Common polymorphisms in the prostaglandin pathway genes and their association with breast cancer susceptibility and survival.
OBJECTIVE
There is evidence that genetic variation in the prostaglandin pathway affects cancer susceptibility and progression. Conflicting data from several studies exist for the association of PTGS2 (cyclooxygenase 2) polymorphisms with breast cancer risk. We investigated associations between common germ-line variations in seven genes in the prostaglandin pathway and breast cancer susceptibility and survival among women with invasive breast cancer in the SEARCH study.


METHODS
DNA samples from 9,030 cases and controls were genotyped for 64 single nucleotide polymorphisms tagging known common variants (minor allele frequency > 0.05) in PTGS1, PTGS2, TBXAS1, PTGIS, PTGES, PTGDS, and PGDS with a two-stage case-control study design.


RESULTS
Four tagging single nucleotide polymorphisms showed modest association with breast cancer susceptibility. All four fit a recessive genetic model. Minor allele homozygotes for PTGISrs5602 [odds ratio (OR), 1.15; 95% confidence interval (95% CI), 1.04-1.27; P = 0.005], PTGISrs8183919 (OR, 1.22; 95% CI, 1.06-1.41; P = 0.006), and TBXASrs41727 (OR, 1.83; 95% CI, 1.22-2.73; P = 0.003) are associated with an increased risk compared with common allele carriers. For PTGISrs44627 minor allele homozygotes (OR, 0.66; 95% CI, 0.5-0.86; P = 0.002), a protective effect was observed.


CONCLUSIONS
Specific PTGIS and TBXAS1 variants may affect breast cancer susceptibility, but common variants in PTGS1, PTGS2, PTGES, PTGDS, and PGDS have no major role in breast cancer susceptibility. None of the variants in the seven genes studied appear to affect survival. Further larger studies correlating clinical and genotypic data are required to establish if the clinical utility of prostaglandin-targeted therapies, as chemoprevention agents, is influenced by an individual's profile of genetic variants in key prostaglandin pathway genes.
Abraham
Jean E
JE
Cancer Research UK Department of Oncology, University of Cambridge, United Kingdom. ja3444@medschl.cam.ac.uk
Harrington
Patricia
P
Driver
Kristy E
KE
Tyrer
Jonathan
J
Easton
Douglas F
DF
Dunning
Alison M
AM
Pharoah
Paul D P
PD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D054834:Lipocalins / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000096:biosynthesis*; D013930:Thromboxane-A Synthase / Q000235:genetics
D054834:Lipocalins; D011453:Prostaglandins; D003577:Cytochrome P-450 Enzyme System; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C472456:PTGIS protein, human; D013930:Thromboxane-A Synthase