Genomic Profiling Reveals the Molecular Landscape of Gastrointestinal Tract Cancers in Chinese Patients

Abstract

Gastrointestinal tract cancers have high incidence and mortality in China, but their molecular characteristics have not been fully investigated. We sequenced 432 tumor samples from the colorectum, stomach, pancreas, gallbladder, and biliary tract to investigate cancer-related mutations and detail the landscape of microsatellite instability (MSI), tumor mutation burden (TMB), and chromosomal instability (CIN). We observed the highest TMB in colorectal and gastric cancers and the lowest TMB in gastrointestinal stromal tumors (GISTs). Twenty-four hyper-mutated tumors were identified only in colorectal and gastric cancers, with a significant enrichment of mutations in the polymerase genes (POLE, POLD1, and POLH) and mismatch repair (MMR) genes. Additionally, CIN preferentially occurred in colorectal and gastric cancers, while pancreatic, gallbladder, and biliary duct cancers had a much lower CIN. High CIN was correlated with a higher prevalence of malfunctions in chromosome segregation and cell cycle genes, including the copy number loss of WRN, NAT1, NF2, and BUB1B, and the copy number gain of MYC, ERBB2, EGFR, and CDK6. In addition, TP53 mutations were more abundant in high-CIN tumors, while PIK3CA mutations were more frequent in low-CIN tumors. In colorectal and gastric cancers, tumors with MSI demonstrated much fewer copy number changes than microsatellite stable (MSS) tumors. In colorectal and gastric cancers, the molecular characteristics of tumors revealed the mutational diversity between the different anatomical origins of tumors. This study provides novel insights into the molecular landscape of Chinese gastrointestinal cancers and the genetic differences between tumor locations, which could be useful for future clinical patient stratification and targeted interventions.

Keywords: chromosomal instability; colorectal cancer; gastric cancer; gastrointestinal cancers; microsatellite instability; tumor mutation load.

FIGURE 1

Somatic mutations of different GI cancers. (A) Bar graph showing the patient composition of commonly mutated genes. (B) The mutation frequency of the top mutated genes in each tumor. (C) The proportion of patients with mutations in each pathway. (D) TMB distribution of each cancer. For (B,C), pairwise comparisons were conducted between every two groups using the Fisher’s exact test. FDR was used for p-value corrections. For (D), one-way ANOVA on ranks test was used to compare all groups, and the Dunn’s test was used for post hoc analyses. *p < 0.05; ***p < 0.001.

FIGURE 2

MMR and polymerase genes showed different mutation frequencies in low-mutated and hyper-mutated tumors. (A) Somatic and germline mutations in MMR and polymerase genes. “g” represents germline mutations; *p < 0.05. (B) The lollipop plot shows the scattered amino acid changes in POLE and POLD1. (C) The mutation number of MMR and polymerase genes in each patient; ***p < 0.001.

FIGURE 3

Chromosome instability in each cancer and its association with gene alterations. (A) The distribution of CIN scores in each cancer. (B) Gene mutations and copy number changes that were significantly different between the high-CIN and low-CIN groups. For (A), the one-way ANOVA on ranks test was used to compare all groups, and the Dunn’s test was used for post hoc analyses. *p < 0.05; ***p < 0.001. For (B), pairwise comparisons were conducted between every two groups using the Fisher’s exact test. FDR was used for p-value correction.

FIGURE 4

Molecular characterization of colorectal cancer. (A) Mutation frequency comparison between our cohort and the MSKCC colorectal cancer cohort. (B) Gene alterations in the sub-groups of colorectal cancers. (C) CIN status in different sub-groups. Dunn’s multiple comparison test is used to compare CIN values between every two groups and * means p < 0.05.

FIGURE 5

Molecular characterization of gastric cancer. (A) Mutation frequency comparisons between our cohort and the MSKCC gastric cancer cohort. (B) Gene alterations in the sub-groups of colorectal cancers. (C) CIN status in different sub-groups.