Polymorphisms in the Janus kinase 2 (JAK)/signal transducer and activator of transcription (STAT) genes: putative association of the STAT gene region with familial breast cancer

Abstract

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway mediates the signals of a wide range of cytokines, growth factors and hormones. Thus, aberrant activation of the JAK/STAT pathway may predispose to malignancy due to deregulation of proliferation, differentiation or apoptosis. In this study, we investigated whether genetic variation in the JAK2 gene and the STAT gene region (STAT3, STAT5A and STAT5B) is associated with breast cancer (BC) risk. We carried out a case-control study using a German sample set with 441 familial, unrelated BC cases and 552 controls matched by age, ethnicity and geographical region. A second similar set (381 cases, 460 controls) was applied to validate the findings. Haplotypes in the JAK2 gene were not associated with the risk of BC. In the STAT gene region, the rare haplotype CAGCC containing the variant alleles of each single nucleotide polymorphism (SNP) was associated with an increased risk odds ratio (ORZ5.83, 95% confidence interval (CI) 1.51-26.28). According to Akaike's information criterion, the best model to describe the relationship between the haplotypes and BC was based on the SNPs rs6503691 (STAT5B) and rs7211777 (STAT3). Carriers of the AC haplotype, which represents the variant alleles of both SNPs, were at an increased risk (ORZ1.41, 95% CI 1.09-1.82). A decreased risk was observed for carriers of the AT haplotype (ORZ0.60, 95% CI 0.38-0.94). Furthermore, individuals with the AC/GC diplotype were at a significantly increased risk (ORZ1.88, 95% CI 1.13-3.14). The observed genetic variation may also influence the inter-individual variation in response to STAT-signalling targeted therapy.

A polymorphism associated with STAT3 expression and response of chronic myeloid leukemia to interferon

“…It is notable that this SNP has been recently reported to be associated with the risk of developing breast cancer. 19 We evaluated the impact of rs6503691 in more detail by taking other prognostic factors into account. On univariate analysis, the leukocyte count, percentage blasts, spleen size, Sokal score and rs6503691 genotype were all significantly associated with response (Table 1B).…”

STAT3 gene polymorphisms and susceptibility to non-small cell lung cancer

“…However, there is only one article that has investigated STAT3 polymorphisms in relation to cancer risk (Vaclavicek et al, 2007). Vaclavicek et al (2007) reported that, although rs2293152 and rs7211777 in the STAT3 gene were not individually associated with familial breast cancer, the haplotypes characterized by rs7211777 and a neighboring SNP rs6503691 in the STAT5B gene were found to modify the risk of familial breast cancer. In the present study, we showed for the first time that SNPs in the STAT3 gene were associated with decreased NSCLC risk.…”

“…These SNPs were selected based on i) previously published associations with various diseases (Ito et al, 2007;Vaclavicek et al, 2007;Barrett et al, 2008), thus increasing the chance of selecting SNPs with functional consequences, and ii) minor allele frequency of ≥0.1 in the Chinese population, using HapMap and National Center for Biotechnology Information dbSNP public databases.…”

“…Despite the important role of STAT3 in cancer development and progression, association studies on single nucleotide polymorphisms (SNPs) in the STAT3 gene with risk of cancer have been rare (Vaclavicek et al, 2007) and there is no data on STAT3 polymorphisms and risk of lung cancer. It has been reported that overexpression of STAT3 is correlated with growth, survival, and radioresistance of NSCLC cells, and that STAT3 inhibition could inhibit tumorigenic ability and enhance the radiosensitivity of NSCLC cells both in vitro and in vivo (Yin et al, 2010;Hsu et al, 2011).…”

SNPs within the GH-signaling pathway are associated with the early IGF1 response to GH replacement therapy in GHD adults

“…Two SNPs in the JAK2 gene have been associated with central adiposity (rs7849191) and blood lipid levels (rs3780378) (21). Lastly, STAT5B SNP rs6503691 has been associated with breast cancer (22) and cholesterol levels in children with idiopathic GHD before, during, and after GH replacement (23), and SOCS2 SNP rs11107116 has been associated with peak height velocity during puberty (24) and adult height (25).…”