Are there two sides to colorectal cancer?

Abstract

Colorectal carcinomas (CRC) that arise proximal (right) or distal (left) to the splenic flexure exhibit differences in incidence according to geographic region, age and gender. Together with observations that tumours in the hereditary cancer syndromes HNPCC and FAP occur predominantly in the right and left colon, respectively, the existence of 2 categories of CRC based on site of origin in the large bowel was proposed more than a decade ago. Differences between normal right and left colonic segments that could favour progression through different tumourigenic pathways are summarized in this review. Accumulating evidence suggests that the risk of CRC conferred by various environmental and genetic factors is different for proximal and distal tumours. Right-and left-sided tumours also exhibit different sensitivities to fluorouracil-based chemotherapy. Such differences are probably related to the molecular characteristics of the tumours, with the microsatellite instability and CpG island methylator phenotypes being associated with right-sided tumours and chromosomal instability with left-sided tumours. Future molecular-based classification systems for CRC that rely upon distinctive gene expression patterns may allow a clearer discrimination of subgroups than that provided by tumour site alone. Until then however, the existence of 2 broadly different groups of cancer defined by site of origin in the colon should be considered in the design of future epidemiologic studies as well as in the design of new clinical trials aimed at testing novel adjuvant therapies.

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

“…Multiple studies have shown that the molecular characteristics of CRC vary according to anatomical sites, including LC and RC; therefore, researchers have focused on the potential etiologies of these two types of CRC 8, 9, 21, 22. Differences between LC and RC have been found.…”

Physical activity, sedentary behavior, and the risk of colon and rectal cancer in the NIH-AARP Diet and Health Study

“…Some studies reported stronger inverse findings for the proximal colon [12,16,17,33,48], while others observed stronger inverse associations for distal colon sites [6,13,18,36,37]. Observed differences may be due to varying etiologies between tumors of the proximal and distal colon [50].…”

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

“…Proximal colorectal tumors are common in humans, 46,47 which raises the possibility that the pathways mediating proximal colon carcinogenesis in PG-expressing mice are similar to the corresponding pathways in humans. Significant differences between the biologic behavior of proximal colonic tumors and the behavior of distal tumors have been noted in the literature 48,49 ; these differences suggest that tumors from these two regions of the colon differ in terms of etiology. It is possible that the mechanisms that mediate proximal colonic tumorigenesis in humans are mimicked in mice as a result of PG expression.…”