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JAMA Oncol. 2017 Apr 1;3(4):464-471. doi: 10.1001/jamaoncol.2016.5194.

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

Author information

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

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.

PMID:
27978560
PMCID:
PMC5564179
DOI:
10.1001/jamaoncol.2016.5194
[Indexed for MEDLINE]
Free PMC Article

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