KRAS mutations are negatively correlated with immunity in colon cancer

Abstract

The heterogeneity of colon cancer tumors suggests that therapeutics targeting specific molecules may be effective in only a few patients. It is therefore necessary to explore gene mutations in colon cancer. In this study, we obtained colon cancer samples from The Cancer Genome Atlas, and the International Cancer Genome Consortium. We evaluated the landscape of somatic mutations in colon cancer and found that KRAS mutations, particularly rs121913529, were frequent and had prognostic value. Using ESTIMATE analysis, we observed that the KRAS-mutated group had higher tumor purity, lower immune score, and lower stromal score than the wild-type group. Through single-sample Gene Set Enrichment Analysis and Gene Set Enrichment Analysis, we found that KRAS mutations negatively correlated with enrichment levels of tumor infiltrating lymphocytes, inflammation, and cytolytic activities. HLA gene expression and checkpoint-related genes were also lower in the KRAS-mutated group. Finally, we found 24 immune-related genes that differed in expression between the KRAS-mutated and wild-type samples, which may provide clues to the mechanism of KRAS -related immune alteration. Our findings are indicative of the prognostic and predictive value of KRAS and illustrate the relationship between KRAS mutations and immune activity in colon cancer.

TCGA database analysis of the tumor mutation burden and its clinical significance in colon cancer

“…Moreover, some scholars have suggested that TTN and TP53 double mutations may take part in tumorigenesis by influencing downstream pathways through the participation of other co-expressed genes on the signaling network (39,40). Similarly, when KRAS is mutated, the downstream signaling pathway (mitogenactivated protein kinase, MAPK) is activated, leading to cell proliferation and tumor progression (41,42).…”

KRAS as a Modulator of the Inflammatory Tumor Microenvironment: Therapeutic Implications

“…Interestingly, the concept of tumor-promoting inflammation has been tightly associated with KRAS mutations [1]. In fact, in colorectal cancers, the majority of the cases with a high prevalence of KRAS mutations correlate with chronic inflammatory diseases [24]. KRAS and its downstream interactors are described as capable of shaping the immune microenvironment through the induction of the nuclear factor kappa light chain enhancer of activated B cells (NF)-kB signaling, which in turn promotes the transcription of several cytokines and chemokines, including interleukin (IL)-1α/β, IL-6, tumor necrosis factor α (TNF-α), Cys-X-Cys Chemokine (CXCL)-1, 2, 5, and 8, monocyte chemoattractant protein 1 (MCP-1 or CCL2), inducible nitric oxide synthase (iNOS), intracellular adhesion molecule 1 (ICAM-1), and endothelial leukocyte adhesion molecule 1 (ELAM1) [1,32].…”

“…Colorectal cancer was, in 2020, the third most frequently diagnosed cancer and the second leading cause of cancer-related deaths in both sexes worldwide [15]. KRAS mutations are present in about 52% of colorectal cancer cases and are in the top 5 of mutated genes in 2 different databases, namely, the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), along with APC, TP53, and TIN [1,[23][24][25][26]. Oncogene KRAS activating mutations KRAS G13D , KRAS G12D , and KRAS G12V are the most frequent mutations in colorectal cancer, with the codon 12 being the most affected [8,12,25,[27][28][29].…”

“…Epidemiological and clinical studies have shown a strong relationship between lung cancer, inflammatory microenvironment, and chronic infection [39], as well as between colorectal cancer and chronic inflammatory diseases [24]. In pancreatic cancer, an extensive stromal remodeling, with inflammatory cells and fibrotic scars, is also a hallmark of this type of cancer.…”

“…KRAS mutations have been tightly associated with modulation of tumor inflammation, which has been gradually recognized as a key contributor for tumorigenesis by affecting the immune response, as well as the efficacy of treatments [1,40]. Therefore, exploring how cancer cells harboring oncogenic KRAS mutations may instigate the inflammatory TME, leading to chronic inflammation and stroma remodeling, is of extreme relevance [16,24,41].…”