title: Genetic variants in the vitamin D pathway and breast cancer disease-free survival.
abstract: Epidemiological studies have investigated the association between vitamin D pathway genes and breast cancer risk; however, little is known about the association between vitamin D pathway genes and breast cancer prognosis. In a retrospective cohort of 1029 patients with early-stage breast cancer, we analyzed the association between 106 tagging single nucleotide polymorphisms (SNPs) in eight vitamin D pathway genes and breast cancer disease-free survival (DFS) using Cox regression analysis adjusted for known prognostic variables. Using a false discovery rate of 10%, six intronic SNPs were significantly associated with poorer DFS: retinoid-X receptor alpha (RXRA) SNPs (rs881658, rs11185659, rs10881583, rs881657 and rs7864987) and plasminogen activator and urokinase receptor (PLAUR) SNP (rs4251864). Treatment received (no systemic therapy, hormone therapy alone or chemotherapy) was an effect modifier of the RXRA SNPs association with DFS (P < 0.05); therefore, we stratified further analysis by treatment group. Among patients who did not receive systemic therapy, RXRA SNP [rs10881583 (P = 0.02)] was associated with poorer DFS, and among patients who received chemotherapy, RXRA SNPs (rs881658, rs11185659, rs10881583, rs881657 and rs7864987) were associated with poorer DFS (P < 0.001 for all SNPs). However, RXRA SNPs: rs10881583 (P < 0.001) and rs881657 (P = 0.02) were associated with improved DFS in patients treated with hormone therapy alone. Our results suggest that SNPs in the RXRA and PLAUR genes in the vitamin D pathway may contribute to breast cancer DFS. In particular, SNPs in RXRA may predict for poorer or improved DFS in patients, according to type of systemic treatment received. If validated, these markers could be used for risk stratification of breast cancer patients.
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center,  Houston, TX 77030, USA.
authors.forename: Mala
authors.initials: M
authors.lastname: Pande
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Thompson
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Do
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Frazier
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Bondy
authors.forename: Abenaa M
authors.initials: AM
authors.lastname: Brewster
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000401:mortality; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium; D008875:Middle Aged; D015999:Multivariate Analysis; D010960:Plasminogen Activators / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D018167:Receptors, Calcitriol / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics*; D047490:Retinoid X Receptor alpha / Q000235:genetics*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D014809:Vitamin D-Binding Protein / Q000235:genetics
chemical_list: C524898:PLAUR protein, human; D018167:Receptors, Calcitriol; D055293:Receptors, Urokinase Plasminogen Activator; D047490:Retinoid X Receptor alpha; D014809:Vitamin D-Binding Protein; D003577:Cytochrome P-450 Enzyme System; D010960:Plasminogen Activators