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CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women
  1. Muriel A Adank1,
  2. Marianne A Jonker2,
  3. Irma Kluijt3,
  4. Saskia E van Mil1,
  5. Rogier A Oldenburg4,
  6. Wolter J Mooi5,
  7. Frans B L Hogervorst3,
  8. Ans M W van den Ouweland4,
  9. Johan J P Gille1,
  10. Marjanka K Schmidt6,
  11. Aad W van der Vaart2,
  12. Hanne Meijers-Heijboer1,
  13. Quinten Waisfisz1
  1. 1Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands
  2. 2Department of Mathematics, Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands
  3. 3Family Cancer Clinic, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  4. 4Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
  5. 5Department of Pathology, VU University Medical Centre, Amsterdam, The Netherlands
  6. 6Division of Experimental Therapy and Molecular Pathology, Division of Epidemiology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  1. Correspondence to Dr Q Waisfisz, VU University Medical Centre, Amsterdam, Department of Clinical Genetics, section Oncogenetics, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands; q.waisfisz{at}


Background Mutations in the CHEK2 gene confer a moderately increased breast cancer risk. The risk for female carriers of the CHEK2*1100delC mutation is twofold increased. Breast cancer risk for carrier women is higher in a familial breast cancer setting which is due to coinheritance of additional genetic risk factors. This study investigated the occurrence of homozygosity for the CHEK2*1100delC allele among familial breast cancer cases and the associated breast cancer risk.

Methods and results Homozygosity for the CHEK2*1100delC allele was identified in 8/2554 Dutch independent familial non-BRCA1/2 breast cancer cases. The genotype relative risk for breast cancer of homozygous and heterozygous familial breast cancer cases was 101.34 (95% CI 4.47 to 121 000) and 4.04 (95% CI 0.88 to 21.0), respectively. Female homozygotes appeared to have a greater than twofold increased breast cancer risk compared to familial CHEK2*1100delC heterozygotes (p=0.044). These results and the occurrence of multiple primary tumours in 7/10 homozygotes indicate a high cancer risk in homozygous women from non-BRCA1/2 families.

Conclusions Intensive breast surveillance is therefore justified in these homozygous women. It is concluded that diagnostic testing for biallelic mutations in CHEK2 is indicated in non-BRCA1/2 breast cancer families, especially in populations with a relatively high prevalence of deleterious mutations in CHEK2.

  • CHEK2*1100delC
  • CHEK2
  • breast cancer
  • cancer risk
  • genetic epidemiology
  • cancer: colon
  • genetic screening/counselling
  • Diagnostics tests
  • genetics
  • cancer: breast
  • epidemiology
  • molecular genetics
  • clinical genetics

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  • Funding This study was funded by The Netherlands Organisation for Scientific Research (NWO) as part of a ZonMw/VIDI grant number 91756341 and the Dutch Cancer Society grant NKI2009-4363.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Written informed consent was obtained from all homozygous females (before death from deceased patients) and their family members to use their DNA for further investigation and to search for new cancer susceptibility genes (following institutional guidelines). Material of additional patients was used following institutional guidelines, breast cancer cases gave informed consent to screen for susceptibility genes. DNA from irreversibly anonymised controls was used following the code for Proper Secondary Use of Human Tissue.

  • Provenance and peer review Not commissioned; externally peer reviewed.