title: Variation in mutation spectrum partly explains regional differences in the breast cancer risk of female BRCA mutation carriers in the Netherlands.
abstract: BACKGROUND
  We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) older than 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk.
  
  
  METHODS
  This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with HRs and ORs. HRs were adjusted for birth year and mutation spectrum.
  
  
  RESULTS
  All BRCA1 carriers and BRCA2 carriers younger than 60 had a significantly lower breast cancer risk in the Northern Netherlands; HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands [HR, 3.99; 95% confidence interval (CI), 1.11-14.35]. Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60, and BRCA2 ≥60 years by -3%, +32%, and +11% to 0.75, 0.50, and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR, 1.03; 95% CI, 0.97-1.09).
  
  
  CONCLUSIONS
  Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers.
  
  
  CONCLUSIONS
  The increased risk in BRCA2 carriers older than 60 may warrant extension of intensive breast screening beyond age 60.
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. j.r.vos01@umcg.nl.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Vos
authors.affiliation: Department of Gynecological Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Natalia
authors.initials: N
authors.lastname: Teixeira
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Dorina M
authors.initials: DM
authors.lastname: van der Kolk
authors.affiliation: Department of Gynecological Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Marian J E
authors.initials: MJ
authors.lastname: Mourits
authors.affiliation: Department of Epidemiology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Matti A
authors.initials: MA
authors.lastname: Rookus
authors.affiliation: Department of Epidemiology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Flora E
authors.initials: FE
authors.lastname: van Leeuwen
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: Margriet
authors.initials: M
authors.lastname: Collée
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Christi J
authors.initials: CJ
authors.lastname: van Asperen
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Arjen R
authors.initials: AR
authors.lastname: Mensenkamp
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Margreet G E M
authors.initials: MG
authors.lastname: Ausems
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Theo A M
authors.initials: TA
authors.lastname: van Os
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Hanne E J
authors.initials: HE
authors.lastname: Meijers-Heijboer
authors.affiliation: Department of Clinical Genetics, University Hospital Maastricht, Maastricht, the Netherlands.
authors.forename: Encarna B
authors.initials: EB
authors.lastname: Gómez-Garcia
authors.affiliation: The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, the Netherlands.
authors.forename: Hans F
authors.initials: HF
authors.lastname: Vasen
authors.affiliation: Department of Epidemiology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Brohet
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: van der Hout
authors.affiliation: Department of Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Jansen
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Jan C
authors.initials: JC
authors.lastname: Oosterwijk
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Geertruida H
authors.initials: GH
authors.lastname: de Bock
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009426:Netherlands; D012307:Risk Factors
chemical_list: D024682:BRCA2 Protein