The impact of a panel of 18 single nucleotide polymorphisms on breast cancer risk in women attending a UK familial-screening clinic: A case-control study

Background:Breast cancer familial-risk clinics offer screening and preventive strategies. Whilst BRCA1/BRCA2 genetic testing provides important risk information for some women, panels of more common breast cancer risk genetic variants may have relevance to greater numbers of women with familial risk.
Methods:Three polygenic risk scores(PRS) based on 18 single nucleotide polymorphisms(SNPs) were investigated in a case-control study of women attending a familial-risk clinic. PRS were derived from published general European population allele odds ratios and frequencies (18-SNPs-SNP18). In women with BRCA1/BRCA2 mutations, 3 SNPs/13 SNPs, respectively generated the PRS estimates. In total 364 incident breast cancer cases(112 with BRCA1/2 mutations) were matched to 1605 controls(691-BRCA1/2) by age last mammogram and BRCA1/2 genetic test result. 87 women with cancer before attendance were also considered. Logistic regression was used to measure PRS performance through odds ratios per inter-quartile range(IQ-OR) and calibration of the observed to expected(O/E) logarithm relative risk when unadjusted and adjusted for phenotypic risk factors assessed by the Tyrer-Cuzick(TC) model.
Results:SNP18 was predictive for non-carriers of BRCA1/2 mutations (IQ-OR 1.55, 95%CI:1.29-1.87, O/E 96%). Findings were unaffected by adjustment from TC (IQ-OR 1.56, 95%CI:1.29-1.89) or when prior cancers were included (IQ-OR 1.55, 95%CI:1.30-1.87). There was some evidence to support polygenic scores with weights for individuals with BRCA1/2 mutations (BRCA1 IQ-OR 1.44, 95%CI:1.17-1.76;BRCA2 IQ-OR 1.44, 95%CI:0.90-2.31).
Conclusion:Polygenic risk scores may be used to refine risk assessment for women at increased familial risk who test negative/have low likelihood of BRCA1/2 mutations. They may alter the recommended prevention strategy for many women attending family-history clinics.