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Functional germline variants in driver genes of breast cancer

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Abstract

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 ≥ 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.

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Acknowledgments

We thank Åsa Ågren (Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Sweden) for her commitment in keeping track of the samples and data and the Northern Sweden Breast Cancer group for providing the clinical data.

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Authors and Affiliations

  1. Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69121, Heidelberg, Germany

    Stella Göhler, Miguel Inacio Da Silva Filho, Kari Hemminki & Asta Försti

  2. Department of Radiation Science, Oncology, Umeå University, 90187, Umeå, Sweden

    Robert Johansson, Roger Henriksson & Per Lenner

  3. Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, 90187, Umeå, Sweden

    Kerstin Enquist-Olsson

  4. Cancer Center Stockholm Gotland, 10239, Stockholm, Sweden

    Roger Henriksson

  5. Center for Primary Health Care Research, Clinical Research Center, Lund University, 20502, Malmö, Sweden

    Kari Hemminki & Asta Försti

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  1. Stella Göhler
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  2. Miguel Inacio Da Silva Filho
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Correspondence to Stella Göhler.

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Göhler, S., Da Silva Filho, M.I., Johansson, R. et al. Functional germline variants in driver genes of breast cancer. Cancer Causes Control 28, 259–271 (2017). https://doi.org/10.1007/s10552-017-0849-3

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  • DOI: https://doi.org/10.1007/s10552-017-0849-3

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