Regulatory Network Analysis of Mutated Genes Based on Multi-Omics Data Reveals the Exclusive Features in Tumor Immune Microenvironment Between Left-Sided and Right-Sided Colon Cancer.

Shujing Ni,Jiaying Mi,Jianjiong Li,Qi Liao,Tianfei Yi,Xiaoxiang Fan,Yanguo Li,Yang Xi,Yuwei Zhang,Lvjun Cen,Derry Minyao Ng,Yangyang Xie,Hao Rong,Xiaoyu Dai,Chen Chen,Meng Ye,Guofang Zhao,Leyi Chen,Shiyun Hu

doi:10.3389/fonc.2021.685515

Abstract

Left-sided colon cancer (LCC) and right-sided colon cancer (RCC) have distinct characteristics in tumor immune microenvironment (TIME). Although existing studies have shown a strong association between gene mutations and TIME, whether the regulatory mechanisms between gene mutations and TIME are different between RCC and LCC is still unclear. In this study, we showed the fractions of CD8+ T cells were higher while those of regulatory T cells were lower in RCC. Besides, a stronger association between gene mutations and TIME was observed in RCC. Specifically, using multi-omics data, we demonstrated the mutations of most top mutated genes (TMGs) including BRAF, PCLO, MUC16, LRP2, ANK3, KMT2D, RYR2 made great contributions to elevated fraction of immune cells by up-regulating immune-related genes directly or indirectly through miRNA and DNA methylation, whereas the effects of APC, TP53 and KRAS mutations on TIME were reversed in RCC. Remarkably, we found the expression levels of several immune checkpoint molecules such as PD-1 and LAG3 were correlated with corresponding DNA methylation levels, which were associated with the mutations of TMGs in RCC. In contrast, the associations between gene mutations and TIME were less significant in LCC. Besides, survival analyses showed APC mutation had adverse impact on immunotherapy while patients with BRAF mutation were more suitable for immunotherapy in colon cancer. We hope that our results will provide a deeper insight into the sophisticated mechanism underlying the regulation between mutations and TIME, and thus boost the discovery of differential immunotherapeutic strategies for RCC and LCC.

Highlights

Colon cancer (CC) is the third leading cause of cancer and the second most common cause of cancer-related deaths worldwide [1]
Primary tumors located in the appendix to the transverse colon are defined as rightsided colon cancer (RCC), whereas tumors located from the splenic flexure to the sigmoid colon are categorized as left-sided colon cancer (LCC). 1134 CC patients with gene mutations were selected from the cBioPortal database, in which 1085 patients with prognosis and location information were used for survival analysis
We analyzed the associations between the location and other kinds of molecular subtype including microsatellite instability (MSI), chromosomal instability (CIN), and CpG island methylator phenotype (CIMP) which are classified based on their distinct genomic and molecular characteristics

Summary

Introduction

Colon cancer (CC) is the third leading cause of cancer and the second most common cause of cancer-related deaths worldwide [1]. Patients with CC are still faced with a high risk of disease recurrence, leading to a major cause of CC mortality [2]. The colon develops from two separate embryonic sections of primitive gut: the midgut, which develops into the cecum, ascending colon, hepatic flexure and proximal two-thirds of transverse colon, is defined as the right (proximal) colon; and the hindgut, which gives rise to the distal third of the transverse colon, splenic flexure, descending colon and sigmoid colon, and is defined as the left (distal) colon [3]. The preferred metastasis sites differ between patients with LCC and RCC too. LCC patients are prone to have liver and lung metastasis, while RCC patients tend to have peritoneal carcinomatosis [6]

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