Prevalence of Germline Mutations in Polyposis and Colorectal Cancer–Associated Genes in Patients With Multiple Colorectal Polyps

Abstract

Guidelines recommend genetic testing of patients with 10 or more cumulative adenomatous polyps. However, little is known about the utility of these tests-especially for older patients. We aimed to determine the prevalence of pathogenic mutations in patients with multiple colorectal polyps, stratified by age. METHODS: We performed a cross-sectional study of patients with 10 or more colorectal polyps who underwent multigene panel testing (MGPT) from March 2012 through December 2016 (n [ 3789). Demographic, clinical and family history data were obtained from test requisition forms and accompanying clinic notes, pedigrees, and pathology reports. Subjects were stratified based on reported polyp histology. Primary outcomes of interest were gene mutations associated with adenomatous polyposis, hamartomatous polyposis, and non-polyposis colorectal cancer syndromes. RESULTS: Based on MGPT, the prevalence of mutations in adenomatous polyposis genes decreased with increasing age in all polyp count groups in the adenoma cohort (P < .001 for 10-19, 20-99, and 100 or more polyps). The prevalence of mutations in all genes of interest also decreased with increasing age but remained above 5% in all age and polyp cohorts. Increased age at testing was associated with a significantly lower risk of a mutation in any gene of interest with multivariate analysis. In the hamartoma cohort, the prevalence of mutations in hamartomatous polyposis genes was high regardless of polyp count (40% with 10-19 polyps, 72.1% with 20-99 polyps, and 50% with 100 or more polyps). CONCLUSION: Our findings support continued genetic testing of patients with 10 or more polyps including adenomas and/or hamartomas. MGPT that includes analysis of polyposis and non-polyposis colorectal cancer genes should be considered for these patients given the high proportion with mutations (above 5%) in all age groups.

Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis

“…Data on multigene panel testing among patients with hamartomatous polyposis are limited. Stanich et al found a high PV detection rate among patients undergoing multigene panel testing with 10-19 (45%), 20-99 (72.1%), and ≥ 100 (58.3%) hamartomas [68]. The majority of PV were found in BMPR1A, SMAD4, STK11, and PTEN, but a small number of patients were found to harbor a CHEK2 PV [68].…”

“…Stanich et al found a high PV detection rate among patients undergoing multigene panel testing with 10-19 (45%), 20-99 (72.1%), and ≥ 100 (58.3%) hamartomas [68]. The majority of PV were found in BMPR1A, SMAD4, STK11, and PTEN, but a small number of patients were found to harbor a CHEK2 PV [68]. The CGA-IGC recommends multigene panel testing for patients with at least three hamartomatous polyps (including hamartomas, Peutz-Jeghers polyps, ganglioneuromas, and juvenile polyps) anywhere in the GI tract but recognizes the absence of data on panel testing for hamartomatous colorectal polyposis.…”

Utility of Genetic Testing in Persons With Multiple Colorectal Polyps

“…A major limitation of the study by Stanich et al 11 was the referral bias inherent in data from a population derived from a testing laboratory. Patients with hamartomatous polyps or tubular adenomas that are being referred and ultimately undergo genetic testing may not be representative of all patients with such pathology.…”

“…In this issue of Clinical Gastroenterology and Hepatology, Stanich et al 11 describe the prevalence of polyposis-and CRC-associated inherited gene mutations in patients with multiple colon polyps (10). In this crosssectional study of 3789 adult patients (age, 18 y) with a history of 10 or more cumulative adenomatous or hamartomatous colorectal polyps who underwent MGPT at Ambry Genetics (Aliso Viejo, CA), Stanich et al 11 calculated the prevalence of pathogenic germline mutations overall and stratified by age, polyp type, and degree of polyposis. Persons with known familial mutations were excluded.…”

“…Currently, and as mentioned previously, referral to a genetics specialist for consideration of MGPT for polyposis-or CRC-associated gene mutations is based on worrisome features such as more than 10 adenomas on a single colonoscopy, unusual polyp histology (hamartomatous polyps), or more than 10 adenomas plus concerning extracolonic manifestation or family history of cancer. [7][8][9][10] However, the results by Stanich et al 11 showed that nearly 14% of all patients with 10 or more adenomatous or hamartomatous polyps, irrespective of other clinical features or family history, had a genetic mutation identified in a CRC-predisposing gene on MGPT. Even in those with fewer than 20 cumulative adenomas (low polyp burden), 7.6% had a diseaseassociated genetic mutation, with 5.3% of these being in nonpolyposis or hamartomatous cancer genes, which would not have been tested for if only genes specific for adenomatous polyposis syndromes were evaluated.…”