[Skip to Content]
[Skip to Content Landing]
Original Investigation
April 2017

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

Author Affiliations
  • 1The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
  • 2Department of Pathology, The Ohio State University Wexner Medical Center, Columbus
  • 3The Ohio State University Comprehensive Cancer Center, Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus
  • 4Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York
  • 5Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus
  • 6Department of Surgery, The Ohio State University Wexner Medical Center, Columbus
  • 7The Ohio State University Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus
  • 8Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio
  • 9Department of Digestive Diseases and Surgery, Cleveland Clinic, Cleveland, Ohio
  • 10Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
  • 11Cancer Center Research, The Christ Hospital Health Network, Cincinnati, Ohio
  • 12TriHealth Cancer Institute, Good Samaritan Hospital, Cincinnati, Ohio
  • 13Columbus Oncology and Hematology Associates, Columbus, Ohio
  • 14Department of Cancer Services, Riverside Methodist Hospital, Columbus, Ohio
  • 15Department of Medicine, MetroHealth Medical Center, Cleveland, Ohio
  • 16Research Institute, MetroHealth Medical Center, Cleveland, Ohio
  • 17Department of Internal Medicine, Summa Cancer Institute, Summa Akron City Hospital, Akron, Ohio
  • 18Summa Center for Clinical Trials, Summa Akron City Hospital, Akron, Ohio
  • 19Department of Hematology/Oncology, Aultman Hospital, Canton, Ohio
  • 20Department of Oncology Clinical Trials, Aultman Hospital, Canton, Ohio
  • 21Mercy Medical Center, Canton, Ohio
  • 22Department of Oncology and Hematology, Genesis HealthCare System, Zanesville, Ohio
  • 23Division of Colon and Rectal Surgery, Mount Carmel East Hospital, Columbus, Ohio
  • 24Department of Clinical Trials, Mount Carmel East Hospital, Columbus, Ohio
  • 25Department of Laboratory Medicine, University of Washington, Seattle
  • 26Myriad Genetics Inc, Salt Lake City, Utah
JAMA Oncol. 2017;3(4):464-471. doi:10.1001/jamaoncol.2016.5194
Key Points

Question  What is the frequency and spectrum of cancer susceptibility gene mutations among patients with colorectal cancer diagnosed at younger than 50 years?

Findings  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.

Meaning  Multigene panel testing should be considered for all patients with early-onset colorectal cancer.

Abstract

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.

×