title: Functional germline variants in driver genes of breast cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69121, Heidelberg, Germany. stella-goehler@gmx.de.
authors.forename: Stella
authors.initials: S
authors.lastname: Göhler
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69121, Heidelberg, Germany.
authors.forename: Miguel Inacio
authors.initials: MI
authors.lastname: Da Silva Filho
authors.affiliation: Department of Radiation Science, Oncology, Umeå University, 90187, Umeå, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Johansson
authors.affiliation: Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, 90187, Umeå, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Enquist-Olsson
authors.affiliation: Department of Radiation Science, Oncology, Umeå University, 90187, Umeå, Sweden.|Cancer Center Stockholm Gotland, 10239, Stockholm, Sweden.
authors.forename: Roger
authors.initials: R
authors.lastname: Henriksson
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69121, Heidelberg, Germany.|Center for Primary Health Care Research, Clinical Research Center, Lund University, 20502, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Department of Radiation Science, Oncology, Umeå University, 90187, Umeå, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Lenner
authors.affiliation: Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69121, Heidelberg, Germany.|Center for Primary Health Care Research, Clinical Research Center, Lund University, 20502, Malmö, Sweden.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013548:Sweden / Q000453:epidemiology
keywords: Breast cancer; Case–control study; Driver genes; Germline variants; Single nucleotide polymorphism