Functional analysis—Make or break for cancer predictability

•Copy number variations (CNVs) are quantitative genome divergences like duplications and deletions.•Rare cancer CNVs affect genes associated with hereditary cancer syndromes.•CNV de novo mutations appear orders of magnitude more frequently than point mutations.•Somatic copy number aberrations (CNAs) reflect genomic instabilities acquired during tumorigenesis.•CNAs are generated by error-prone DNA double-strand break repair activities, which represent a potential breast cancer risk marker.

Copy number variations (CNVs) encompass a variety of genetic alterations including deletions and amplifications and cluster in regions of the human genome with intrinsic instability. Small-sized CNVs can act as initial genetic changes giving rise to larger CNVs such as acquired somatic copy number aberrations (CNAs) promoting cancer formation. Previous studies provided evidence for CNVs as an underlying cause of elevated breast cancer risk when targeting breast cancer susceptibility genes and of accelerated breast cancer progression when targeting oncogenes. With the development of novel techniques for genome-wide detection of CNVs at increasingly higher resolution, it became possible to qualitatively and quantitatively analyse manifestation of DNA damage resulting from defects in any of the large variety of DNA double-strand break (DSB) repair mechanisms. Breast carcinogenesis, particularly in familial cases, has been linked with a defect in the homologous recombination (HR) pathway, which in turn switches damage removal towards alternative, more error-prone DSB repair pathways such as microhomology-mediated non-homologous end joining (mmNHEJ). Indeed, increased error-prone DSB repair activities were detected in peripheral blood lymphocytes from individuals with familial breast cancer risk independently of specific gene mutations. Intriguingly, sequence analysis of breakpoint regions revealed that the majority of genome aberrations found in breast cancer specimens are formed by mmNHEJ. Detection of pathway-specific error-prone DSB repair activities by functional testing was proposed to serve as biomarker for hereditary breast cancer risk and responsiveness to therapies targeting HR dysfunction. Identification of specific error-prone DSB repair mechanisms underlying CNAs and ultimately mammary tumour formation highlights potential targets for future breast cancer prevention regimens.