Mutation burden and other molecular markers of prognosis in colorectal cancer treated with curative intent: results from the QUASAR 2 clinical trial and an Australian community-based series

摘要: Summary Background Molecular indicators of colorectal cancer prognosis have been assessed in several studies, but most analyses restricted to a handful markers. We aimed identify prognostic biomarkers for by sequencing panels multiple driver genes. Methods In stage II or III cancers from the QUASAR 2 open-label randomised phase 3 clinical trial and an Australian community-based series, we used targeted next-generation 82 113 genes, respectively, including main drivers. investigated molecular pathways tumorigenesis, analysed individual gene mutations, combinations global measures such as microsatellite instability (MSI) mutation burden (total number non-synonymous mutations coding indels) associations with relapse-free survival univariable multivariable models, principally Cox proportional hazards models. Findings (511 tumours), TP53, KRAS, BRAF , GNAS were independently associated shorter (p POLE mutant tumours. extended analysis 1732 which MSI status available, KRAS specifically poor MSI-negative cancers. MSI-positive had better than that wild-type . Mutations genes NF1 NRAS MAPK pathway co-occurred, DNA damage-response TP53 ATM mutually exclusive. compared model based on gold standard clinicopathological variables our new incorporating variables, burden, both cohort, was significantly (p=0·00004 p=0·0057, likelihood ratio test). Interpretation Multigene identified two previously unreported involving total confirmed Even modest-sized panel can provide important information use practice outperform MSI-based Funding UK Technology Strategy Board, National Institute Health Research Oxford Biomedical Centre, Cancer Australia Project, Council Victoria, Ludwig Research, Victorian Government.