cancer Genetics Registry N=38 and African American subjects ascertained through the Wayne State University EpiCore N=13) for somatic mutations. Mutation profiling of tumor DNA from 51 CRCs diagnosed age <50 was performed using NGS sequencing with multigene panels in 2 sets (Qiagen GeneRead Cancer panel of 124 genes [N=36 tumors], Qiagen Qiaseq Comprehensive Cancer Panel of 275 genes [15 tumors]). We observed differences in CRC somatic mutations by race and by age. There was marked heterogeneity among tumors with regard to numbers of somatic mutations, with an average of 659 (range 39-10,267) variants detected per tumor, with 19/51 (37%) tumors classified as hypermutated. Among the most frequently mutated genes in young CRC tumors were APC (98% of tumors), PIK3CA (92% of tumors), NOTCH2 (86% of tumors), PTCH1 (82%), BRCA2 (67%), BRCA1 (84%), HNF1A (100%), RAD50 (29%), POLE (27%), MSH6 (39%), and FGFR3 (39%). These mutation profiles differ markedly from those of TCGA older-onset, nonhypermutated tumors. We identified differences in somatic mutations by race, including mutations in PTEN (NHW: 21% vs. AA: 8%), TGFBR2 (NHW: 32% vs. AA: 15%), FBXW7 (NHW: 47% vs. AA: 8%), and KRAS (NHW: 45% vs. AA: 31%). The relatively high prevalence of hypermutated tumors in this racially diverse cohort highlights the critical gaps in knowledge about pathways involved in pathogenesis of young-onset CRCs and how genomic information could guide precision therapies. Citation Format: Laura S. Rozek, Tingting Qin, Erika Koeppe, Peter Ulintz, Joel K. Greenson, Michele L. Cote, Elean M. Stoffel. Somatic mutations in African American and non-Hispanic White young-onset colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5364.