The somatic mutation landscape of Chinese Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the fifth leading cause of cancer-related death in China. The incidence of Chinese CRC has increased dramatically with the changes of dietary and lifestyle. However, the genetic landscape of Chinese colorectal cancer mutation is still poorly understood. In this study, we have performed whole exome-sequencing analysis of 63 CRC cases. We found that Chinese CRC were hypermutated, which were enriched in ECM-receptor interaction, antigen processing and presentation, and focal adhesion. Analysis with clinical characteristics indicated that the deficiency of CRC driver gene, FCGBP and NBPF1 conferred CRC development and was showed worse survival rates, which could be the novel regulators and, diagnostic and prognostic biomarkers for Chinese CRC. Taken together, the application of whole exome-sequencing unveiled previously unsuspected somatic mutation landscape in Chinese CRCs, which may expand the understanding of disease mechanisms and provide an alternative personalized treatment for Chinese CRC patients.

Keywords: Colorectal cancer; FCGBP; NBPF1; Whole exome-sequencing.

Figure 1

Mutation plot summary of colorectal cancer samples. (A) Variant classification. X axis indicated variant numbers. Y axis represented different variant classification. (B) Variant type. X axis indicated variant numbers. Y axis represented different variant type. (C) SNVs type. X axis indicated the ratio. Y axis represented the type of nucleotide substitution. (D) Top10 mutated genes. X axis indicated variant numbers. Y axis represented different genes. The genes were ordered by their mutation frequency.

Figure 2

Somatic mutation characteristics of Chinese CRC. A, Mutation frequencies of DNA damage response and repair genes. B, Mutation frequency in 63 Chinese CRC. C, A display of the various categories of mutations across samples is shown for SNVs (non-synonymous SNV, synonymous SNV, stopgain SNV and splicing) and InDels (non-frameshift deletion, non-frameshift insertion, frameshift deletion and frameshift insertion).

Figure 3

Mutational signatures and disease ontology in Chinese CRC. A, Three distinct mutation signatures (A-C) were extracted from Chinese CRCs and were shown according to cosine similarity, the correspondence is: Signature A and Signature 1 (age/spontaneous deamination of 5-methylcyotosine); Signature B and Signature 5 (unknown etiology; found in all cancer types); Signature C and Signature 6 (mismatch repair deficiency and microsatellite instability). B, Disease Ontology enrichment analysis for the somatic mutation genes in Chinese CRC.

Figure 4

FCGBP is a novel biomarker for CRC. A, Expression levels of FCGBP in different stages of COAD from the TCGA database. B, Expression levels of FCGBP in different stages of READ from the TCGA database. C, Expression levels of FCGBP in normal, Caucasian, African American and Asian CRC patients. D, Lower expression levels of FCGBP indicate poor survival rate in CRC patients from the TCGA database.

Figure 5

NBPF1 is a SMG and novel biomarker for CRC. A, Mutation frequencies of SMGs of Chinese CRC. B, Expression levels of NBPF1 in normal and COAD samples from the TCGA database. C, Expression levels of NBPF1 in normal and READ samples from the TCGA database. D, Lower expression levels of NBPF1 indicate poor survival rate in CRC patients from the TCGA database.