Variation in the FGFR2 gene and the effects of postmenopausal hormone therapy on invasive breast cancer.
BACKGROUND
Breast cancer concern is a major reason for the recent marked reduction in use of postmenopausal hormone therapy, although equally effective means of controlling menopausal symptoms are lacking. Single nucleotide polymorphisms (SNP) in the fibroblast growth factor receptor 2 (FGFR2) gene are substantially associated with postmenopausal breast cancer risk and could influence hormone therapy effects.


METHODS
We interrogated eight SNPs in intron 2 of the FGFR2 gene for 2,166 invasive breast cancer cases from the Women's Health Initiative clinical trial and one-to-one matched controls to confirm an association with breast cancer risk. We used case-only analyses to examine the dependence of estrogen plus progestin and estrogen-alone odds ratios on SNP genotype.


RESULTS
Seven FGFR2 SNPs, including six in a single linkage disequilibrium region, were found to associate strongly (P < 10(-7)) with breast cancer risk. SNP rs3750817 (minor allele T with frequency 0.39) had an estimated per-minor-allele odds ratio of 0.78, and was not in such strong linkage disequilibrium with the other SNPs. The genotype of this SNP related significantly (P < 0.05) to hormone therapy odds ratios. For estrogen plus progestin, the odds ratios (95% confidence intervals) at 0, 1, and 2 minor SNP alleles were 1.52 (1.14-2.02), 1.33 (1.01-1.75), and 0.69 (0.41-1.17), whereas the corresponding values for estrogen alone were 0.74 (0.51-1.09), 0.99 (0.68-1.44), and 0.34 (0.15-0.76).


CONCLUSIONS
Postmenopausal women having TT genotype for SNP rs3750817 have a reduced breast cancer risk and seem to experience comparatively favorable effects of postmenopausal hormone therapy.
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. rprentic@fhcrc.org
Ross L
RL
Prentice
Ying
Y
Huang
David A
DA
Hinds
Ulrike
U
Peters
Mary
M
Pettinger
David R
DR
Cox
Erica
E
Beilharz
Rowan T
RT
Chlebowski
Jacques E
JE
Rossouw
Bette
B
Caan
Dennis G
DG
Ballinger
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017698:Postmenopause / Q000235:genetics*; D011372:Progestins / Q000627:therapeutic use; D011379:Prognosis; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D012307:Risk Factors
D014408:Biomarkers, Tumor; D004967:Estrogens; D011372:Progestins; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2