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Novel genetic markers of breast cancer survival identified by a genome-wide association study.

ABSTRACT: Only two genome-wide association studies (GWAS) have been conducted to date to identify potential markers for total mortality after diagnosis of breast cancer. Here, we report the identification of two single-nucleotide polymorphisms (SNP) associated with total mortality from a two-stage GWAS conducted among 6,110 Shanghai-resident Chinese women with tumor-node-metastasis (TNM) stage I to IV breast cancer. The discovery stage included 1,950 patients and evaluated 613,031 common SNPs. The top 49 associations were evaluated in an independent replication stage of 4,160 Shanghai patients with breast cancer. A consistent and highly significant association with total mortality was documented for SNPs rs3784099 and rs9934948. SNP rs3784099, located in the RAD51L1 gene, was associated with total morality in both the discovery stage (P = 1.44 × 10(-8)) and replication stage (P = 0.06; P-combined = 1.17 × 10(-7)). Adjusted HRs for total mortality were 1.41 [95% confidence interval (CI), 1.18-1.68] for the AG genotype and 2.64 (95% CI, 1.74-4.03) for the AA genotype, when compared with the GG genotype. The variant C allele of rs9934948, located on chromosome 16, was associated with a similarly elevated risk of total mortality (P-combined = 5.75 × 10(-6)). We also observed this association among 1,145 patients with breast cancer of European ancestry from the Nurses' Health Study (NHS; P = 0.006); the association was highly significant in a combined analysis of NHS and Chinese data (P = 1.39 × 10(-7)). Similar associations were observed for these two SNPs with breast cancer-specific mortality. This study provides strong evidence suggesting that the RAD51L1 gene and a chromosome 16 locus influence breast cancer prognosis.

SUBMITTER: Shu XO

PROVIDER: S-EPMC3294129 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Novel genetic markers of breast cancer survival identified by a genome-wide association study.

Shu Xiao Ou XO Long Jirong J Lu Wei W Li Chun C Chen Wendy Y WY Delahanty Ryan R Cheng Jiarong J Cai Hui H Zheng Ying Y Shi Jiajun J Gu Kai K Wang Wen-Jing WJ Kraft Peter P Gao Yu-Tang YT Cai Qiuyin Q Zheng Wei W

Cancer research 20120109 5

Only two genome-wide association studies (GWAS) have been conducted to date to identify potential markers for total mortality after diagnosis of breast cancer. Here, we report the identification of two single-nucleotide polymorphisms (SNP) associated with total mortality from a two-stage GWAS conducted among 6,110 Shanghai-resident Chinese women with tumor-node-metastasis (TNM) stage I to IV breast cancer. The discovery stage included 1,950 patients and evaluated 613,031 common SNPs. The top 49 ...[more]

PMID: 22232737

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Project description:BackgroundClustering 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.MethodsTo 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).ResultsMultiple 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).ConclusionThe 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.

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Novel genetic markers of breast cancer survival identified by a genome-wide association study.

Publications

Novel genetic markers of breast cancer survival identified by a genome-wide association study.

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