Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies

Mala Pande, Aron Joon, Abenaa M. Brewster, Wei V. Chen, John L. Hopper, Cathy Eng, Sanjay Shete, Graham Casey, Fredrick Schumacher, Yi Lin, Tabitha A. Harrison, Emily White, Habibul Ahsan, Irene L. Andrulis, Alice S. Whittemore, Esther M. John, Aung Ko Win, Enes Makalic, Daniel F. Schmidt, Miroslaw K. KapuscinskiHeather M. Ochs-Balcom, Steven Gallinger, Mark A. Jenkins, Polly A. Newcomb, Noralane Morey Lindor, Ulrike Peters, Christopher I. Amos, Patrick M. Lynch

Research output: Contribution to journalArticle

Abstract

Background Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype. Methods To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at P<5.0E-04 (n = 549, at 60 loci) were analyzed for replication (n = 293 cases and 2,103 controls). Results Multiple correlated SNPs in intron 1 of the ROBO1 gene were suggestively associated with the breast-colorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06). Conclusion The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation.

Original languageEnglish (US)
Article numbere0196245
JournalPLoS One
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2018

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Genome-Wide Association Study
Genetic Predisposition to Disease
colorectal neoplasms
Genetic Markers
breast neoplasms
Colorectal Neoplasms
Genes
Breast Neoplasms
Phenotype
phenotype
Introns
Tumors
genome-wide association study
penetrance
loci
tumor suppressor genes
genes
Penetrance
Tumor Suppressor Genes
meta-analysis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Pande, M., Joon, A., Brewster, A. M., Chen, W. V., Hopper, J. L., Eng, C., ... Lynch, P. M. (2018). Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies. PLoS One, 13(4), [e0196245]. https://doi.org/10.1371/journal.pone.0196245

Genetic susceptibility markers for a breast-colorectal cancer phenotype : Exploratory results from genome-wide association studies. / Pande, Mala; Joon, Aron; Brewster, Abenaa M.; Chen, Wei V.; Hopper, John L.; Eng, Cathy; Shete, Sanjay; Casey, Graham; Schumacher, Fredrick; Lin, Yi; Harrison, Tabitha A.; White, Emily; Ahsan, Habibul; Andrulis, Irene L.; Whittemore, Alice S.; John, Esther M.; Win, Aung Ko; Makalic, Enes; Schmidt, Daniel F.; Kapuscinski, Miroslaw K.; Ochs-Balcom, Heather M.; Gallinger, Steven; Jenkins, Mark A.; Newcomb, Polly A.; Lindor, Noralane Morey; Peters, Ulrike; Amos, Christopher I.; Lynch, Patrick M.

In: PLoS One, Vol. 13, No. 4, e0196245, 01.04.2018.

Research output: Contribution to journalArticle

Pande, M, Joon, A, Brewster, AM, Chen, WV, Hopper, JL, Eng, C, Shete, S, Casey, G, Schumacher, F, Lin, Y, Harrison, TA, White, E, Ahsan, H, Andrulis, IL, Whittemore, AS, John, EM, Win, AK, Makalic, E, Schmidt, DF, Kapuscinski, MK, Ochs-Balcom, HM, Gallinger, S, Jenkins, MA, Newcomb, PA, Lindor, NM, Peters, U, Amos, CI & Lynch, PM 2018, 'Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies', PLoS One, vol. 13, no. 4, e0196245. https://doi.org/10.1371/journal.pone.0196245
Pande, Mala ; Joon, Aron ; Brewster, Abenaa M. ; Chen, Wei V. ; Hopper, John L. ; Eng, Cathy ; Shete, Sanjay ; Casey, Graham ; Schumacher, Fredrick ; Lin, Yi ; Harrison, Tabitha A. ; White, Emily ; Ahsan, Habibul ; Andrulis, Irene L. ; Whittemore, Alice S. ; John, Esther M. ; Win, Aung Ko ; Makalic, Enes ; Schmidt, Daniel F. ; Kapuscinski, Miroslaw K. ; Ochs-Balcom, Heather M. ; Gallinger, Steven ; Jenkins, Mark A. ; Newcomb, Polly A. ; Lindor, Noralane Morey ; Peters, Ulrike ; Amos, Christopher I. ; Lynch, Patrick M. / Genetic susceptibility markers for a breast-colorectal cancer phenotype : Exploratory results from genome-wide association studies. In: PLoS One. 2018 ; Vol. 13, No. 4.
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abstract = "Background Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype. Methods To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at P<5.0E-04 (n = 549, at 60 loci) were analyzed for replication (n = 293 cases and 2,103 controls). Results Multiple correlated SNPs in intron 1 of the ROBO1 gene were suggestively associated with the breast-colorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06). Conclusion The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation.",
author = "Mala Pande and Aron Joon and Brewster, {Abenaa M.} and Chen, {Wei V.} and Hopper, {John L.} and Cathy Eng and Sanjay Shete and Graham Casey and Fredrick Schumacher and Yi Lin and Harrison, {Tabitha A.} and Emily White and Habibul Ahsan and Andrulis, {Irene L.} and Whittemore, {Alice S.} and John, {Esther M.} and Win, {Aung Ko} and Enes Makalic and Schmidt, {Daniel F.} and Kapuscinski, {Miroslaw K.} and Ochs-Balcom, {Heather M.} and Steven Gallinger and Jenkins, {Mark A.} and Newcomb, {Polly A.} and Lindor, {Noralane Morey} and Ulrike Peters and Amos, {Christopher I.} and Lynch, {Patrick M.}",
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T1 - Genetic susceptibility markers for a breast-colorectal cancer phenotype

T2 - Exploratory results from genome-wide association studies

AU - Pande, Mala

AU - Joon, Aron

AU - Brewster, Abenaa M.

AU - Chen, Wei V.

AU - Hopper, John L.

AU - Eng, Cathy

AU - Shete, Sanjay

AU - Casey, Graham

AU - Schumacher, Fredrick

AU - Lin, Yi

AU - Harrison, Tabitha A.

AU - White, Emily

AU - Ahsan, Habibul

AU - Andrulis, Irene L.

AU - Whittemore, Alice S.

AU - John, Esther M.

AU - Win, Aung Ko

AU - Makalic, Enes

AU - Schmidt, Daniel F.

AU - Kapuscinski, Miroslaw K.

AU - Ochs-Balcom, Heather M.

AU - Gallinger, Steven

AU - Jenkins, Mark A.

AU - Newcomb, Polly A.

AU - Lindor, Noralane Morey

AU - Peters, Ulrike

AU - Amos, Christopher I.

AU - Lynch, Patrick M.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Background Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype. Methods To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at P<5.0E-04 (n = 549, at 60 loci) were analyzed for replication (n = 293 cases and 2,103 controls). Results Multiple correlated SNPs in intron 1 of the ROBO1 gene were suggestively associated with the breast-colorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06). Conclusion The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation.

AB - Background Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype. Methods To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at P<5.0E-04 (n = 549, at 60 loci) were analyzed for replication (n = 293 cases and 2,103 controls). Results Multiple correlated SNPs in intron 1 of the ROBO1 gene were suggestively associated with the breast-colorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06). Conclusion The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation.

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