Identification of novel variants in colorectal cancer families by high-throughput exome sequencing

Melissa S. DeRycke, Shanaka R. Gunawardena, Sumit Middha, Yan Asmann, Daniel J Schaid, Shannon K. McDonnell, Shaun M. Riska, Bruce W. Eckloff, Julie M Cunningham, Brooke L. Fridley, Daniel J. Serie, William R. Bamlet, Mine Cicek, Mark A. Jenkins, David J. Duggan, Daniel Buchanan, Mark Clendenning, Robert W. Haile, Michael O. Woods, Steven N. GallingerGraham Casey, John D. Potter, Polly A. Newcomb, Loïc Le Marchand, Noralane Morey Lindor, Stephen N Thibodeau, Ellen L Goode

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. Methods: We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign. Results: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. Conclusions: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility. Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk.

Original languageEnglish (US)
Pages (from-to)1239-1251
Number of pages13
JournalCancer Epidemiology Biomarkers and Prevention
Volume22
Issue number7
DOIs
StatePublished - Jul 2013

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Exome
Colorectal Neoplasms
Hereditary Nonpolyposis Colorectal Neoplasms
Chromosomes, Human, Pair 15
Genetic Loci
Chromosomes, Human, Pair 1
Pedigree
DNA Sequence Analysis
Genes
Nucleotides
Mutation

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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Identification of novel variants in colorectal cancer families by high-throughput exome sequencing. / DeRycke, Melissa S.; Gunawardena, Shanaka R.; Middha, Sumit; Asmann, Yan; Schaid, Daniel J; McDonnell, Shannon K.; Riska, Shaun M.; Eckloff, Bruce W.; Cunningham, Julie M; Fridley, Brooke L.; Serie, Daniel J.; Bamlet, William R.; Cicek, Mine; Jenkins, Mark A.; Duggan, David J.; Buchanan, Daniel; Clendenning, Mark; Haile, Robert W.; Woods, Michael O.; Gallinger, Steven N.; Casey, Graham; Potter, John D.; Newcomb, Polly A.; Le Marchand, Loïc; Lindor, Noralane Morey; Thibodeau, Stephen N; Goode, Ellen L.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 22, No. 7, 07.2013, p. 1239-1251.

Research output: Contribution to journalArticle

DeRycke, MS, Gunawardena, SR, Middha, S, Asmann, Y, Schaid, DJ, McDonnell, SK, Riska, SM, Eckloff, BW, Cunningham, JM, Fridley, BL, Serie, DJ, Bamlet, WR, Cicek, M, Jenkins, MA, Duggan, DJ, Buchanan, D, Clendenning, M, Haile, RW, Woods, MO, Gallinger, SN, Casey, G, Potter, JD, Newcomb, PA, Le Marchand, L, Lindor, NM, Thibodeau, SN & Goode, EL 2013, 'Identification of novel variants in colorectal cancer families by high-throughput exome sequencing', Cancer Epidemiology Biomarkers and Prevention, vol. 22, no. 7, pp. 1239-1251. https://doi.org/10.1158/1055-9965.EPI-12-1226
DeRycke, Melissa S. ; Gunawardena, Shanaka R. ; Middha, Sumit ; Asmann, Yan ; Schaid, Daniel J ; McDonnell, Shannon K. ; Riska, Shaun M. ; Eckloff, Bruce W. ; Cunningham, Julie M ; Fridley, Brooke L. ; Serie, Daniel J. ; Bamlet, William R. ; Cicek, Mine ; Jenkins, Mark A. ; Duggan, David J. ; Buchanan, Daniel ; Clendenning, Mark ; Haile, Robert W. ; Woods, Michael O. ; Gallinger, Steven N. ; Casey, Graham ; Potter, John D. ; Newcomb, Polly A. ; Le Marchand, Loïc ; Lindor, Noralane Morey ; Thibodeau, Stephen N ; Goode, Ellen L. / Identification of novel variants in colorectal cancer families by high-throughput exome sequencing. In: Cancer Epidemiology Biomarkers and Prevention. 2013 ; Vol. 22, No. 7. pp. 1239-1251.
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abstract = "Background: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. Methods: We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign. Results: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. Conclusions: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility. Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk.",
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T1 - Identification of novel variants in colorectal cancer families by high-throughput exome sequencing

AU - DeRycke, Melissa S.

AU - Gunawardena, Shanaka R.

AU - Middha, Sumit

AU - Asmann, Yan

AU - Schaid, Daniel J

AU - McDonnell, Shannon K.

AU - Riska, Shaun M.

AU - Eckloff, Bruce W.

AU - Cunningham, Julie M

AU - Fridley, Brooke L.

AU - Serie, Daniel J.

AU - Bamlet, William R.

AU - Cicek, Mine

AU - Jenkins, Mark A.

AU - Duggan, David J.

AU - Buchanan, Daniel

AU - Clendenning, Mark

AU - Haile, Robert W.

AU - Woods, Michael O.

AU - Gallinger, Steven N.

AU - Casey, Graham

AU - Potter, John D.

AU - Newcomb, Polly A.

AU - Le Marchand, Loïc

AU - Lindor, Noralane Morey

AU - Thibodeau, Stephen N

AU - Goode, Ellen L

PY - 2013/7

Y1 - 2013/7

N2 - Background: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. Methods: We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign. Results: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. Conclusions: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility. Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk.

AB - Background: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. Methods: We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign. Results: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. Conclusions: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility. Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk.

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