Polymorphisms in cycloxygenase-2 gene and breast cancer prognosis: association between PTGS2 haplotypes and histopathological features.

Cyclooxygenase-2 (COX-2) overexpression is associated with worse prognosis in breast cancer. COX-2 is encoded by a polymorphic gene, called PTGS2, and its expression may be genetically influenced. In this article, we investigate the association between PTGS2 haplotypes and histopathological parameters with prognostic value on the clinical outcome of breast cancer. The study involved 606 women under current treatment for non-metastatic breast cancer. Patients were genotyped for rs689465, rs689466, rs20417, and rs5275, and their haplotypes were inferred. The distribution of PTGS2 genotypes and haplotypes was evaluated according to histopathological categorical groups used for prognostic determination of low/intermediate versus high risk of tumor recurrence. Our results indicate positive associations between variant genotypes of rs689465 and estrogen receptor negativity (OR: 1.59, 95% CI: 1.04-2.44, P: 0.02) or HER2 positivity (OR: 1.79, 95% CI: 1.00-3.18, P: 0.03), and between variant genotypes of rs20417 and estrogen receptor negativity (OR: 1.75, 95% CI: 1.15-2.57, P: 0.005), progesterone receptor negativity (OR: 1.56, 95% CI: 1.09-2.22, P: 0.01) or HER2 positivity (OR: 1.80, 95% CI: 1.04-3.13, P: 0.02). In contrast, variant genotypes of rs689466 are negatively associated with estrogen receptor negativity (OR: 0.57, 95% CI: 0.33-0.98, P: 0.03). A total of eight haplotypes were inferred, and there was a significant difference in their distribution as a function of tumor size (P: 0.011), estrogen receptor status (P: 0.018), and HER2 status (P: 0.025). PTGS2 haplotype *7 (formed by rs689465G, rs689466A, rs20417C, and rs5275T) is positively associated with higher tumor size (OR: 3.72, 95% CI: 1.19-11.22, P: 0.006), estrogen receptor negativity (OR: 2.43, 95% CI: 0.97-5.98, P: 0.032), progesterone receptor negativity (OR: 2.58, 95% CI: 1.05-6.39, P: 0.02), and HER2 positivity (OR: 4.17, 95% CI: 1.19-14.44, P: 0.007). Our results suggest that PTGS2 haplotype *7 may contribute to higher growth of untreated breast cancer and that PTGS2 haplotypes need to be considered in the characterization of breast cancer prognosis.

Polymorphisms in regulatory regions of cyclooxygenase-2 gene and breast cancer risk in Brazilians: a case-control study.

BACKGROUND: Cyclooxygenase-2 (COX-2) is up-regulated in several types of cancer, and it is hypothesized that COX-2 expression may be genetically influenced. Here, we evaluate the association between single-nucleotide polymorphisms (SNPs) in the COX-2 gene (PTGS2) and the occurrence of breast cancer among Brazilian women. METHODS: The study was conducted prospectively in two steps: First, we screened the promoter region and three fragments of the 3'-untranslated region of PTGS2 from 67 healthy Brazilians to identify SNPs and to select those with a minor allele frequency (MAF) of at least 0.10. The MAF of these selected SNPs was further characterized in 402 healthy volunteers to evaluate potential differences related to heterogeneous racial admixture and to estimate the existence of linkage disequilibrium among the SNPs. The second step was a case-control study with 318 patients and 273 controls designed to evaluate PTGS2 genotype- or haplotype-associated risk of breast cancer. RESULTS: The screening analysis indicated nine SNPs with the following MAFs: rs689465 (0.22), rs689466 (0.15), rs20415 (0.007), rs20417 (0.32), rs20419 (0.015), rs5270 (0.02), rs20424 (0.007), rs5275 (0.22) and rs4648298 (0.01). The SNPs rs689465, rs689466, rs20417 and rs5275 were further studied: Their genotypic distributions followed Hardy-Weinberg equilibrium and the MAFs were not affected by gender or skin color. Strong linkage disequilibrium was detected for rs689465, rs20417 and rs5275 in the three possible pairwise combinations. In the case-control study, there was a significant increase of rs5275TC heterozygotes in cases compared to controls (OR = 1.44, 95% CI = 1.01-2.06; P = 0.043), and the haplotype formed by rs689465G, rs689466A, rs20417G and rs5275C was only detected in cases. The apparent association with breast cancer was not confirmed for rs5275CC homozygotes or for the most frequent rs5275C-containing haplotypes. CONCLUSIONS: Our results indicate no strong association between the four most frequent PTGS2 SNPs and the risk of breast cancer.