Genomic and Prognostic Heterogeneity Among RAS/BRAFV600E/TP53 Co-Mutated Resectable Colorectal Liver Metastases

Background: Hepatic resection is potentially curative for patients with colorectal liver metastases, but the treatment benefit varies. KRAS / NRAS ( RAS) / TP53 co-mutations are associated with a poor prognosis after resection, but there is large variation in patient outcome within the mutation groups, and genetic testing is currently not used to determine the likely benefit from surgery. We have investigated the potential for improved prognostic stratification by combined biomarker analysis with DNA copy number aberrations (CNAs) in a tumor heterogeneity setting. Methods We determined the mutation status of KRAS , NRAS , BRAF , and TP53 in 441 liver lesions from 171 patients treated by partial hepatectomy for metastatic colorectal cancer. CNAs were profiled in 232 tumors from 67 of the patients. Results Driver mutations in KRAS, NRAS, BRAF V600E , and TP53 , and high-level amplifications affecting cancer-critical genes such as ERBB2 and EGFR , were predominantly homogeneous within patients. RAS / BRAF V600E and TP53 co-mutations were associated with a poor patient outcome (hazard ratio, HR, 3.9, 95% confidence interval, CI, 1.3–11.1, p  = 0.012) in multivariable analyses with clinicopathological variables. The genome-wide CNA burden and intra-patient inter-metastatic CNA heterogeneity varied within both the mutated and the wild-type groups. Combined prognostic analyses of RAS / BRAF V600E / TP53 mutations and CNAs, either as a high CNA burden or high inter-metastatic CNA heterogeneity, identified patients with a particularly poor outcome (co-mutation/high CNA burden: HR 2.7, 95% CI 1.2–5.9, p  = 0.013; co-mutation/high CNA heterogeneity: HR 2.5, 95% CI 1.1–5.6, p  = 0.022). Conclusions DNA copy number profiling identified genomic and prognostic heterogeneity among patients with resectable colorectal liver metastases with co-mutated RAS / BRAF V600E / TP53 .