Mutational analysis of clinically relevant cancer related genes in colorectal cancer.

Abstract

615 Background: Whole genome sequencing of colorectal cancer (CRC) has identified common mutations that have been implicated in tumorigenesis. We investigated the association between genetic mutations in known cancer related signaling pathways, and clinicopathological variables in patients with CRC. Methods: DNA samples of patients with CRC were genotyped for Single Nucleotide Polymorphisms (SNPs) including potentially clinically relevant mutations using the Sequenom platform. Results: Tissue from 68 patients was genotyped. 163 mutations were identified in 21 cancer related genes. 45% of patients had stage III CRC & 10% had stage IV CRC at diagnosis. 17 patients developed metastatic CRC. 59 patients had at least 1 mutation. Mutations occurring in at least 5% of patients included KRAS(35%), PIK3R1(34%), TP53(32%), PHLPP2(32%), BRAF(16%), PIK3CA(13%), APC(13%), IDH1(12%), FBXW(7%) & MET(6%). Less frequent mutations (<5%) included GNAS, PTPN, NRAS, STK11, TBX3, and EGFR. KRAS mutations were associated with mucinous histology (P=0.04). TP53 mutations were associated with nodal disease at diagnosis (p=0.03). There was no statistically significant difference in overall survival in patients with KRAS, PIK3, TP53 or BRAF mutations as compared to their wild type (WT) counterparts. No mutation was predictive of disease progression. In patients with mCRC and TP53 mutations, DFS was significantly shorter when mutations in APC, FBXW7, IDH1, MET and NRAS were present (10 months verses 15.5 months p=0.01). Mutations in APC, FBXW7, IDH1, MET and NRAS only occurred in the presence of other mutations. A trend towards reduced DFS was seen in KRAS WT patients with mCRC when mutations in APC, FBXW7, IDH1, MET and NRAS were present (9 months vs. 22 months, p=0.2). A trend towards reduced DFS was seen in patients with mCRC & 3 or more distinct mutations (10 months vs. 18 months p=0.2). Conclusions: These results suggest that mutations in known cancer related signaling pathways occur frequently in patients with CRC. Mutations in APC, FBXW7, IDH1, MET and NRAS conferred a shorter DFS in patients with mCRC &, TP53 mutations, KRAS wild type patients and patients with multiple distinct mutations