Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.

IMPORTANCE: Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. OBJECTIVE: To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. DESIGN, SETTING, AND PARTICIPANTS: Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016. Mismatch repair (MMR) deficiency was determined by microsatellite instability and/or immunohistochemistry. Germline DNA was tested for mutations in 25 cancer susceptibility genes using next-generation sequencing. MAIN OUTCOMES AND MEASURES: Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. RESULTS: In total 450 patients younger than 50 years were included in the study, and 75 gene mutations were found in 72 patients (16%). Forty-eight patients (10.7%) had MMR-deficient tumors, and 40 patients (83.3%) had at least 1 gene mutation: 37 had Lynch syndrome (13, MLH1 [including one with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic MUTYH mutations); and 1 patient had somatic MLH1 methylation. Four hundred two patients (89.3%) had MMR-proficient tumors, and 32 patients (8%) had at least 1 gene mutation: 9 had mutations in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2); 10 patients had mutations in low-penetrance CRC genes (3, APC c.3920T>A, p.I1307K; 7, monoallelic MUTYH). Importantly, 24 of 72 patients (33.3%) who were mutation positive did not meet established genetic testing criteria for the gene(s) in which they had a mutation. CONCLUSIONS AND RELEVANCE: Of 450 patients with early-onset CRC, 72 (16%) had gene mutations. Given the high frequency and wide spectrum of mutations, genetic counseling and testing with a multigene panel could be considered for all patients with early-onset CRC.

Evaluation of a web-based family medicine case library for self-directed learning in a third-year clerkship.

BACKGROUND AND OBJECTIVES: Web-based cases are well accepted by medical students and enable faculty to deliver equivalent educational experiences to all students. A 2009 literature search revealed no study investigating student use patterns of Web-based case libraries for self-directed learning. We investigated third-year students' use of a Web-based case program for self-directed learning in a family medicine clerkship. METHODS: We analyzed Design A Case usage patterns of 210 medical students during academic year 2008--2009. We compared board score differences between these students and those from the previous 5 years who did not use Design A Case. We analyzed data from a 13-item survey, administered to a subgroup of 85 students, about the strengths, weaknesses, and acceptability of the program. RESULTS: Students completed, on average, four cases, which was beyond the requirement of three. They reported that the content was highly relevant to cases they saw in clinic. Almost 75% preferred the self-directed Web-based learning over didactics, and most (64%) felt they learned more electronically. Use of the cases was associated with equivalent Board scores versus didactic lectures. CONCLUSIONS: In our setting, self-directed learning using a Web-based case program was highly acceptable to students. Web-based cases may provide an option for family medicine educators who wish to deliver equivalent educational experiences across sites.