Comprehensive assessment of genomic heterogeneity, coalterations, and outcomes of patients with colorectal cancer: An AACR GENIE project analysis.

Abstract

Colorectal cancer remains a leading cause of cancer mortality in the United States and can be characterized by racial and sex-based disparities. The objective of the current study was to characterize the genomic heterogeneity of colorectal cancer among diverse demographic groups, assess coalteration patterns and their impact on long-term outcomes among patients with colorectal cancer. Data from the American Association for Cancer Research GENIE registry were analyzed to assess genomic alterations in colorectal cancer. The cohort included 20,542 samples from 19,542 patients, stratified by race or ethnicity, sex, and age of onset (<50 years for early-onset colorectal cancer). Genomic alterations and coalterations among the 48 most prevalent loci were evaluated for any association with overall survival in an external Memorial Sloan Kettering Cancer Center cohort. Among 19,542 patients, KRAS mutations were more prevalent among Black patients (57.1%) compared with White (41.8%) and Asian (43.4%) patients (P < .001), whereas TP53 alterations were more frequent among Asian (75.6%) than White (69.9%) or Black (71.9%) patients (P < .001). Coalterations with KRAS were associated with improved survival over KRAS alteration alone, a pattern less-frequently observed among Black patients. Sex-based differences were also observed, with BRAF mutations more prevalent among females (14.6% vs 9.7%; P < .001) and TP53 mutations more common among males (73% vs 70.5%;P = .009). Although KRAS alterations tended to co-occur with alterations in ATM, ARID1A, CREBBP, FAT1, KMT2B, and KMT2D genes among patients with "early onset" colorectal cancer (all p & q < 0.05), alterations of these gene pairs were mutually exclusive among individuals with late onset colorectal cancer. Genomic alterations and coalteration patterns varied relative to race/ethnicity, sex, and age at disease onset. Differences in genomic alteration patterns of colorectal cancer somatic tumor cells are an important consideration to help address disparities among different demographic groups.