Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes

Melissa S. DeRycke, Shanaka Gunawardena, Jessica R. Balcom, Angela M. Pickart, Lindsey A. Waltman, Amy J. French, Shannon McDonnell, Shaun M. Riska, Zachary C. Fogarty, Melissa C. Larson, Sumit Middha, Bruce W. Eckloff, Yan Asmann, Matthew J. Ferber, Robert W. Haile, Steven Gallinger, Mark Clendenning, Christophe Rosty, Aung K. Win, Daniel D. Buchanan & 6 others John L. Hopper, Polly A. Newcomb, Loic Le Marchand, Ellen L Goode, Noralane Morey Lindor, Stephen N Thibodeau

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Mutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next-generation sequencing technologies have made it possible to sequencing panels of genes known and suspected to influence colorectal cancer susceptibility. Methods: Targeted sequencing of 36 known or putative CRC susceptibility genes was conducted for 1231 CRC cases from five subsets: (1) Familial Colorectal Cancer Type X (n = 153); (2) CRC unselected by tumor immunohistochemical or microsatellite stability testing (n = 548); (3) young onset (age <50 years) (n = 333); (4) proficient mismatch repair (MMR) in cases diagnosed at ≥50 years (n = 68); and (5) deficient MMR CRCs with no germline mutations in MLH1, MSH2, MSH6, or PMS2 (n = 129). Ninety-three unaffected controls were also sequenced. Results: Overall, 29 nonsense, 43 frame-shift, 13 splice site, six initiator codon variants, one stop codon, 12 exonic deletions, 658 missense, and 17 indels were identified. Missense variants were reviewed by genetic counselors to determine pathogenicity; 13 were pathogenic, 61 were not pathogenic, and 584 were variants of uncertain significance. Overall, we identified 92 cases with pathogenic mutations in APC, MLH1, MSH2, MSH6, or multiple pathogenic MUTYH mutations (7.5%). Four cases with intact MMR protein expression by immunohistochemistry carried pathogenic MMR mutations. Conclusions: Results across case subsets may help prioritize genes for inclusion in clinical gene panel tests and underscore the issue of variants of uncertain significance both in well-characterized genes and those for which limited experience has accumulated.

Original languageEnglish (US)
Pages (from-to)553-569
Number of pages17
JournalMolecular Genetics and Genomic Medicine
Volume5
Issue number5
DOIs
StatePublished - Jan 1 2017

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Neoplasm Genes
Colorectal Neoplasms
DNA Mismatch Repair
Genes
Mutation
Hereditary Neoplastic Syndromes
Initiator Codon
Germ-Line Mutation
Terminator Codon
Genetic Testing
Age of Onset
Microsatellite Repeats
Virulence
Immunohistochemistry
Technology

Keywords

  • Colorectal cancer
  • Familial Colorectal Cancer Type X
  • germline variants
  • young onset

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

DeRycke, M. S., Gunawardena, S., Balcom, J. R., Pickart, A. M., Waltman, L. A., French, A. J., ... Thibodeau, S. N. (2017). Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Molecular Genetics and Genomic Medicine, 5(5), 553-569. https://doi.org/10.1002/mgg3.317

Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. / DeRycke, Melissa S.; Gunawardena, Shanaka; Balcom, Jessica R.; Pickart, Angela M.; Waltman, Lindsey A.; French, Amy J.; McDonnell, Shannon; Riska, Shaun M.; Fogarty, Zachary C.; Larson, Melissa C.; Middha, Sumit; Eckloff, Bruce W.; Asmann, Yan; Ferber, Matthew J.; Haile, Robert W.; Gallinger, Steven; Clendenning, Mark; Rosty, Christophe; Win, Aung K.; Buchanan, Daniel D.; Hopper, John L.; Newcomb, Polly A.; Le Marchand, Loic; Goode, Ellen L; Lindor, Noralane Morey; Thibodeau, Stephen N.

In: Molecular Genetics and Genomic Medicine, Vol. 5, No. 5, 01.01.2017, p. 553-569.

Research output: Contribution to journalArticle

DeRycke, MS, Gunawardena, S, Balcom, JR, Pickart, AM, Waltman, LA, French, AJ, McDonnell, S, Riska, SM, Fogarty, ZC, Larson, MC, Middha, S, Eckloff, BW, Asmann, Y, Ferber, MJ, Haile, RW, Gallinger, S, Clendenning, M, Rosty, C, Win, AK, Buchanan, DD, Hopper, JL, Newcomb, PA, Le Marchand, L, Goode, EL, Lindor, NM & Thibodeau, SN 2017, 'Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes', Molecular Genetics and Genomic Medicine, vol. 5, no. 5, pp. 553-569. https://doi.org/10.1002/mgg3.317
DeRycke MS, Gunawardena S, Balcom JR, Pickart AM, Waltman LA, French AJ et al. Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. Molecular Genetics and Genomic Medicine. 2017 Jan 1;5(5):553-569. https://doi.org/10.1002/mgg3.317
DeRycke, Melissa S. ; Gunawardena, Shanaka ; Balcom, Jessica R. ; Pickart, Angela M. ; Waltman, Lindsey A. ; French, Amy J. ; McDonnell, Shannon ; Riska, Shaun M. ; Fogarty, Zachary C. ; Larson, Melissa C. ; Middha, Sumit ; Eckloff, Bruce W. ; Asmann, Yan ; Ferber, Matthew J. ; Haile, Robert W. ; Gallinger, Steven ; Clendenning, Mark ; Rosty, Christophe ; Win, Aung K. ; Buchanan, Daniel D. ; Hopper, John L. ; Newcomb, Polly A. ; Le Marchand, Loic ; Goode, Ellen L ; Lindor, Noralane Morey ; Thibodeau, Stephen N. / Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. In: Molecular Genetics and Genomic Medicine. 2017 ; Vol. 5, No. 5. pp. 553-569.
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abstract = "Background: Mutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next-generation sequencing technologies have made it possible to sequencing panels of genes known and suspected to influence colorectal cancer susceptibility. Methods: Targeted sequencing of 36 known or putative CRC susceptibility genes was conducted for 1231 CRC cases from five subsets: (1) Familial Colorectal Cancer Type X (n = 153); (2) CRC unselected by tumor immunohistochemical or microsatellite stability testing (n = 548); (3) young onset (age <50 years) (n = 333); (4) proficient mismatch repair (MMR) in cases diagnosed at ≥50 years (n = 68); and (5) deficient MMR CRCs with no germline mutations in MLH1, MSH2, MSH6, or PMS2 (n = 129). Ninety-three unaffected controls were also sequenced. Results: Overall, 29 nonsense, 43 frame-shift, 13 splice site, six initiator codon variants, one stop codon, 12 exonic deletions, 658 missense, and 17 indels were identified. Missense variants were reviewed by genetic counselors to determine pathogenicity; 13 were pathogenic, 61 were not pathogenic, and 584 were variants of uncertain significance. Overall, we identified 92 cases with pathogenic mutations in APC, MLH1, MSH2, MSH6, or multiple pathogenic MUTYH mutations (7.5{\%}). Four cases with intact MMR protein expression by immunohistochemistry carried pathogenic MMR mutations. Conclusions: Results across case subsets may help prioritize genes for inclusion in clinical gene panel tests and underscore the issue of variants of uncertain significance both in well-characterized genes and those for which limited experience has accumulated.",
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T1 - Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes

AU - DeRycke, Melissa S.

AU - Gunawardena, Shanaka

AU - Balcom, Jessica R.

AU - Pickart, Angela M.

AU - Waltman, Lindsey A.

AU - French, Amy J.

AU - McDonnell, Shannon

AU - Riska, Shaun M.

AU - Fogarty, Zachary C.

AU - Larson, Melissa C.

AU - Middha, Sumit

AU - Eckloff, Bruce W.

AU - Asmann, Yan

AU - Ferber, Matthew J.

AU - Haile, Robert W.

AU - Gallinger, Steven

AU - Clendenning, Mark

AU - Rosty, Christophe

AU - Win, Aung K.

AU - Buchanan, Daniel D.

AU - Hopper, John L.

AU - Newcomb, Polly A.

AU - Le Marchand, Loic

AU - Goode, Ellen L

AU - Lindor, Noralane Morey

AU - Thibodeau, Stephen N

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: Mutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next-generation sequencing technologies have made it possible to sequencing panels of genes known and suspected to influence colorectal cancer susceptibility. Methods: Targeted sequencing of 36 known or putative CRC susceptibility genes was conducted for 1231 CRC cases from five subsets: (1) Familial Colorectal Cancer Type X (n = 153); (2) CRC unselected by tumor immunohistochemical or microsatellite stability testing (n = 548); (3) young onset (age <50 years) (n = 333); (4) proficient mismatch repair (MMR) in cases diagnosed at ≥50 years (n = 68); and (5) deficient MMR CRCs with no germline mutations in MLH1, MSH2, MSH6, or PMS2 (n = 129). Ninety-three unaffected controls were also sequenced. Results: Overall, 29 nonsense, 43 frame-shift, 13 splice site, six initiator codon variants, one stop codon, 12 exonic deletions, 658 missense, and 17 indels were identified. Missense variants were reviewed by genetic counselors to determine pathogenicity; 13 were pathogenic, 61 were not pathogenic, and 584 were variants of uncertain significance. Overall, we identified 92 cases with pathogenic mutations in APC, MLH1, MSH2, MSH6, or multiple pathogenic MUTYH mutations (7.5%). Four cases with intact MMR protein expression by immunohistochemistry carried pathogenic MMR mutations. Conclusions: Results across case subsets may help prioritize genes for inclusion in clinical gene panel tests and underscore the issue of variants of uncertain significance both in well-characterized genes and those for which limited experience has accumulated.

AB - Background: Mutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next-generation sequencing technologies have made it possible to sequencing panels of genes known and suspected to influence colorectal cancer susceptibility. Methods: Targeted sequencing of 36 known or putative CRC susceptibility genes was conducted for 1231 CRC cases from five subsets: (1) Familial Colorectal Cancer Type X (n = 153); (2) CRC unselected by tumor immunohistochemical or microsatellite stability testing (n = 548); (3) young onset (age <50 years) (n = 333); (4) proficient mismatch repair (MMR) in cases diagnosed at ≥50 years (n = 68); and (5) deficient MMR CRCs with no germline mutations in MLH1, MSH2, MSH6, or PMS2 (n = 129). Ninety-three unaffected controls were also sequenced. Results: Overall, 29 nonsense, 43 frame-shift, 13 splice site, six initiator codon variants, one stop codon, 12 exonic deletions, 658 missense, and 17 indels were identified. Missense variants were reviewed by genetic counselors to determine pathogenicity; 13 were pathogenic, 61 were not pathogenic, and 584 were variants of uncertain significance. Overall, we identified 92 cases with pathogenic mutations in APC, MLH1, MSH2, MSH6, or multiple pathogenic MUTYH mutations (7.5%). Four cases with intact MMR protein expression by immunohistochemistry carried pathogenic MMR mutations. Conclusions: Results across case subsets may help prioritize genes for inclusion in clinical gene panel tests and underscore the issue of variants of uncertain significance both in well-characterized genes and those for which limited experience has accumulated.

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KW - germline variants

KW - young onset

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