Age-associated mutations in RAS-mutated versus RAS-nonmutated metastatic colorectal cancer.

Abstract

171 Background: Mutational profiling is recommended for selecting targeted therapy for metastatic colorectal cancer (mCRC). Evidence suggests that among patients with mutations in one of three RAS genes who underwent resection of liver metastasis, those with early onset mCRC had worse outcomes compared to those with late onset mCRC. The goal of this study was to explore whether other mutated genes in mCRC exhibit an association between age and wild type versus mutant RAS status. Methods: Between October 2018 and October 2020, 974 tumor samples from patients with mCRC were identified. Samples meeting requirements were profiled with the Oncotype MAP Pan-Cancer Tissue test, which sequences 257 genes from tumor tissue, including all 3 RAS genes ( HRAS, KRAS, NRAS). Using the Oncotype MAP assay, single base variants, indels, copy number alterations and structural variants/fusions were identified. Tumor mutational burden (TMB) and microsatellite instability (MSI) were also determined. To identify genes for which there was an association between age group (patients ≤50 years vs >50 years) and RAS status we used Fisher’s Exact Test. Results: Of the 974 samples, 840 met minimum tumor tissue requirements for DNA sequencing (3mm2 and 15% tumor cellularity). Of these, 759 samples were successfully sequenced for NGS. Median turnaround time from the date of sample accessioning to the date of laboratory report was 5 days (interquartile range, IQR, 4-6 days). TMB varied from 0-227 mutations per megabase (median 6, IQR 4-8), and was high (≥10 mut/Mb) in 117 samples (15%). Of 775 specimens processed for MSI, 714 could be measured and approximately 7% were MSI-high. A total of 496 RAS variants were identified, of which 391 were pathogenic, likely pathogenic, or variants of unknown significance (349 KRAS, 34 NRAS, 8 HRAS). Of the 27 genes with at least 78 mutations in the data set, there was an association between RAS status and patient age for mutations at SMAD4, ABCC1, and RICTOR (Fisher’s Exact test, P < 0.05). For all three, mutations at these genes are relatively more prevalent in samples from young RAS wild type patients compared to young RAS mutant patients (Table). Conclusions: The Oncotype MAP Pan-Cancer Tissue test identified numerous genomic changes in mCRC samples. There appears to be an association between age group and RAS status for three mutated genes, SMAD4, ABCC1, and RICTOR. The clinical implication is unclear and warrants further investigation with outcomes data.[Table: see text]