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Functional germline variants in driver genes of breast cancer
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
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2017 (English)In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 28, no 4, 259-271 p.Article in journal (Refereed) Published
Abstract [en]

Purpose Germline 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. Methods After 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. Results TBX3 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 (r (2) ae<yen> 0.80) were located in regulatory regions. RUNX1 and TTN showed also several signatures of positive selection. Conclusion The 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.

Place, publisher, year, edition, pages
SPRINGER , 2017. Vol. 28, no 4, 259-271 p.
Keyword [en]
Breast cancer, Driver genes, Germline variants, Case-control study, Single nucleotide polymorphism
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-134217DOI: 10.1007/s10552-017-0849-3ISI: 000398480200001PubMedID: 28238063OAI: oai:DiVA.org:umu-134217DiVA: diva2:1110655
Available from: 2017-06-16 Created: 2017-06-16 Last updated: 2017-06-16

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Citation style
  • apa
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