Colorectal Cancer Incidence Trends in the United States and United Kingdom: Evidence of Right- to Left-Sided Biological Gradients with Implications for Screening

Abstract

Several lines of evidence support the premise that screening colonoscopy reduces colorectal cancer (CRC) incidence, but there may be differential benefits for right-and left-sided tumors. To better understand the biological basis of this differential effect, we derived biomathematical models of CRC incidence trends in U.S. and U.K. populations, representing relatively high-and low-prevalence screening, respectively. Using the Surveillance Epidemiology and End Results (SEER) and the Office for National Statistics (ONS) registries (both 1973-2006), we derived stochastic multistage clonal expansion (MSCE) models for right-sided (proximal colon) and left-sided (distal colon and rectal) tumors. The MSCE concept is based on the initiation-promotionprogression paradigm of carcinogenesis and provides a quantitative description of natural tumor development from the initiation of an adenoma (via biallelic tumor suppressor gene inactivation) to the clinical detection of CRC. From 1,228,036 (SEER: 340,582; ONS: 887,454) cases, parameter estimates for models adjusted for calendaryear and birth-cohort effects showed that adenoma initiation rates were higher for right-sided tumors, whereas, paradoxically, adenoma growth rates were higher for left-sided tumors. The net effect was a higher cancer risk in the right colon only after age 70 years. Consistent with this finding, simulations of adenoma development predicted that the relative prevalence for right-versus left-sided tumors increases with increasing age, a differential effect most striking in women. Using a realistic biomathematical description of CRC development for two nationally representative registries, we show age-and sex-dependent biological gradients for right-and leftsided colorectal tumors. These findings argue for an age-, sex-, and site-directed approach to CRC screening.

Distribution, size and shape of colorectal adenomas as determined by a colonoscopist with a high lesion detection rate: Influence of age, sex and colonoscopy indication

“…This difference in the influence of gender on the regional distribution of adenomas in our patient group, as compared to the distribution of cancers, may be related to gender differences in the biological behavior of the mucosa of the right and left colon. 30 With increasing life expectancy, especially in women, and with improving health of aging people, the future age limits for colonoscopy screening 31 may have to be reconsidered. We suggest that the reported left-to-right shift of colonic adenomas 19,20 is partly due to recent improvements in the detection of right colonic adenomas.…”

Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence

“…This process is best illustrated for colorectal cancer-the total period from first initiated cell to clinical cancer presentation is termed the sojourn time and is approximately 50 years [54], whereas the period from the first clinically identifiable adenoma (only a few millimetres in size) to incident cancer is approximately 20 years, and the period from a clinically relevant adenoma (i.e. larger high-risk lesion) to cancer presentation is approximately 7 years.…”

Associations between Genes in the One-Carbon Metabolism Pathway and Advanced Colorectal Adenoma Risk in Individuals with Low Folate Intake

“…A fully functional ADA, facilitating the irreversible degradation and removal of adenosine, may be necessary in the setting of increased purine and pyrimidine metabolism in carcinogenesis. Previous studies have observed higher levels of ADA activity in cancerous colorectal tissue, as compared with normal adjacent tissue from the same subjects, and in cancerous bladder tissue, as compared with normal adjacent tissue from the same subjects and from cancer-free subjects (34,37 proliferation (39), and its gene product is a useful prognostic marker for certain types of cancer (40,41). CDO1 catalyzes the production of cysteine sulfinate from cysteine, which is metabolized from homocysteine and serine.…”