Biological Sciences Division
Published April 26, 2018 | Version v1
Journal article Open

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

Creators

  • 1. University of Texas
  • 2. University of Melbourne
  • 3. University of Virginia
  • 4. Case Western Reserve University
  • 5. Fred Hutchinson Cancer Center
  • 6. University of Chicago
  • 7. University of Toronto
  • 8. Stanford University
  • 9. University at Buffalo
  • 10. Mayo Clinic
  • 11. Dartmouth College

Description

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.

Data availability

Data are available from the Institutional Data Access / Ethics Committees for researchers who meet the criteria for access to confidential data, from the two consortia: Colon Cancer Family Registry (CCFR) and Breast Cancer Family Registry (BCFR). Accession codes are not reported because the GWAS data are not available through dbGAP but can be accessed by submitting a proposal and obtaining approval from the CCFR/BCFR (CCFR: http://www.coloncfr.org/collaboration; BCFR: http://www.bcfamilyregistry.org/for-researchers/initiate-collaborations). The CFRs have data and resource sharing plans in compliance with current NIH guidelines. This process is managed by the CCFR Program Manager (atemplet@fredhutch.org) and BCFR Review Coordinator (jenny.nguyen@cpic.org). Approved data requests are processed by the respective Informatics Center data management personnel. Contact information a. CCFR: http://www.coloncfr.org/about-us/program-manager b. BCFR: Jeanine Genkinger, PhD, MHS, Associate Professor, Department of Epidemiology, Mailman School of Public Health, Co-Director, Database Shared Resource, Herbert Irving Comprehensive Cancer Center (jg3081@cumc.columbia.edu), and Richard Buchsbaum, Data Manager (RB539@columbia.edu).

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journal.pone.0196245.pdf

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Additional details

Identifiers

DOI
10.1371/journal.pone.0196245
Other
oai:uchicago.tind.io:6583

Funding

National Cancer Institute
UM1 CA164920
National Cancer Institute
UM1 CA167551
National Cancer Institute
U01/U24 CA074783
National Cancer Institute
U01/U24 CA074799
National Cancer Institute
U01 CA074778
National Cancer Institute
U01/U24 CA097735
National Cancer Institute
U01/U24 CA074794
National Cancer Institute
U01/U24 CA074800
National Cancer Institute
U01/U24 CA074806
National Cancer Institute
U01 CA137088
National Cancer Institute
K05 CA154337
National Cancer Institute
U01 CA188392
National Cancer Institute
K07 CA160753
National Cancer Institute
U01 CA122839
National Cancer Institute
R01 CA143237
National Heart, Lung, and Blood Institute
HHSN268201100046C
National Heart, Lung, and Blood Institute
HHSN268201100001C
National Heart, Lung, and Blood Institute
HHSN268201100002C
National Heart, Lung, and Blood Institute
HHSN268201100003C
National Heart, Lung, and Blood Institute
HHSN268201100004C
National Heart, Lung, and Blood Institute
HHSN271201100004C

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Public Health Sciences