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Functional germline variants in driver genes of breast cancer

  • Göhler, Stella1
  • Da Silva Filho, Miguel Inacio1
  • Johansson, Robert2
  • Enquist-Olsson, Kerstin3
  • Henriksson, Roger2, 4
  • Hemminki, Kari1, 5
  • Lenner, Per2
  • Försti, Asta1, 5
  • 1 German Cancer Research Center (DKFZ), Department of Molecular Genetic Epidemiology, Im Neuenheimer Feld 580, Heidelberg, 69121, Germany , Heidelberg (Germany)
  • 2 Umeå University, Department of Radiation Science, Oncology, Umeå, 90187, Sweden , Umeå (Sweden)
  • 3 Umeå University, Department of Public Health and Clinical Medicine/Nutritional Research, Umeå, 90187, Sweden , Umeå (Sweden)
  • 4 Cancer Center Stockholm Gotland, Stockholm, 10239, Sweden , Stockholm (Sweden)
  • 5 Lund University, Center for Primary Health Care Research, Clinical Research Center, Malmö, 20502, Sweden , Malmö (Sweden)
Published Article
Cancer Causes & Control
Publication Date
Feb 25, 2017
DOI: 10.1007/s10552-017-0849-3
Springer Nature


PurposeGermline mutations in tumour suppressor genes cause various cancers. These genes are also somatically mutated in sporadic tumours. We hypothesized that there may also be cancer-related germline variants in the genes commonly mutated in sporadic breast tumours.MethodsAfter excluding the well-characterized breast cancer (BC) genes, we screened 15 novel genes consistently classified as BC driver genes in next-generation sequencing approaches for single nucleotide polymorphisms (SNPs). Altogether 40 SNPs located in the core promoter, 5′- and 3′-UTR or which were nonsynonymous SNPs were genotyped in 782 Swedish incident BC cases and 1,559 matched controls. After statistical analyses, further evaluations related to functional prediction and signatures of selection were performed.ResultsTBX3 was associated with BC risk (rs2242442: OR = 0.76, 95% CI 0.64–0.92, dominant model) and with less aggressive tumour characteristics. An association with BC survival and aggressive tumour characteristics was detected for the genes ATR (rs2227928: HR = 1.63; 95% CI 1.00–2.64, dominant model), RUNX1 (rs17227210: HR = 3.50, 95% CI 1.42–8.61, recessive model) and TTN (rs2303838: HR = 2.36; 95% CI 1.04–5.39; rs2042996: HR = 2.28; 95% CI 1.19–4.37, recessive model). According to the experimental ENCODE data all these SNPs themselves or SNPs in high linkage disequilibrium with them (r2 ≥ 0.80) were located in regulatory regions. RUNX1 and TTN showed also several signatures of positive selection.ConclusionThe study gave evidence that germline variants in BC driver genes may have impact on BC risk and/or survival. Future studies could discover further germline variants in known or so far unknown driver genes which contribute to cancer development.

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