Novel genetic markers of breast cancer survival identified by a genome-wide association study.
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.
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA. xiao-ou.shu@vanderbilt.edu
Xiao Ou
XO
Shu
Jirong
J
Long
Wei
W
Lu
Chun
C
Li
Wendy Y
WY
Chen
Ryan
R
Delahanty
Jiarong
J
Cheng
Hui
H
Cai
Ying
Y
Zheng
Jiajun
J
Shi
Kai
K
Gu
Wen-Jing
WJ
Wang
Peter
P
Kraft
Yu-Tang
YT
Gao
Qiuyin
Q
Cai
Wei
W
Zheng
D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000401:mortality*; D002885:Chromosomes, Human, Pair 16; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
D004268:DNA-Binding Proteins; D005819:Genetic Markers; C413002:RAD51B protein, human