title: Prevalence of theCHEK2R95* germline mutation.
abstract: BACKGROUND
  While germlineCHEK2mutations have been linked to a moderately elevated cancer risk, to date, a limited number of such mutations have been identified. Recently, we reported a germline nonsense mutation (C283T; R95*), introducing an early stop-codon, in two Norwegian patients diagnosed with locally advanced breast cancer. Both patients were resistant to anthracycline therapy, resembling what has been observed forTP53mutations.
  
  
  METHODS
  In the present study, we screened a large population based sample, including 3748 non-cancer individuals and 7081 incident cancer cases (breast cancer,n= 1717; prostate cancern= 2501, lung cancern= 1331 and colorectal cancern= 1532), for the distribution ofCHEK2R95*.
  
  
  RESULTS
  We found that 12 individuals (0.11 %) carried the R95* variant: 4 non-cancer individuals (0.11 %), 4 breast cancer cases (0.23 %), and 4 prostate cancer cases (0.16 %). Although the low number of observations precluded formal statistical assessment, our data may indicate an elevated risk for breast (OR: 2.19, 95 % CI: 0.55-8.75) and prostate cancer (OR: 1.5, 95 % CI: 0.36-6.00) associated withCHEK2R95*. By mining international databanks, we found no individuals carrying the R95* mutation, indicating it to be restricted to the Norwegian population.
  
  
  CONCLUSIONS
  We provide proof-of-concept that previously unknownCHEK2germline mutations may be present in certain populations. Notably, germline mutations in tumours are in general missed by contemporary massive parallel sequencing strategies, since tumour mutations are usually filtered against the germline. The fact that theCHEK2R95* mutation may be associated with resistance to anthracyclines in cancer patients emphasizes its possible clinical importance.
authors.affiliation: Section of Oncology, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway ; Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Stian
authors.initials: S
authors.lastname: Knappskog
authors.affiliation: Section of Oncology, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway ; Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Beryl
authors.initials: B
authors.lastname: Leirvaag
authors.affiliation: Section of Oncology, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway ; Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Liv B
authors.initials: LB
authors.lastname: Gansmo
authors.affiliation: Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Romundstad
authors.affiliation: Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Hveem
authors.affiliation: Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Vatten
authors.affiliation: Section of Oncology, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway ; Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Per E
authors.initials: PE
authors.lastname: Lønning