Background: PMBC most likely arises from combinations of less penetrant SNPs of common genes in combination with other environmental and lifestyle risk factors. Adiposity has the largest population attributable risk (PAR) for PMBC of all other factors at 21.3%. Of all the identified genes associated with human adiposity, the fat mass and obesity-associated gene (FTO) has been reported to have the strongest association and therefore a high PAR in the White population. Results from independent studies suggest that SNPs in the FTO gene are associated with PMBC. Furthermore, SNPs in several genes, i.e. estrogen receptor (ERS1), prostaglandin-endoperoxide synthase 2 (COX-2), ghrelin-obestatin ligand for growth hormone secretagouge receptor (GHRL), growth hormone secretagouge receptor (GHSR), interleukine 6 (IL6), mitogen-activated protein kinase (MAP3K1), are also associated with PMBC. To our knowledge the association between the complex of SNPs in these genes and PMBC has not been evaluated.
Methods: Cases with a confirmed diagnosis of primary invasive breast cancer were identified from the MyCode cohort. Controls, matched by date of blood donation and age, were identified from the same cohort. Three controls were matched to each case. Demographic, pathology and clinical data were retrieved and verified by reviewing electronic medical records. The SNP genotyping was performed on a Life Technologies TaqMan OpenArray Genotyping System (Applied BiosystemsLife Technologies, Foster City, CA) and analyzed using the Life Technologies TaqMan Genotyper Software. Logistic regression models were used to analyze the association between PMBC and SNPs. Each SNP was tested individually adjusting for common clinical risk factors (age, first degree breast cancer family history, smoking, alcohol, metabolic syndrome, hormone replacement therapy). Then Multiple-SNP nonepistatic analysis was performed to fit multiple SNPs simultaneously with adjustment for other common clinical factors.
Results: Cases (N=159) and controls (N=829) had a mean age of 65 years (± 9) and 64 years (± 9), respectively, at the time of entry into the cohort. A higher proportion of cases (26.5%) were diagnosed with metabolic syndrome, defined by the WHO criteria, compared with controls (4.0%) (p=0.0003). Self-reported family history of breast cancer was almost 4 fold higher among cases than controls (p=0.001). 41 SNPs were tested individually of the association of PMBC, among them 9 SNPs related to inflammatory pathways were tested in multiple SNPs model. One polymorphism in the MAP3K1gene (rs889312) showed increased risk of PMBC among homozygotes for the minor allele C (OR=1.98; 95% CI=1.08-3.63, p=0.03). Homozygotes for the A allele of rs689470 (PTGS2 gene) had a statistically significant increased risk of PMBC (OR= 3.38; 95% CI=1.09-10.51, p=0.03) while homozygotes for the G allele of rs2383529 had a lower risk for PMBC (OR= 0.32; 95% CI=0.11-0.92, p=0.03). In addition, we found a lower risk for PMBC for homozygotes for the C alleles of rs3020314 (ESR1 gene) (OR= 0.51; 95% CI=0.26-0.98; p=0.04). Similarly, the estimated risk of PMBC was lower (OR=0.13; 95% CI=0.03-0.55, p= 0.006) for homozygotes for the A allele of rs7801617 (IL6 gene).
Conclusion: Our preliminary findings concur with previous reports suggesting polymorphisms of 2 genes, MAP3K1 and PTGS2 increase the risk of PMBC independent of the well-established risk factors for PMBC. MAP3K1 gene acts in the MAPK-signaling pathway and is responsible for regulation of transcription of estrogen receptor; while, PTGS2 is an inflammatory mediator that is reported to up-regulate aromatase expression and subsequently local synthesis of estrogen in the breast. Further study is to evaluate independence of these SNPs with the known risk factors, as well as to test SNPs interactions effect.
Citation Format: Xiaowei(Sherry) Yan, Azadeh Stark, Xin Chu, Ryan Colonie, Jessica Webster, Ling Li, Jill Barnholtz-Sloan, Jeffrey Prichard, Victor Vogel, James F. Evans. Polymorphisms in chronic inflammation mediated pathway genes associated with risk of postmenopausal breast cancer (PMBC). [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 65.