Multi-omics Approach Reveals Distinct Differences in Left- and Right-Sided Colon Cancer

Abstract

Increasing evidence suggests that left-sided colon cancer (LCC) and right-sided colon cancer (RCC) are emerging as two different colorectal cancer types with distinct clinical characteristics. However, the discrepancy in the underlying molecular event between these types of cancer has not been thoroughly elucidated to date and warrants comprehensive investigation. To this end, an integrated dataset from The Cancer Genome Atlas was used to compare and contrast LCC and RCC, covering mutation, DNA methylation, gene expression, and miRNA. Briefly, the signaling pathway cross-talk is more prevalent in RCC than LCC, such as RCC-specific PI3K pathway, which often exhibits cross-talk with the RAS and P53 pathways. Meanwhile, methylation signatures revealed that RCC was hypermethylated relative to LCC. In addition, differentially expressed genes ( = 253) and differentially expressed miRNAs ( = 16) were determined between LCC and RCC. Especially for Prostate Cancer Susceptibility Candidate 1 (), a gene that was closely associated with hypermethylation, was the top significantly downregulated gene in RCC. Multi-omics comparison of LCC and RCC suggests that there are more aggressive markers in RCC and that tumor heterogeneity occurs within the location-based subtypes of colon cancer. These results clarify the debate regarding the conflicting prognosis between LCC and RCC, as proposed by different studies. The underlying molecular features present in LCC and RCC identified in this study are beneficial for adopting reasonable therapeutic approaches to prolong overall survival and progression-free survival in colorectal cancer patients. .

Molecular pathway analysis indicates a distinct metabolic and immune phenotype in women with right-sided colon cancer

“…Downregulation of PRAC1 is thought to be repressed via hypermethylation of one of the differentially methylated regions situated on the CpG island shore in RCCs. It is also hypothesized to be a tumor suppressor gene through its interactions with cotranscribed HOXB13 (downregulated in women with RCC when compared to women with LCC in our analysis, but not differentially expressed in men) (Hu et al, 2018). MUC12 is one of the MUC genes that code for glycoproteins important for mucosal barrier function, decreased MUC12 expression has been correlated with poorer survival for stage II and III CRC patients (Matsuyama et al, 2010).…”

“…MUC12 and PRAC1 were similarly downregulated in both men and women when comparing RCCs to LCCs. Recent studies have examined mRNA expression using data from TCGA and GEO comparing patients with RCC to LCC have revealed similar changes to HOXC6, PRAC1 and MUC12 (Hu et al, 2018; Peng et al, 2018). The PRAC1 gene is associated with hypermethylation, and reported to be expressed in the prostate, rectum and left-sided colon.…”

“…However, in this study, only one population cohort was examined and did not correct for multiple comparison testing (Peng et al, 2018). Another study used data from both the Cancer Genome Atlas (TCGA) and GSE14333 to examine somatic mutations, genome-wide mRNA and miRNA, and DNA methylation profiles associated with RCC and found a correlation in the phosphoinositide 3-kinase (PI3K) signaling pathway (Hu et al, 2018).…”

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

“…The ConsensusDriver algorithm identified 25 significantly mutated genes (≥5% of tumors) in all three tumor locations, including mutations in the WNT, P53 and TGF-b pathways, in agreement with other studies. [8,10,11,19] In addition, we identified several novel driver mutations within the DNAH8, DST, PAPPA, and TNR genes (Fig 2).…”

“…Other studies that have looked at differences between RCC and LCC included the transverse colon in their definition of right-sided colon cancers. [9,10] Given that embryologically the right colon and only the first two-thirds of the transverse colon have a common origin, including the entire transverse colon as part of the right colon may lead to conflicting results. Other studies have included rectal cancers in their analysis of left-sided colon cancers.…”