Clinicopathogenomic analysis of mismatch repair proficient colorectal adenocarcinoma uncovers novel prognostic subgroups with differing patterns of genetic evolution

Abstract

Cancer somatic genetic evolution is a direct contributor to heterogeneity at the clonal and molecular level in colorectal adenocarcinoma (COAD). We sought to determine the extent to which genetic evolution may be detected in COAD in routinely obtained single clinical specimens and establish clinical significance with regard to clinicopathologic and outcome data. 123 cases of routinely collected mismatch repair proficient COAD was sequenced on the Illumina Truseq Amplicon assay. Measures of intratumoral heterogeneity were assessed and the preferential timing of mutational events was assessed and compared to clinicopathologic data. Survival subanalysis was performed on 55 cases. Patient age (p=0.013) and specimen percent tumor (p=0.033) was associated with clonal diversity, and biopsy (p=0.044) and metastasis (p=0.044) returned fewer mutations per case. APC and TP53 mutations preferentially occurred early while alterations in FBXW7, FLT3, SMAD4, GNAS, and PTEN preferentially occurred as late events. Temporal heterogeneity was evident in KRAS and PIK3CA mutations. Hierarchical clustering revealed a TP53 mutant subtype and a MAPK-PIK3CA subtype with differing patterns of late mutational events. Survival subanalysis showed a decreased median progression free survival for the MAPK-PIK3CA subtype (8 months vs. 13 months; univariate logrank p=0.0380, cox model p= 0.018). Neoadjuvant therapy associated mutations were found for ERBB2 (p=0.0481) and FBXW7 (p=0.015). Our data indicate novel molecular subtypes of mismatch repair proficient COAD display differing patterns of genetic evolution which correlate with clinical outcomes. Furthermore, we report treatment acquired and/or selected mutations in ERBB2 and FBXW7. This article is protected by copyright. All rights reserved.

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