Common germline genetic variation in antioxidant defense genes and survival after diagnosis of breast cancer.
OBJECTIVE
The prognosis of breast cancer varies considerably among individuals, and inherited genetic factors may help explain this variability. Of particular interest are genes involved in defense against reactive oxygen species (ROS) because ROS are thought to cause DNA damage and contribute to the pathogenesis of cancer.


METHODS
We examined associations between 54 polymorphisms that tag the known common variants (minor allele frequency > 0.05) in 10 genes involved in oxidative damage repair (CAT, SOD1, SOD2, GPX1, GPX4, GSR, TXN, TXN2, TXNRD1, and TXNRD2) and survival in 4,470 women with breast cancer.


RESULTS
Two single nucleotide polymorphisms (SNPs) in GPX4 (rs713041 and rs757229) were associated with all-cause mortality even after adjusting for multiple hypothesis testing (adjusted P = .0041 and P = .0035). These SNPs are correlated with each other (r2 = 0.61). GPX4 rs713041 is located near the selenocysteine insertion sequence element in the GPX4 3' untranslated region, and the rare allele of this SNP is associated with an increased risk of death, with a hazard ratio of 1.27 per rare allele carried (95% CI, 1.13 to 11.43). This effect was not attenuated after adjusting for tumor stage, grade, or estrogen receptor status. We found that the common allele is preferentially expressed in normal lymphocytes, normal breast, and breast tumors compared with the rare allele, but there were no differences in total levels of GPX4 mRNA across genotypes.


CONCLUSIONS
These data provide strong support for the hypothesis that common variation in GPX4 is associated with prognosis after a diagnosis of breast cancer.
Udler
Miriam
M
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. miriam.udler@srl.cam.ac.uk
Maia
Ana-Teresa
AT
Cebrian
Arancha
A
Brown
Clement
C
Greenberg
David
D
Shah
Mitul
M
Caldas
Carlos
C
Dunning
Alison
A
Easton
Douglas
D
Ponder
Bruce
B
Pharoah
Paul
P
D000368:Aged; D000704:Analysis of Variance; D000975:Antioxidants / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D014644:Genetic Variation; D005838:Genotype; D018095:Germ-Line Mutation; D005979:Glutathione Peroxidase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012042:Registries; D018570:Risk Assessment; D012494:Sampling Studies; D016019:Survival Analysis; D006113:United Kingdom / Q000453:epidemiology
D000975:Antioxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; C080439:selenium-independent glutathione peroxidase