Are germ line copy number variations (CNV) of gene regulative Elements responsible for hereditary breast cancer?

Introduction:

BRCA1/2 are responsible for up to 30% of hereditary breast cancer cases. Additional 10% could be assigned to other moderate and low penetrant genes. The rest remains still unexplained. Therefore, we searched for dose effects by CNVs differing between hereditary breast cancer patients without mutations in BRCA1/2 and a control group above 69 years without any personal and familial cancer history.

Material and methods:

DNA was isolated from blood by standard procedures. For CNV detection we used array based comparative genome hybridization (aCGH) optimized for CNV analysis from Agilent. In order to equal individual CNVs in the reference we used male DNA from Promega – pool of 12 Caucasian individuals -. We compared CNVs from six patients with hereditary breast cancer and six probands from the control cohort.

Results:

We could identify 107 regions covering CNVs with opposite genomic dose in both groups. Eight loci were significant with chi² test lower 0.05. Most differentiating CNV is in 14q21.1 (41610227 – 41610839) [chi²= 0,006261], and 1q21.3(152761081 – 152770183) [chi²= 0,015]. Due to the noticeable absence of coding regions in most of those CNVs regions, we recognized regulative elements like Transcription Factor ChIP-seq motifs, Conserved Transcription Factor Binding Sites, or mRNA sites.

Discussion:

Our data suggest hereditary breast cancer effects by CNVs. Many significant differences in the genomic dose between both groups hit regulative elements, probably relevant for gene regulation. Perhaps, the higher dose in 1q21.3 could result in protection against developing cancer. Whereas a higher dose in 14q21.1 is more correlated with hereditary breast cancer.