Genetic predisposition to colorectal polyps and colorectal cancer (CRC) is more common than previously recognized. Approximately 5%-10% of all individuals diagnosed with CRC have a known genetic association. However, among those with early-onset CRC (diagnosed at age less than 50 years), recent studies show that up to 20% have an associated genetic mutation.1,2 In addition, the risk of CRC in patients with certain hereditary syndromes, such as familial adenomatous polyposis (FAP), approaches 80%-90% without timely management.3 This overall high risk of CRC and extracolonic malignancies in patients with a hereditary syndrome, along with the rising rates of early-onset CRC, underscores the importance of early diagnosis and management of a hereditary condition.
Despite increasing awareness of hereditary polyposis and nonpolyposis syndromes, referral rates for genetic counseling and testing remain low.4 As gastroenterologists we have several unique opportunities, in clinic and in endoscopy, to identify patients at risk for hereditary syndromes.
Personal and family history
Reviewing personal medical history and family history in detail should be a routine part of our practice. This is often when initial signs of a potential hereditary syndrome can be detected. For example, if a patient reports a personal or family history of colorectal polyps or CRC, additional information that becomes important includes age at time of diagnosis, polyp burden (number and histologic subtype), presence of inflammatory bowel disease, and history of any extracolonic malignancies. Patients with multiple colorectal polyps (e.g. more than 10-20 adenomas or more than 2 hamartomas) and those with CRC diagnosed at a young age (younger than 50 years) should be considered candidates for genetic evaluation.5
Lynch syndrome (LS), an autosomal dominant condition caused by loss of DNA mismatch repair (MMR) genes, is the most common hereditary CRC syndrome, accounting for 2%-4% of all CRCs.3,6 Extracolonic LS-associated cancers to keep in mind while reviewing personal and family histories include those involving the gastrointestinal (GI) tract such as gastric, pancreatic, biliary tract, and small intestine cancers, and also non-GI tract cancers including endometrial, ovarian, urinary tract, and renal cancers along with brain tumors, and skin lesions including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas. Notably, after CRC, endometrial cancer is the second most common cancer among women with LS. Prior diagnosis of endometrial cancer should also prompt additional history-taking and evaluation for LS.
As the National Comprehensive Cancer Network (NCCN) highlights in its recent guidelines, several key findings in family history that should prompt referral to genetics for evaluation and testing for LS include: one or more first-degree relatives (FDR) with CRC or endometrial cancer diagnosed at less than 50 years of age, one or more FDR with CRC or endometrial cancer and another synchronous or metachronous LS-related cancer, two or more FDR or second-degree relatives (SDR) with LS-related cancer (including at least one diagnosed at age less than 50 years), and three or more FDR or SDR with LS-related cancers (regardless of age).5
Comprehensive assessment of family history should include all cancer diagnoses in first- and second-degree relatives, including age at diagnosis and cancer type, as well as ethnicity, as these inform the likelihood that the patient harbors a germline pathogenic variant associated with cancer predisposition.5 Given the difficulty of eliciting this level of detail, the family histories elicited in clinical settings are often limited or incomplete. Unknown family history should not be mistaken for unremarkable family history. Alternatively, if family history is unimpressive, this is not necessarily reassuring, as there can be variability in disease penetrance, including autosomal recessive syndromes that may skip generations, and de novo mutations do occur. In fact, among individuals with early-onset CRC diagnosed at age less than 50, only half of mutation carriers reported a family history of CRC in an FDR.2 Thus, individuals with concerning personal histories should undergo a genetic evaluation even if family history is not concerning.