BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors

Genet Med. 2019 Aug;21(8):1708-1718. doi: 10.1038/s41436-018-0406-9. Epub 2019 Jan 15.

Abstract

Purpose: Breast cancer (BC) risk prediction allows systematic identification of individuals at highest and lowest risk. We extend the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk model to incorporate the effects of polygenic risk scores (PRS) and other risk factors (RFs).

Methods: BOADICEA incorporates the effects of truncating variants in BRCA1, BRCA2, PALB2, CHEK2, and ATM; a PRS based on 313 single-nucleotide polymorphisms (SNPs) explaining 20% of BC polygenic variance; a residual polygenic component accounting for other genetic/familial effects; known lifestyle/hormonal/reproductive RFs; and mammographic density, while allowing for missing information.

Results: Among all factors considered, the predicted UK BC risk distribution is widest for the PRS, followed by mammographic density. The highest BC risk stratification is achieved when all genetic and lifestyle/hormonal/reproductive/anthropomorphic factors are considered jointly. With all factors, the predicted lifetime risks for women in the UK population vary from 2.8% for the 1st percentile to 30.6% for the 99th percentile, with 14.7% of women predicted to have a lifetime risk of ≥17-<30% (moderate risk according to National Institute for Health and Care Excellence [NICE] guidelines) and 1.1% a lifetime risk of ≥30% (high risk).

Conclusion: This comprehensive model should enable high levels of BC risk stratification in the general population and women with family history, and facilitate individualized, informed decision-making on prevention therapies and screening.

Keywords: BOADICEA; PRS; breast cancer; rare variants; risk prediction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / genetics
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Breast Neoplasms / epidemiology*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Checkpoint Kinase 2 / genetics
  • Fanconi Anemia Complementation Group N Protein / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing*
  • Humans
  • Multifactorial Inheritance / genetics
  • Mutation / genetics
  • Ovarian Neoplasms / epidemiology
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Polymorphism, Single Nucleotide / genetics
  • Risk Assessment
  • Risk Factors

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Fanconi Anemia Complementation Group N Protein
  • PALB2 protein, human
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human