Specific Mutations in APC, with Prognostic Implications in Metastatic Colorectal Cancer

Abstract

Purpose Loss-of-function mutations in the adenomatous polyposis coli (<i>APC</i>) gene are common in metastatic colorectal cancer (mCRC). However, the characteristic of <i>APC</i> specific mutations in mCRC is poorly understood. Here, we explored the clinical and molecular characteristics of N-terminal and C-terminal side APC mutations in Chinese patients with mCRC.Materials and Methods Hybrid capture-based next-generation sequencing was performed on tumor tissues from 275 mCRC pati-ents to detect mutations in 639 tumor-associated genes. The prognostic value and gene-pathway difference between <i>APC</i> specific mutations in mCRC patients were analyzed.Results APC mutations were highly clustered, accounting for 73% of all mCRC patients, and most of them were truncating mutations. The tumor mutation burden of the N-terminal side <i>APC</i> mutations group (n=76) was significantly lower than that of the C-terminal side group (n=123) (p < 0.001), further confirmed by the public database. Survival analysis showed that mCRC patients with N-terminus side <i>APC</i> mutations had longer overall survival than C-terminus side. Tumor gene pathway analysis showed that gene mutations in the RTK/RAS, Wnt and transforming growth factor β signaling pathways of the C-terminal group were significantly higher than those of the N-terminal group (p < 0.05). Additionally, <i>KRAS, AMER1, TGFBR2,</i> and <i>ARID1A</i> driver mutations were more common in patients with C-terminal side <i>APC</i> mutations.Conclusion <i>APC</i> specific mutations have potential function as mCRC prognostic biomarkers. There are obvious differences in the gene mutation patterns between the C-terminus and N-terminus APC mutations group, which may have certain guiding significance for the subsequent precise treatment of mCRC.