What is the frequency and spectrum of cancer susceptibility gene mutations among patients with colorectal cancer diagnosed at younger than 50 years?
In this cohort study of 450 patients with early-onset colorectal cancer, 72 (16%) had a pathogenic mutation. Panel testing identified mutations in patients that may have otherwise been missed; specifically, 24 of 72 patients (33.3%) who were mutation positive did not meet testing criteria for the gene(s) in which they had a mutation.
Multigene panel testing should be considered for all patients with early-onset colorectal cancer.
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.
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.
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.
Pearlman R, Frankel WL, Swanson B, Zhao W, Yilmaz A, Miller K, Bacher J, Bigley C, Nelsen L, Goodfellow PJ, Goldberg RM, Paskett E, Shields PG, Freudenheim JL, Stanich PP, Lattimer I, Arnold M, Liyanarachchi S, Kalady M, Heald B, Greenwood C, Paquette I, Prues M, Draper DJ, Lindeman C, Kuebler JP, Reynolds K, Brell JM, Shaper AA, Mahesh S, Buie N, Weeman K, Shine K, Haut M, Edwards J, Bastola S, Wickham K, Khanduja KS, Zacks R, Pritchard CC, Shirts BH, Jacobson A, Allen B, de la Chapelle A, Hampel H, for the Ohio Colorectal Cancer Prevention Initiative Study Group. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017;3(4):464–471. doi:10.1001/jamaoncol.2016.5194