TY - JOUR
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 M.
AU - Peters, Ulrike
AU - Amos, Christopher I.
AU - Lynch, Patrick M.
N1 - Publisher Copyright:
© 2018 Pande et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/4
Y1 - 2018/4
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.
UR - https://www.scopus.com/pages/publications/85046017038
U2 - 10.1371/journal.pone.0196245
DO - 10.1371/journal.pone.0196245
M3 - Article
C2 - 29698419
AN - SCOPUS:85046017038
SN - 1932-6203
VL - 13
JO - PLOS ONE
JF - PLOS ONE
IS - 4
M1 - e0196245
ER -