title: Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus.
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authors.lastname: Pearlman
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Frankel
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Benjamin
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authors.lastname: Swanson
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Weiqiang
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authors.lastname: Zhao
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Ahmet
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authors.lastname: Yilmaz
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Kristin
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authors.lastname: Miller
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Jason
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authors.lastname: Bacher
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Christopher
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authors.lastname: Bigley
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Lori
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authors.lastname: Nelsen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Electra
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authors.lastname: Paskett
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Shields
authors.affiliation: Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, New York.
authors.forename: Jo L
authors.initials: JL
authors.lastname: Freudenheim
authors.affiliation: Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Stanich
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Ilene
authors.initials: I
authors.lastname: Lattimer
authors.affiliation: Department of Surgery, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Mark
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authors.lastname: Arnold
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.affiliation: Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio.
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authors.lastname: Kalady
authors.affiliation: Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio.
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authors.affiliation: Department of Digestive Diseases and Surgery, Cleveland Clinic, Cleveland, Ohio.
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authors.lastname: Greenwood
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio.
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authors.lastname: Prues
authors.affiliation: TriHealth Cancer Institute, Good Samaritan Hospital, Cincinnati, Ohio.
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authors.initials: DJ
authors.lastname: Draper
authors.affiliation: TriHealth Cancer Institute, Good Samaritan Hospital, Cincinnati, Ohio.
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authors.lastname: Lindeman
authors.affiliation: Columbus Oncology and Hematology Associates, Columbus, Ohio.
authors.forename: J Philip
authors.initials: JP
authors.lastname: Kuebler
authors.affiliation: Department of Cancer Services, Riverside Methodist Hospital, Columbus, Ohio.
authors.forename: Kelly
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authors.lastname: Reynolds
authors.affiliation: Department of Medicine, MetroHealth Medical Center, Cleveland, Ohio.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Brell
authors.affiliation: Research Institute, MetroHealth Medical Center, Cleveland, Ohio.
authors.forename: Amy A
authors.initials: AA
authors.lastname: Shaper
authors.affiliation: Department of Internal Medicine, Summa Cancer Institute, Summa Akron City Hospital, Akron, Ohio.
authors.forename: Sameer
authors.initials: S
authors.lastname: Mahesh
authors.affiliation: Summa Center for Clinical Trials, Summa Akron City Hospital, Akron, Ohio.
authors.forename: Nicole
authors.initials: N
authors.lastname: Buie
authors.affiliation: Department of Hematology/Oncology, Aultman Hospital, Canton, Ohio.
authors.forename: Kisa
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authors.lastname: Weeman
authors.affiliation: Department of Oncology Clinical Trials, Aultman Hospital, Canton, Ohio.
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authors.lastname: Shine
authors.affiliation: Mercy Medical Center, Canton, Ohio.
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authors.lastname: Haut
authors.affiliation: Mercy Medical Center, Canton, Ohio.
authors.forename: Joan
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authors.lastname: Edwards
authors.affiliation: Department of Oncology and Hematology, Genesis HealthCare System, Zanesville, Ohio.
authors.forename: Shyamal
authors.initials: S
authors.lastname: Bastola
authors.affiliation: Department of Oncology and Hematology, Genesis HealthCare System, Zanesville, Ohio.
authors.forename: Karen
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authors.lastname: Wickham
authors.affiliation: Division of Colon and Rectal Surgery, Mount Carmel East Hospital, Columbus, Ohio.
authors.forename: Karamjit S
authors.initials: KS
authors.lastname: Khanduja
authors.affiliation: Department of Clinical Trials, Mount Carmel East Hospital, Columbus, Ohio.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Zacks
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Pritchard
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Shirts
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle.
authors.forename: Angela
authors.initials: A
authors.lastname: Jacobson
authors.affiliation: Myriad Genetics Inc, Salt Lake City, Utah.
authors.forename: Brian
authors.initials: B
authors.lastname: Allen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus.
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus.
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authors.lastname: Hampel
mesh_terms: D000328:Adult; D017668:Age of Onset; D015179:Colorectal Neoplasms / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009386:Neoplastic Syndromes, Hereditary / Q000453:epidemiology* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015995:Prevalence