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

PLoS One. 2018 Apr 26;13(4):e0196245. doi: 10.1371/journal.pone.0196245. eCollection 2018.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cluster Analysis
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Female
  • Genetic Markers
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Receptors, Immunologic / genetics
  • Roundabout Proteins

Substances

  • Genetic Markers
  • Nerve Tissue Proteins
  • Receptors, Immunologic

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