Preventive strategies in familial and hereditary colorectal cancer

Globally, colorectal cancer (CRC) is the third-most common cancer and the second-most common cause of cancer deaths [1]. Most CRC is considered sporadic and does not occur due to genetic or familial predisposition. Several studies have demonstrated associations between lifestyle factors – physical inactivity, unhealthful diets, smoking, high alcohol consumption, excess body weight, and metabolic syndrome – and the incidence of CRC [2,3]. CRC screening and surveillance strategies have contributed to a considerable decrease in incidence and mortality among older individuals, and medications that are more common to older individuals such as aspirin, metformin, and statins have also been shown to mitigate cancer risk [[4], [5], [6], [7]]. At the same time, there has been a noticeable rise in CRC burden among younger adults over the last few decades [8]. One important strategy in CRC prevention for individuals of all ages is the identification and diagnosis of hereditary cancer syndromes, as up to 10% of CRC occurs in individuals who carry pathogenic or likely pathogenic germline variant (PGV) that confers an increased risk of cancer [9].

Several approaches have been deployed to identify individuals who may carry PGVs associated with CRC. Universal microsatellite instability testing by polymerase chain reaction (MSI PCR) or mismatch repair protein-deficiency testing by immunohistochemistry (MMR IHC) is used to screen for Lynch syndrome. More recently, somatic tumor mutation testing has been shown to help detect variants that require germline genetic testing [10]. Recent National Comprehensive Cancer Network (NCCN) guidelines in the United States recommend multigene panel testing over single gene testing in those diagnosed with CRC under age 50 and to consider germline genetic testing for all individuals diagnosed with CRC. These guidelines have also recommended expansion of testing to first-degree relatives of affected individuals or to individuals with multiple second-degree relatives affected with a Lynch-related cancer, highlighting the importance of family history ascertainment in cancer risk assessment [11]. After testing and confirmation of a PGV, cascade testing of family members is essential to successful cancer prevention strategies [12].

Lynch syndrome is the most common hereditary CRC predisposition syndrome, accounting for 3–5% of all CRCs, and at least 10% of CRC under the age of 50 years. Polyposis syndromes such as familial adenomatous polyposis (FAP) or MUTYH-associated polyposis (MAP) account for a smaller proportion of CRCs [9]. Importantly, the wider adoption of next-generation sequencing in the evaluation of hereditary cancer predisposition syndromes is also starting to elucidate other CRC-related genes such as GREM1, POLE/POLD1, and RNF43, among others. This review will provide an overview of the diagnosis and CRC preventive approaches, including surveillance, surgery, and chemoprevention, of hereditary and familial CRC syndromes.

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