Abstract SY14-01: Colon cancer screening and genetics
Authors: Carethers John M. 
Published: July 2017

Colorectal cancer (CRC) is the third most prevalent and second deadliest cancer in the U.S. with 134,490 cases and 49,190 deaths in 2016. Its pathogenesis stems from genetic susceptibility coupled with environmental interactions in the colon that synergize ideal conditions for neoplastic growth, initially from benign adenomatous polyps that might progress to carcinoma over several years. Adenoma initiation and progression to carcinoma may take one of a few identified genetic pathways that determine the tempo of progression as well as morbidity and mortality of the patient. Each patient’s CRC is genetically unique with variable numbers of passenger mutations and propelled by 2-8 driver mutations. CRCs can be classified as hypermutated, possessing hundreds to thousands of somatic mutations and including CRCs driven by defects in DNA mismatch repair and POLE mutations; and non-hypermutated, with tens of somatic mutations containing multiple copy number alterations and aneuploidy with oncogenic activation of KRAS and PIK3CA coupled with mutations and loss of heterozygosity of tumor suppressors APC and TP53. Epigenetic events as well as inflammatory-driven cellular alterations in DNA mismatch repair further contribute to CRC pathogenesis and metastasis. Because CRC is deadly, prevention through screening (and/or surveillance in high-risk patients) is an ideal and effective approach. Screening provides the opportunity to identify and remove the adenoma precursors before they can become CRC; it also can utilize the somatic genetic knowledge to effectively screen patients noninvasively. There are seven CRC screening tests suggested by the USPSTF and a Multi-society Task Force for effective screening, with varying abilities to detect significant colonic neoplasia and various specificities; even the most noninvasive and least sensitive test has shown a durable reduction in CRC mortality and is cost effective. Thus, any of the seven CRC screening tests is better than no test. Noninvasive strategies include guaiac-based fecal occult blood testing, fecal immunochemical testing, fecal DNA testing, and CT colonography. Luminal-invasive tests include flexible sigmoidoscopy and colonoscopy and their combinations with a noninvasive test. If any of the noninvasive tests shows a positive result, a colonoscopy should be performed to identify the cause of the positive test. For high-risk patients or the surveillance of patients, colonoscopy is the modality that should be used. Knowledge of the patient’s age and family history and personal adenoma or CRC history can influence when to commence screening; additionally, multiple lines of evidence suggest that race should be included in the algorithm influencing the timing and tempo of screening and/or surveillance.

Citation Format: John M. Carethers. Colon cancer screening and genetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY14-01. doi:10.1158/1538-7445.AM2017-SY14-01