Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer
Authors: Rachel Pearlman, Wendy L. Frankel, Benjamin Swanson, Weiqiang Zhao, Ahmet Yilmaz, Kristin Miller, Jason Bacher, Christopher Bigley, Lori Nelsen, Paul J. Goodfellow, Richard M. Goldberg, Electra Paskett, Peter G. Shields, Jo L. Freudenheim, Peter P. Stanich, Ilene Lattimer, Mark Arnold, Sandya Liyanarachchi, Matthew Kalady, Brandie Heald, Carla Greenwood, Ian Paquette, Marla Prues, David J. Draper, Carolyn Lindeman, J. Philip Kuebler, Kelly Reynolds, Joanna M. Brell, Amy A. Shaper, Sameer Mahesh, Nicole Buie, Kisa Weeman, Kristin Shine, Mitchell Haut, Joan Edwards, Shyamal Bastola, Karen Wickham, Karamjit S. Khanduja, Rosemary Zacks, Colin C. Pritchard, Brian H. Shirts, Angela Jacobson, Brian Allen, Albert de la Chapelle, Heather Hampel
Journal: JAMA Oncology (2016)

<h3>Importance</h3> 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. <h3>Objective</h3> To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. <h3>Design, Setting, and Participants</h3> 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. <h3>Main Outcomes and Measures</h3> Mutation prevalence and spectrum in patients with early-onset CRC was determined. Clinical characteristics were assessed by mutation status. <h3>Results</h3> 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,<i>MLH1</i>[including one with constitutional<i>MLH1</i>methylation]; 16,<i>MSH2</i>; 1,<i>MSH2</i>/monoallelic<i>MUTYH</i>; 2,<i>MSH6</i>; 5,<i>PMS2</i>); 1 patient had the<i>APC</i>c.3920T&gt;A, p.I1307K mutation and a<i>PMS2</i>variant; 9 patients (18.8%) had double somatic MMR mutations (including 2 with germline biallelic<i>MUTYH</i>mutations); and 1 patient had somatic<i>MLH1</i>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,<i>APC</i>; 1,<i>APC/PMS2</i>; 2, biallelic<i>MUTYH</i>; 1,<i>SMAD4</i>); 13 patients had mutations in high- or moderate-penetrance genes not traditionally associated with CRC (3,<i>ATM</i>; 1,<i>ATM/CHEK2</i>; 2,<i>BRCA1</i>; 4,<i>BRCA2</i>; 1,<i>CDKN2A</i>; 2,<i>PALB2</i>); 10 patients had mutations in low-penetrance CRC genes (3,<i>APC</i>c.3920T&gt;A, p.I1307K; 7, monoallelic<i>MUTYH</i>). 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. <h3>Conclusions and Relevance</h3> 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.