Cause, Epidemiology, and Histology of Polyps and Pathways to Colorectal Cancer

Abstract

Colorectal cancer is the second leading cause of cancer-associated mortality, with a lifetime risk of approximately 4% to 5%. Colorectal cancer develops from the sequential acquisition of defined genetic mutations in the colonic epithelium. Tumorigenesis from normal tissue to cancer occurs largely through 3 pathways: the chromosomal instability pathway, the microsatellite instability pathway, and the sessile serrated pathway. Colorectal cancer incidence and mortality have decreased by approximately 35% since the beginning of screening programs in the 1990s, although other factors such as use of aspirin for coronary disease prevention and decreased smoking rates may also be important. In this review, we discuss the etiology, epidemiology, and histology of colorectal polyps and cancer.

Keywords: Adenoma; Colon cancer screening; Colon polyp; Colorectal cancer.

Fig. 1.

Pathways of colorectal carcinogenesis. Activation of the Wnt pathway (primarily via APC mutation) or a mutation in BRAF can initiate colorectal tumorigenesis. BRAF mutations promote tumorigenesis via the serrated neoplasia pathway, leading to microsatellite instability (MSI) with hypermutation or microsatellite stable (MSS) without hypermutation (indicated in the figure). Colorectal tumor classifications include chromosomal instability (CIN), MSI, and the serrated pathway (see CMS). EMT, epithelial to mesenchymal transition; H, high; L, low; neg, negative. (From Nguyen LH, Goel A, Chung DC. Pathways of Colorectal Carcinogenesis. Gastroenterology. 2020 Jan;158(2):291–302.)

Fig. 2.

Mutational landscape in microsatellite stable (MSS) colorectal cancer. Seshagiri and colleagues performed somatic exome sequencing of 57 MSS colorectal cancers. Genes were evaluated for significance using Q score criteria. Each circle represents a gene, and the size of the circle is proportional to the mutation count for that gene. The genes are represented in order of increasing number of expected mutations from left to right on the x axis. Genes with a statistically significant Q score are labeled. (From Seshagiri S, Stawiski EW, Durinck S, Modrusan Z, Storm EE, Conboy CB, Chaudhuri S, Guan Y, Janakiraman V, Jaiswal BS, Guillory J, Ha C, Dijkgraaf GJ, Stinson J, Gnad F, Huntley MA, Degenhardt JD, Haverty PM, Bourgon R, Wang W, Koeppen H, Gentleman R, Starr TK, Zhang Z, Largaespada DA, Wu TD, de Sauvage FJ. Recurrent R-spondin fusions in colon cancer. Nature. 2012 Aug 30;488(7413):660–4.)

Fig. 3.

Incidence rates of colorectal cancer and prevalence rates of adenomas/SSLs by age. (A) CRC incidence rates by age and compared across time periods (screening era of 2014–2018 vs an unscreened era in 1975). (B) Prevalence rates of adenomas on screening colonoscopy compared with SSLs on index colonoscopy by age. Figure was produced from data found in References ^,,,