Association Study Of Polymorphisms In Fgfr2 And Tnrc9 Genes With The Susceptibility Of Breast Cancer

Breast cancer is the most common cancer and the leading cause of cancer related death among women worldwide, accounting for 23%. Although the incidence rate of breast cancer in China is about one-third of that in the United States, it has been significantly increasing dramatically in recent years in both urban and rural areas, especially in big cities such as Shanghai, Beijing and et al. Breast cancer has already been one of main causes contributing to disease related deaths and a serious one to be resolved in public health. However, the exact mechanisms of breast cancer are still unclear. It is well accepted that the etiology of breast cancer appears to entail a complex combination of genetic and environmental.Individuals with different genetic backgrounds differ from risk of breast cancer. So the most important task is identification of the breast cancer susceptibility genes in high risk population. Twin and family-based studies indicate that a substantial proportion of breast cancer is due to inherited susceptibility, but only 5% cases are associated with inherited mutations of known high-penetrance genes (e.g., BRCA1, BRCA2, ATM et al.). Thus, it is crucial to investigate other genetic risk factors of breast cancer in general population, especially low-penetrance gene.Genome-wide association study (GWAS) has been one of the powerful tools for low-penetrance gene/loci study in complex diseases. Recently, a large-scale genome-wide association study identified five new independent low-penetrance susceptibility loci that were strongly associated with breast cancer in populations of diverse ethnicity. Four of these (FGFR2, TNRC9, MAP3K1 and LSP1) contain plausible causative genes, among which FGFR2 and TNRC9 have the most significant effects to breast cancer risk. FGFR2 belongs to the receptor tyrosine kinases (RTKs), which may increase proliferation, differentiation and enhance the invasiveness by activating its signal transduction pathways. Besides, over-expression of FGFR2 is observed in breast cancer cell lines, as well as in breast tumor tissues. TNRC9 belongs to the large family of HMG-box proteins that function as architectural factors in the modification of chromatin structure by bending and unwinding DNA. And it has been implicated in breast cancer metastasis to the bone. Thus, we conducted a case-control study aiming to investigate the association of FGFR2 and TNRC9 genes polymorphisms with breast cancer risk in a Chinese population.PartⅠGenetic variants in FGFR2 contribute to susceptibility of breast cancer in Chinese womenFibroblast growth factor receptor 2 (FGFR2) belongs to the FGFR family, which plays an important role in cell growth, invasiveness, motility and angiogenesis. In human breast cancer, expression of FGFR2 is estrogen receptor (ER)-dependent and correlates with a lower rate of apoptosis. Recently, whole genome association studies have identified several single nucleotide polymorphisms (SNPs) of FGFR2 as novel breast cancer susceptibility loci. Thus, we hypothesized that variants of FGFR2 were associated with breast cancer susceptibility in Chinese women.[Objective] To comprehensively investigate the associations of polymorphisms in FGFR2 and breast cancer risk in Chinese women, and whether these associations are stronger in women with a reproductive history suggestive of greater exposure to endogenous estrogens.[Methods] This case-control study included 1,049 histologically confirmed incident breast cancer patients and 1,073 cancer-free controls frequency-matched for age and area. We genotyped three FGFR2 polymorphisms (rs2981582, rs1219648 and rs2420946) using the SNPstream platform. [Results] Each of the three SNPs was significantly associated with increased breast cancer risk in a dose-dependent manner. Compared to women with 0-2 risk loci, those with 3 risk loci had a 1.36-fold increased odds of breast cancer (95% CI = 1.13-1.62, P = 0.001). In stratified analyses, associations between the presence of 3 risk loci and breast cancer were stronger among women with ER and/or progesterone receptor (PR)-positive cancers, premenopausal women, and women with an older age at first live birth. Furthermore, there was a significant additive interaction between risk genotypes and menopausal status (P for multiplication interaction/additive interaction: 0.083/0.037).[Conclusion] These findings indicate that genetic variants in FGFR2 may contribute to breast cancer occurrence in Chinese women, possibly through pathways related to estrogen and/or progesterone.PartⅡGenetic variants in TNRC9 and risk of breast cancer: a case-control analysisTrinucleotide repeat-containing 9 (TNRC9) belongs to the large and diverse family of HMG-box proteins that function as architectural factors in the modification of chromatin structure by bending and unwinding DNA. And it has been implicated in breast cancer metastasis to the bone. Recently, several single nucleotide polymorphisms (SNPs) of TNRC9 were identified as novel breast cancer susceptibility loci by whole genome association studies, especially in estrogen receptor positive tumors. Thus, we hypothesized that polymorphisms of TNRC9 were associated with breast cancer risk in Chinese women.[Objective] To investigate the roles of the polymorphisms in TNRC9 in the development of breast cancer.[Methods] We conducted a case-control study with 1,049 breast cancer patients and 1,073 cancer-free controls in a Chinese population, and genotyped three polymorphisms (rs3803662, rs12443621 and rs8051542) of the TNRC9 gene using the SNPstream platform.[Results] None of the three polymorphisms were significantly associated with breast cancer risk in single locus analyses. However, in statification analyses for ER/PR, associations between the rs12443621, rs8051542 and breast cancer were stronger among women with ER positive cancers.[Conclusion] Our data indicate that TNRC9 polymorphisms may be the susceptibility loci for women with ER positive cancers in Chinese population.