The landscape of somatic mutation in sporadic Chinese colorectal cancer

Abstract

Colorectal cancer is the fifth prevalent cancer in China. Nevertheless, a large-scale characterization of Chinese colorectal cancer mutation spectrum has not been carried out. In this study, we have performed whole exome-sequencing analysis of 98 patients’ tumor samples with matched pairs of normal colon tissues using Illumina and Complete Genomics high-throughput sequencing platforms. Canonical CRC somatic gene mutations with high prevalence (>10%) have been verified, including TP53, APC, KRAS, SMAD4, FBXW7 and PIK3CA. PEG3 is identified as a novel frequently mutated gene (10.6%). APC and Wnt signaling exhibit significantly lower mutation frequencies than those in TCGA data. Analysis with clinical characteristics indicates that APC gene and Wnt signaling display lower mutation rate in lymph node positive cancer than negative ones, which are not observed in TCGA data. APC gene and Wnt signaling are considered as the key molecule and pathway for colorectal cancer initiation, and these findings greatly undermine their importance in tumor progression for Chinese patients. Taken together, the application of next-generation sequencing has led to the determination of novel somatic mutations and alternative disease mechanisms in colorectal cancer progression, which may be useful for understanding disease mechanism and personalizing treatment for Chinese patients.

Clonal Evolution and Timing of Metastatic Colorectal Cancer

“…Recurrent driver mutations in the cohort were found encompassing cancer genes with known roles in CRC [ 24 , 25 ], such as APC (MIM: 611731; 53.3%, 16/30 cases), TP53 (MIM: 191170; 53.3%, 16/30 cases), KRAS (MIM: 190070; 46.7%, 14/30 cases), SMAD4 (MIM: 600993; 20%, 6/30 cases), PIK3CA (MIM: 171834; 10%, 3/30 cases), and SMAD2 (MIM: 601366; 6.7%, 2/30 cases), consistent with previous reports [ 26 , 27 , 28 , 29 ]. High concordance in driver genes was observed between primary CRC and metastatic tumours, in agreement with previous reporting [ 30 ]; of which, 88% of shared (between the primary tumour and corresponding metastatic lesions) driver mutations were clonal.…”

The somatic mutation landscape of Chinese Colorectal Cancer

“…We categorized 63 Chinese CRC cases into three groups based on mutation rates combining with MMR genes and HR genes. The mutation rates in our study were around 60/Mb for each sample, which were much higher than previous Western and Chinese CRC [6][7][8][9][10][11][12][13] . According to gene mutation frequency, the top mutant genes were not APC or TP53, but HYDIN, FLG, FCGBP, MUC16, MUC12, MUC5B, OBSCN, PDE4DIP, TNXB and ADAMTS7.…”

Recurrent Neoantigens in Colorectal Cancer as Potential Immunotherapy Targets

“…Neoantigen-based immunotherapy is complementary to ICIs since it has no specific requirement for patient's MSI status nor tumor mutation burden (TMB). Current studies on CRC genomics mainly focus on the dissection of tumor occurrence and metastasis mechanisms, and rarely analyze into tumor-specific neoantigens [6][7][8][9][10][11]. By integrating the mutation data of already existing CRC cohorts and combining the common HLA genotypes in this population [12,13], our study is expected to find the common neoantigens in CRC patients and facilitate further development of off-the-shelf neoantigen-based immunotherapy.…”