Common germline polymorphisms in COMT, CYP19A1, ESR1, PGR, SULT1E1 and STS and survival after a diagnosis of breast cancer.
Although preliminary evidence suggests that germline variation in genes involved in steroid hormone metabolism may alter breast cancer prognosis, this has not been systematically evaluated. We examined associations between germline polymorphisms in 6 genes involved in the steroid hormone metabolism and signaling pathway (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival among women with breast cancer participating in SEARCH, a population-based case-control study. Blood samples from up to 4,470 women were genotyped for 4 possible functional SNPs in CYP19A1 and 106 SNPs tagging the common variation in the remainder of the genes. The genotypes of each polymorphism were tested for association with survival after breast cancer diagnosis using Cox regression analysis. Significant evidence of an association was observed for a COMT polymorphism (rs4818 p = 0.016) under the codominant model. This SNP appeared to fit a dominant model better (HR = 0.80 95% CI: 0.69-0.95, p = 0.009); however, the result was only marginally significant after permutation analysis adjustment for multiple hypothesis tests (p = 0.047). To further evaluate this finding, somatic expression microarray data from 8 publicly available datasets were used to test the association between survival and tumor COMT gene expression; no statistically significant associations were observed. A correlated SNP in COMT, rs4860, has recently been associated with breast cancer prognosis in Chinese women in a dominant model. These results suggest that COMT rs4818, or a variant it tags, is associated with breast cancer prognosis. Further study of COMT and its putative association with breast cancer prognosis is warranted.
Udler
Miriam S
MS
Strangeways Research Laboratory, Departments of Public Health and Primary Care and Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom.
Azzato
Elizabeth M
EM
Healey
Catherine S
CS
Ahmed
Shahana
S
Pooley
Karen A
KA
Greenberg
David
D
Shah
Mitul
M
Teschendorff
Andrew E
AE
Caldas
Carlos
C
Dunning
Alison M
AM
Ostrander
Elaine A
EA
Caporaso
Neil E
NE
Easton
Douglas
D
Pharoah
Paul D
PD
D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D018275:Carcinoma, Lobular / Q000175:diagnosis / Q000235:genetics / Q000401:mortality; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D017027:Protein Tyrosine Phosphatases; D012307:Risk Factors; D015238:Sulfotransferases / Q000235:genetics; D015996:Survival Rate
D002352:Carrier Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047908:Intracellular Signaling Peptides and Proteins; C439067:MRFAP1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D019363:Cytochrome P-450 CYP1A1; D002394:Catechol O-Methyltransferase; D015238:Sulfotransferases; C020122:estrone sulfotransferase; D017027:Protein Tyrosine Phosphatases; C489397:UBASH3B protein, human