Right and left-sided colon cancers - specificity of molecular mechanisms in tumorigenesis and progression

Abstract

Background: Given the differences in embryonic origin, vascular and nervous supplies, microbiotic burden, and main physiological functions of left and right colons, tumor location is increasingly suggested to dictate tumor behavior affecting pathology, progression and prognosis. Right-sided colon cancers arise in the cecum, ascending colon, hepatic flexure and/or transverse colon, while left-sided colon cancers arise in the splenic flexure, descending, and/or sigmoid colon. In contrast to prior reports, we attempt to delineate programs of tumorigenesis independently for each side. Methods: Four hundred and eleven samples were extracted from The Cancer Genome Atlas-COAD cohort, based on a conservative sample inclusion criterion. Each side was independently analyzed with respect to their respective normal tissue, at the level of transcription, post-transcription, miRNA control and methylation in both a stage specific and stage-agnostic manner. Results: Our results indicate a suppression of enzymes involved in various stages of carcinogen breakdown including CYP2C8, CYP4F12, GSTA1, and UGT1A within right colon tumors. This implies its reduced capacity to detoxify carcinogens, contributing to a genotoxic tumor environment, and subsequently a more aggressive phenotype. Additionally, we highlight a crucial nexus between calcium homeostasis (sensing, mobilization and absorption) and immune/GPCR signaling within left-sided tumors, possibly contributing to its reduced proliferative and metastatic potential. Interestingly, two genes SLC6A4 and HOXB13 show opposing regulatory trends within right and left tumors. Post-transcriptional regulation mediated by both RNA-binding proteins (e.g. NKRF (in left) and MSI2 (in right)) and miRNAs (e.g. miR-29a (in left); miR-155, miR181-d, miR-576 and miR23a (in right)) appear to exhibit side-specificity in control of their target transcripts and is pronounced in right colon tumors. Additionally, methylation results depict location-specific differences, with increased hypomethylation in open seas within left tumors, and increased hypermethylation of CpG islands within right tumors. Conclusions: Differences in molecular mechanisms captured here highlight distinctions in tumorigenesis and progression between left and right colon tumors, which will serve as the basis for future studies, influencing the efficacies of existing and future diagnostic, prognostic and therapeutic interventions.

Differences in the On- and Off-Tumor Microbiota between Right- and Left-Sided Colorectal Cancer

“…The term colorectal cancer encompasses a heterogeneous group of tumors of the lower gastrointestinal tract. Cancer location can be defined in relation to the colonic splenic flexure (Figure 1), with tumors of the caecum, ascending and transverse colon, termed right-sided colorectal cancer, and tumors of the descending colon, sigmoid colon, and the rectum, termed left-sided colorectal cancer [1,2]. The right and left colon have distinctive embryological origins, developing from the midgut and hindgut, respectively [3].…”

Differential DNA Methylation in Prostate Tumors from Puerto Rican Men

“…Therefore, RREB-1 acts as a repressor of AR [ 27 , 28 ]. CYP4F12 is expressed differentially in colon [ 29 ] and liver tumor tissues [ 30 , 31 ]. Expression of CYP4F12 is positively correlated with low clinical stages and is a prognostic biomarker for overall survival in liver cancer.…”

Prognostic nomograms for predicting overall survival and cause-specific survival of signet ring cell carcinoma in colorectal cancer patients

“…The prognostic value of primary tumor location in metastatic colorectal adenocarcinoma has been reported, with right-side colon cancer having a worse prognosis[ 25 - 28 ]. However, different results were reported for the SRCC subgroup of CRC.…”