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¹ Division of Molecular Genetic Epidemiology C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
² Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Center of Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Cologne, Germany
³ Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
⁴ Department of Gynaecology and Obstetrics, Klinikum rechts der Isar at the Technical University, Munich, Germany
⁵ Division of Oncology, Department of Gynaecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany
⁶ Institute of Human Genetics, University of Regensburg, Regensburg, Germany
⁷ Division of Molecular Genetics, Department of Gynaecology and Obstetrics, Clinical Center University of Düsseldorf, Düsseldorf, Germany
⁸ Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
⁹ Center for Family and Community Medicine, Karolinska Institute, Huddinge, Sweden

(Requests for offprints should be addressed to A Vaclavicek; Email: a.vaclavicek{at}dkfz.de)

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 (OR = 5.83, 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 (OR = 1.41, 95% CI 1.09–1.82). A decreased risk was observed for carriers of the AT haplotype (OR = 0.60, 95% CI 0.38–0.94). Furthermore, individuals with the AC/GC diplotype were at a significantly increased risk (OR = 1.88, 95% CI 1.13–3.14). The observed genetic variation may also influence the inter-individual variation in response to STAT-signalling targeted therapy.

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