Common Polymorphisms in the Prostaglandin Pathway Genes and Their Association with Breast Cancer Susceptibility and Survival

Abstract

Purpose: 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. Experimental Design: 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. Conclusion: 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.Breast cancer is the most common cancer among women in developed countries and accounts for 18% of all cancers (1). Although a few, rare, strongly predisposing alleles are well established (e.g., deleterious alleles of BRCA1 and BRCA2), these account for only 2% to 5% of all breast cancer cases (2) and <25% of the excess familial risk of breast cancer can be explained by variants in the known susceptibility genes (3). It is likely that the unexplained excess is due to multiple low to moderate risk alleles in numerous genes, that is, a polygenic model of cancer susceptibility (4).There has been increasing interest in the role of the prostaglandin pathway in both cancer susceptibility and tumor progression, with a particular focus on the enzyme cyclooxygenase (COX)

Variants of gene for microsomal prostaglandin E2 synthase show association with disease and severe inflammation in rheumatoid arthritis

“…According to NCBI single-nucleotide polymorphisms (SNPs) database, there are 249 SNPs in the PTGES gene region, including four coding SNPs (two synonymous and two non-synonymous SNPs). Whereas none of the studied variants in PTGES gene had a significant effect on the risk of lymphoma, 14 nonfatal myocardian infarction or ischemic stroke, 15 and breast cancer susceptibility, 16 in a large-scale association study one SNP in the 5¢ region of the PTGES gene was associated with hypertension in women in the Japanese population. 17 SNPs in the PTGES gene could modify enzyme expression levels or activity and alter inducible PGE 2 biosynthesis.…”

CYP2W1, CYP4F11 and CYP8A1 Polymorphisms and Interaction of CYP2W1 Genotypes with Risk Factors in Mexican Women with Breast Cancer

“…Six polymorphisms in CYP8A1 have been reported in BCa. Homozygotes for the minor alleles of rs5602 (67730 T>C), rs477627 (9650 T>C) and rs6125671 (14110 G>A) were associated with an increased BCa risk compared with common alleles, and a protective effect was observed for minor allele homozygotes with the rs477627 (9650 T>C) polymorphism in a Caucasian population (Abraham et al, 2009). For rs6095541 (48110188 C>T) and rs6095543 (48113300 T>C) in women with progesterone positive BCa an association of BCa with this allele in Caucasian individuals has been shown (Mavaddat et al, 2009).…”

“…PGI2 is a potent antimitogenic and anti-metastatic cancer agent (Hohn et al, 1981). The association between CYP8A1 SNP and cancer (lung, colorectal, thyroid and breast) has been well-documented (Keith et al, 2004;Kajita et al, 2005;Gustafsson et al, 2007;Abraham et al, 2009). Six polymorphisms in CYP8A1 have been reported in BCa.…”

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

“…Genome-wide association studies also reveal that certain single nucleotide polymorphisms within the TXS gene (the TBXAS1) may predispose individuals to breast cancer (46), while inhibition of TXS activity enhances apoptosis of lung carcinoma A549 cells in vitro, implicating a role for TXA 2 also in tumour cell survival (36). In the prostate, an increased expression of TXS and the TPα/TPβ isoforms directly correlate with the tumour Gleason score and pathologic stage (32,33,47), where expression of both TXS and the TP is mainly found in areas of perineural invasion, a recognized mechanism by which PCa cells invade the prostatic capsule and metastasize to other tissues (20,32).…”