Clustering of known low and moderate risk alleles rather than a novel recessive high‐risk gene in non‐BRCA1/2 sib trios affected with breast cancer

Abstract

Breast cancer risk is approximately twice as high in first-degree relatives of female breast cancer cases than in women in the general population. Less than half of this risk can be attributed to the currently known genetic risk factors. Recessive risk alleles represent a relatively underexplored explanation for the remainder of familial risk. To address this, we selected 19 non-BRCA1/2 breast cancer families in which at least three siblings were affected, while no first-degree relatives of the previous or following generation had breast cancer. Germline DNA from one of the siblings was subjected to exome sequencing, while all affected siblings were genotyped using SNP arrays to assess haplotype sharing and to calculate a polygenic risk score (PRS) based on 160 low-risk variants. We found no convincing candidate recessive alleles among exome sequencing variants in genomic regions for which all three siblings shared two haplotypes. However, we found two families in which all affected siblings carried the CHEK2*1100delC. In addition, the average normalized PRS of the "recessive" family probands (0.81) was significantly higher than that in both general population cases (0.35, P = .026) and controls (P = .0004). These findings suggest that the familial aggregation is, at least in part, explained by a polygenic effect of common low-risk variants and rarer intermediate-risk variants, while we did not find evidence of a role for novel recessive risk alleles.

Population‐specific validation and comparison of the performance of 77‐ and 313‐variant polygenic risk scores for breast cancer risk prediction

“…[19][20][21] The PRSMAN panel was designed to target 883 PRS-associated variants in breast, ovarian, and other cancer types that were published by July 2020 (Table S1). 8,10,[15][16][17][22][23][24][25][26][27][28][29][30][31][32][33][34][35] The Roche probe design algorithm excluded 39 SNPs from the PRSMAN panel before its production. The final 844 targeted SNPs are listed in Table S2.…”