Article Text

Download PDFPDF
Original article
Addition of a 161-SNP polygenic risk score to family history-based risk prediction: impact on clinical management in non-BRCA1/2 breast cancer families
  1. Inge M M Lakeman1,
  2. Florentine S Hilbers1,2,
  3. Mar Rodríguez-Girondo3,
  4. Andrew Lee4,
  5. Maaike P G Vreeswijk1,
  6. Antoinette Hollestelle5,
  7. Caroline Seynaeve5,
  8. Hanne Meijers-Heijboer6,
  9. Jan C Oosterwijk7,
  10. Nicoline Hoogerbrugge8,
  11. Edith Olah9,
  12. Hans F A Vasen10,
  13. Christi J van Asperen11,
  14. Peter Devilee1,12
  1. 1 Department of Human Genetics, Leids Universitair Medisch Centrum, Leiden, The Netherlands
  2. 2 Breast International Group (BIG), Brussels, Belgium
  3. 3 Department of Medical Statistics and Bioinformatics, Leids Universitair Medisch Centrum, Leiden, The Netherlands
  4. 4 Public Health and Primary Care, Centre for Cancer Gentic Epidemiology, Cambridge University, Cambridge, UK
  5. 5 Department of Medical Oncology, Erasmus MC Kanker Instituut, Rotterdam, The Netherlands
  6. 6 Department of Clinical Genetics, VU medisch centrum, Amsterdam, The Netherlands
  7. 7 Department of Genetics, Universitair Medisch Centrum Groningen, Groningen, The Netherlands
  8. 8 Department of Human Genetics, Universitair Medisch Centrum Sint Radboud, Nijmegen, The Netherlands
  9. 9 Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
  10. 10 Department of Gastroenterology and Hepatology, Leids Universitair Medisch Centrum, Leiden, The Netherlands
  11. 11 Department of Clinical Genetics, Leids Universitair Medisch Centrum, Leiden, The Netherlands
  12. 12 Department of Pathology, Leids Universitair Medisch Centrum, Leiden, The Netherlands
  1. Correspondence to Dr Peter Devilee, Human Genetics, Leids Universitair Medisch Centrum, Leiden 2333ZA, Netherlands; p.devilee{at}


Background The currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based polygenic risk score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families.

Methods 101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm breast cancer lifetime risk with the effect of the sPRS.

Results The mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95% CI 1.03 to 1.28, p=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7% and 19.8 % of the women according to breast screening guidelines from the USA (National Comprehensive Cancer Network), UK (National Institute for Health and Care Excellence and the Netherlands (Netherlands Comprehensive Cancer Organisation), respectively.

Conclusion Our results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families.

  • cancer: breast
  • clinical genetics
  • genetic epidemiology
  • genetic screening/counselling
  • polygenic risk score

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • IMML and FSH contributed equally.

  • Contributors PD and CvA designed and supervised the project. AH, CS, HMH, JO, NH, EO, HV, and CvA have recruited the included breast cancer families and provided the DNA samples. MV, and FH contributed to DNA sample preparation. FH, and IL were responsible for data acquisition. AL has calculated the BOADICEA scores. IL analysed the results with support from MRG. IL, MRG, PD and CvA were involved in data interpretation. IL wrote the manuscript with support from MRG, CvA and PD. All authors read and approved the final manuscript.

  • Funding This work was supported by the Dutch Cancer Society (KWF), grants UL2009-4388 and UL2014-7473.

  • Competing interests None declared.

  • Patient consent for publication Not required.

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

  • Data availability statement Data are available upon reasonable request. No data are available.