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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
Author(s) -
Hilbers Florentine S.,
Hof Peter J.,
Meijers Caro M.,
Mei Hailiang,
Michailidou Kyriaki,
Dennis Joe,
Hogervorst Frans B. L.,
Nederlof Petra M.,
Asperen Christi J.,
Devilee Peter
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33039
Subject(s) - breast cancer , genetics , proband , chek2 , haplotype , allele , exome sequencing , biology , population , single nucleotide polymorphism , exome , cancer , genotype , germline mutation , medicine , gene , mutation , environmental health
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.