Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer

Ohio Colorectal Cancer Prevention Initiative Study Group

Research output: Contribution to journalArticle

114 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)464-471
Number of pages8
JournalJAMA Oncology
Volume3
Issue number4
DOIs
StatePublished - Jan 1 2017

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Neoplasm Genes
Colorectal Neoplasms
Mutation
DNA Mismatch Repair
Penetrance
Genes
Genetic Testing
Methylation
Neoplasms
Hereditary Neoplastic Syndromes
Hereditary Nonpolyposis Colorectal Neoplasms
Microsatellite Instability
Genetic Counseling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. / Ohio Colorectal Cancer Prevention Initiative Study Group.

In: JAMA Oncology, Vol. 3, No. 4, 01.01.2017, p. 464-471.

Research output: Contribution to journalArticle

Ohio Colorectal Cancer Prevention Initiative Study Group. / Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. In: JAMA Oncology. 2017 ; Vol. 3, No. 4. pp. 464-471.
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title = "Prevalence and spectrum of germline cancer susceptibility gene mutations among 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.",
author = "{Ohio Colorectal Cancer Prevention Initiative Study Group} and Rachel Pearlman and Frankel, {Wendy L.} and Benjamin Swanson and Weiqiang Zhao and Ahmet Yilmaz and Kristin Miller and Jason Bacher and Christopher Bigley and Lori Nelsen and Goodfellow, {Paul J.} and Goldberg, {Richard M.} and Electra Paskett and Shields, {Peter G.} and Freudenheim, {Jo L.} and Stanich, {Peter P.} and Ilene Lattimer and Mark Arnold and Sandya Liyanarachchi and Matthew Kalady and Brandie Heald and Carla Greenwood and Ian Paquette and Marla Prues and Draper, {David J.} and Carolyn Lindeman and Kuebler, {J. Philip} and Kelly Reynolds and Brell, {Joanna M.} and Shaper, {Amy A.} and Sameer Mahesh and Nicole Buie and Kisa Weeman and Kristin Shine and Mitchell Haut and Joan Edwards and Shyamal Bastola and Karen Wickham and Khanduja, {Karamjit S.} and Rosemary Zacks and Pritchard, {Colin C.} and Shirts, {Brian H.} and Angela Jacobson and Brian Allen and {De La Chapelle}, Albert and Heather Hampel",
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TY - JOUR

T1 - Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer

AU - Ohio Colorectal Cancer Prevention Initiative Study Group

AU - Pearlman, Rachel

AU - Frankel, Wendy L.

AU - Swanson, Benjamin

AU - Zhao, Weiqiang

AU - Yilmaz, Ahmet

AU - Miller, Kristin

AU - Bacher, Jason

AU - Bigley, Christopher

AU - Nelsen, Lori

AU - Goodfellow, Paul J.

AU - Goldberg, Richard M.

AU - Paskett, Electra

AU - Shields, Peter G.

AU - Freudenheim, Jo L.

AU - Stanich, Peter P.

AU - Lattimer, Ilene

AU - Arnold, Mark

AU - Liyanarachchi, Sandya

AU - Kalady, Matthew

AU - Heald, Brandie

AU - Greenwood, Carla

AU - Paquette, Ian

AU - Prues, Marla

AU - Draper, David J.

AU - Lindeman, Carolyn

AU - Kuebler, J. Philip

AU - Reynolds, Kelly

AU - Brell, Joanna M.

AU - Shaper, Amy A.

AU - Mahesh, Sameer

AU - Buie, Nicole

AU - Weeman, Kisa

AU - Shine, Kristin

AU - Haut, Mitchell

AU - Edwards, Joan

AU - Bastola, Shyamal

AU - Wickham, Karen

AU - Khanduja, Karamjit S.

AU - Zacks, Rosemary

AU - Pritchard, Colin C.

AU - Shirts, Brian H.

AU - Jacobson, Angela

AU - Allen, Brian

AU - De La Chapelle, Albert

AU - Hampel, Heather

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

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