Molecular Basis of Colorectal Cancer and Overview of Inherited Colorectal Cancer Syndromes
Colorectal cancer etiology is multifactorial, with genetic and environmental factors contributing to various degrees in each individual patient. Underlying genetic and molecular pathways produce unique subsets of colorectal cancers that have distinct but
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Key Concepts • Colorectal cancer is a genetically heterogeneous disease that arises via at least three main oncogenic pathways: chromosomal instability, microsatellite instability, and the methylator phenotype. Each pathway produces distinct but overlapping clinical phenotypes. These pathways are represented in sporadic colorectal cancer as well as in hereditary colorectal cancer syndromes. • Identification and diagnosis of a hereditary colorectal cancer syndrome require a high level of suspicion and appropriate knowledge to evaluate the patient and at-risk family members. These syndromes have distinct genetic and clinical traits and are broadly classified into polyposis (adenomatous, hamartomatous, serrated polyps) and nonpolyposis (HNPCC and Lynch syndrome). • Familial adenomatous polyposis is a multisystem disease that confers a near 100 % colorectal cancer malignancy risk. Close endoscopic surveillance and timely prophylactic surgery are required to limit colorectal cancer formation. Desmoid disease and duodenal adenocarcinoma are other leading causes of morbidity and mortality. • MutYH-associated polyposis (MAP) is a recessively inherited syndrome that carries an approximately 75 % lifetime risk of colorectal cancer. Annual colonoscopic surveillance is necessary, and surgery is indicated for uncontrolled polyp burden or the development of adenocarcinoma. Extended colectomy should be offered in healthy patients. • The hamartomatous syndromes (Peutz-Jeghers syndrome, juvenile polyposis syndrome, and PTEN hamartoma syndrome) are rare but are associated with significant colorectal cancer and extracolonic multisystem malignancy. Early recognition and extensive screening and surveillance protocols are required. • Serrated polyposis syndrome is characterized by numerous and/or large serrated polyps. Although no genetic etiology has been identified, it carries an approximately
25 % risk of developing colorectal cancer. Annual colonoscopic surveillance is necessary and surgery is indicated for uncontrolled polyp burden or the development of adenocarcinoma. Extended colectomy should be offered in healthy patients. • Lynch syndrome is the most common of the hereditary syndromes and is responsible for about 3 % of all colorectal cancers. Universal screening and systematic molecular analysis of newly diagnosed colorectal cancer for DNA mismatch repair deficiency provide an effective approach to identifying patients at risk for Lynch syndrome. • Patients with Lynch syndrome face significantly elevated risks for colorectal and extracolonic cancers in multiple organs. Lynch syndrome patients benefit from colonoscopic screening and participation in a hereditary registry. • After the development of an initial colorectal cancer, patients with Lynch syndrome have high risk for metachronous colorectal neoplasia. Extended resection (total abdominal colectomy for colon cancer and total proctocolectomy for rectal cancer) should be considered weighing risks of future malignancy and quality of life.
Introduction Our understanding of
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