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Breast and ovarian cancer risks in a large series of clinically ascertained families with a high proportion of BRCA1 and BRCA2 Dutch founder mutations
  1. Richard M Brohet1,2,
  2. Maria E Velthuizen3,4,
  3. Frans B L Hogervorst1,
  4. Hanne EJ Meijers-Heijboer5,6,
  5. Caroline Seynaeve7,
  6. Margriet J Collée7,
  7. Senno Verhoef8,
  8. Margreet G E M Ausems4,
  9. Nicoline Hoogerbrugge9,
  10. Christi J van Asperen10,
  11. Encarna Gómez García11,
  12. Fred Menko6,
  13. Jan C Oosterwijk12,
  14. Peter Devilee10,
  15. Laura J van't Veer13,
  16. Flora E van Leeuwen1,
  17. Douglas F Easton14,
  18. Matti A Rookus1,
  19. Antonis C Antoniou14,
  20. HEBON Resource
  1. 1Department of Epidemiology & Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  2. 2Research Center Linnaeus Institute, Spaarne Hospital, Hoofddorp, The Netherlands
  3. 3The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands
  4. 4Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  5. 5Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
  6. 6Department of Clinical Genetics, Free University Medical Center, Amsterdam, The Netherlands
  7. 7Departmentt of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands
  8. 8Familial Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  9. 9Department of Human Genetics, University Medical Center St. Radboud, Nijmegen, The Netherlands
  10. 10Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  11. 11Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
  12. 12Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  13. 13UCFS Departments of Pathology and Laboratory Medicine, The University of California, San Francisco, USA
  14. 14Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, UK
  1. Correspondence to Dr Matti A Rookus, Department of Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands; m.rookus{at}nki.nl

Abstract

Background BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations.

Methods We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a modified segregation analysis model.

Results The average cumulative breast cancer risk by age 70 years was estimated to be 45% (95% CI 36 to 52%) for BRCA1 and 27% (95% CI 14 to 38%) for BRCA2 mutation carriers. The corresponding cumulative risks for ovarian cancer were 31% (95% CI 17 to 43%) for BRCA1 and 6% (95% CI 2 to 11%) for BRCA2 mutation carriers. In BRCA1 families, breast cancer relative risk (RR) increased with more recent birth cohort (pheterogeneity = 0.0006) and stronger family histories of breast cancer (pheterogeneity<0.001). For BRCA1, our data suggest a significant association between the location of the mutation and the ratio of breast to ovarian cancer (p<0.001). By contrast, in BRCA2 families, no evidence was found for risk heterogeneity by birth cohort, family history or mutation location.

Conclusions BRCA1 mutation carriers conferred lower overall breast and ovarian cancer risks than reported so far, while the estimates of BRCA2 mutations were among the lowest. The low estimates for BRCA1 might be due to older birth cohorts, a moderate family history, or founder mutations located within specific regions of the gene. These results are important for a more accurate counselling of BRCA1/2 mutation carriers.

  • Cancer: Breast
  • Clinical Genetics
  • Genetic Epidemiology
  • Oncology

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