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Functional germline variants in driver genes of breast cancer

Göhler, Stella; da Silva Filho, Miguel Inacio LU ; Johansson, Robert; Enquist-Olsson, Kerstin; Henriksson, Roger; Hemminki, Kari LU ; Lenner, Per and Försti, Asta LU (2017) In Cancer Causes and Control 28(4). p.259-271
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... (More)

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 (r2 ≥ 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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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast cancer, Case–control study, Driver genes, Germline variants, Single nucleotide polymorphism
in
Cancer Causes and Control
volume
28
issue
4
pages
259 - 271
publisher
Springer
external identifiers
  • scopus:85013755443
  • wos:000398480200001
ISSN
0957-5243
DOI
10.1007/s10552-017-0849-3
language
English
LU publication?
yes
id
196b1da1-ab49-4c82-9de0-aca4138cf71a
date added to LUP
2017-03-09 12:42:41
date last changed
2018-01-07 11:54:48
@article{196b1da1-ab49-4c82-9de0-aca4138cf71a,
  abstract     = {<p>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<sup>2</sup> ≥ 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.</p>},
  author       = {Göhler, Stella and da Silva Filho, Miguel Inacio and Johansson, Robert and Enquist-Olsson, Kerstin and Henriksson, Roger and Hemminki, Kari and Lenner, Per and Försti, Asta},
  issn         = {0957-5243},
  keyword      = {Breast cancer,Case–control study,Driver genes,Germline variants,Single nucleotide polymorphism},
  language     = {eng},
  month        = {02},
  number       = {4},
  pages        = {259--271},
  publisher    = {Springer},
  series       = {Cancer Causes and Control},
  title        = {Functional germline variants in driver genes of breast cancer},
  url          = {http://dx.doi.org/10.1007/s10552-017-0849-3},
  volume       = {28},
  year         = {2017},
}