A case-control evaluation of 143 single nucleotide polymorphisms for breast cancer risk stratification with classical factors and mammographic density

Int J Cancer. 2020 Apr 15;146(8):2122-2129. doi: 10.1002/ijc.32541. Epub 2019 Jul 13.


Panels of single nucleotide polymorphisms (SNPs) stratify risk for breast cancer in women from the general population, but studies are needed assess their use in a fully comprehensive model including classical risk factors, mammographic density and more than 100 SNPs associated with breast cancer. A case-control study was designed (1,668 controls, 405 cases) in women aged 47-73 years attending routine screening in Manchester UK, and enrolled in a wider study to assess methods for risk assessment. Risk from classical questionnaire risk factors was assessed using the Tyrer-Cuzick model; mean percentage visual mammographic density was scored by two independent readers. DNA extracted from saliva was genotyped at selected SNPs using the OncoArray. A predefined polygenic risk score based on 143 SNPs was calculated (SNP143). The odds ratio (OR, and 95% confidence interval, CI) per interquartile range (IQ-OR) of SNP143 was estimated unadjusted and adjusted for Tyrer-Cuzick and breast density. Secondary analysis assessed risk by oestrogen receptor (ER) status. The primary polygenic risk score was well calibrated (O/E OR 1.10, 95% CI 0.86-1.34) and accuracy was retained after adjustment for Tyrer-Cuzick risk and mammographic density (IQ-OR unadjusted 2.12, 95% CI% 1.75-2.42; adjusted 2.06, 95% CI 1.75-2.42). SNP143 was a risk factor for ER+ and ER- breast cancer (adjusted IQ-OR, ER+ 2.11, 95% CI 1.78-2.51; ER- 1.81, 95% CI 1.16-2.84). In conclusion, polygenic risk scores based on a large number of SNPs improve risk stratification in combination with classical risk factors and mammographic density, and SNP143 was similarly predictive for ER-positive and ER-negative disease.

Keywords: SNPs; Tyrer-Cuzick; breast cancer; breast density; risk prediction; risk stratification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Breast Density
  • Breast Neoplasms / diagnostic imaging
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Mammography
  • Middle Aged
  • Overweight / genetics
  • Overweight / pathology
  • Polymorphism, Single Nucleotide
  • Risk