Abstract 2834: Genetic variants in TGFβ pathway genes and ovarian cancer risk

Abstract

Abstract The transforming growth factor (TGF) β signaling pathway plays a crucial role in cell proliferation, differentiation, apoptosis, extracellular matrix production and other cellular functions. Dysregulation and genetic variations of major genes in this pathway may be involved in the process of carcinogenesis. In this study, 218 single nucleotide polymorphisms (SNPs) in 21 major genes of TGFβ pathway were genotyped in 339 Caucasian ovarian cancer cases and 349 age, gender, and ethnicity matched controls. We analyzed the association between these SNPs and the risk as well as clinical outcomes of ovarian cancer. In the risk analysis, 16 SNPs were found significantly associated with ovarian risk, among these SNPs, a dose-response effect of increased risk for ovarian cancer with increased unfavorable genotype (UFG: defined as the allele related with increased ovarian risk) was observed (P for trend < 0.0001). Compared with individuals carrying ≤ 6 UFGs, subjects carrying ≥ 9 UFGs conferred a 3.7-fold increased risk of ovarian cancer (ORs =3.71, 95%CI=2.52-5.45, P<0.0001). The most significant individual association was found for INHBC: rs2228225. Patients carrying at least one variant allele of this SNP conferred 63% increased risk for ovarian cancer (OR = 1.63, 95%CI= 1.20-2.22, P=0.0018). Potential high-order gene-gene interactions were identified using the classification and regression tree analysis (CART). Eight terminal nodes were identified representing eight groups of patients with different probability for ovarian cancer (ORs ranging from 2.87 to 6.68). In the analysis of clinical outcomes, 13 SNPs were significantly associated with the risk of death. The top two SNPs were from BMP1. Patients carried rare homozygous genotype of either one of the SNP has a nearly two-fold increased risk for death (rs3857979: HR= 1.80, 95%CI= 1.23- 2.65, P=0.0026; rs4075478: HR=1.89, 95%CI=1.22- 2.91, P=0.004). A cumulative effect was also observed (P for trend < 0.0001). The median survival times decreased from 83.3 months for patients with ≤5UFGs to 26.8 months for those with ≥ 9UFGs (log rank P < 0.0001). Survival tree analysis identified eight terminal nodes representing eight groups of patients with different survival probability. Interestingly, the two BPM1 SNPs that were most significant in survival analysis were also significantly associated with poor response for chemotherapy (rs3857979: OR= 1.90, 95%CI= 1.04-3.48, P=0.0375; rs4075478: HR=2.39, 95%CI=1.17-4.86, P=0.0166), indicating that these two SNPs were predictive markers for response. In conclusion, our result demonstrates that genetic variations within TGFβ pathway may have modulate the risk and clinical outcomes of ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2834.