PLoS ONE (Jan 2018)

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 Kapuscinski,
  • Heather M Ochs-Balcom,
  • Steven Gallinger,
  • Mark A Jenkins,
  • Polly A Newcomb,
  • Noralane M Lindor,
  • Ulrike Peters,
  • Christopher I Amos,
  • Patrick M Lynch

DOI
https://doi.org/10.1371/journal.pone.0196245
Journal volume & issue
Vol. 13, no. 4
p. e0196245

Abstract

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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.