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 M. 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 2018

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies'. Together they form a unique fingerprint.

  • Cite this

    Pande, M., Joon, A., Brewster, A. M., Chen, W. V., Hopper, J. L., Eng, C., Shete, S., Casey, G., Schumacher, F., Lin, Y., Harrison, T. A., White, E., Ahsan, H., Andrulis, I. L., Whittemore, A. S., John, E. M., Win, A. K., Makalic, E., Schmidt, D. F., ... 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