Germline Genomic Copy Number Variation Contribution to Cancer Predisposition

Abstract

Abstract The majority of familial cancer remains with unknown genetic aetiology. Issues impairing the discovery of new genes in complex diseases such as cancer include multifactorial origin, incomplete penetrance of the disease and late‐onset. The authors present an outline of the contribution of constitutive deoxyribonucleic acid copy number variations (CNVs) in cancer predisposition. Even though the mechanisms by which germline CNVs influence disease are hitherto largely speculative, nowadays it is consensual that they play a major role in a range of human pathologies. Point mutations have been far more commonly described, mainly because sequencing is the first‐tier diagnostic test, but deletions and duplications of known cancer genes have been reported as an alternative mechanism for cancer susceptibility. Additionally, CNV screening in familial cancer cohorts with unknown genetic aetiology has pointed to new candidate genes for high cancer risk. Therefore, this type of genomic variation must be taken into account in the cancer risk assessment. Key Concepts: Structural variation, including copy number variation (CNV), is responsible for a large fraction of the genetic diversity of the human genome. CNVs can be inherited in a Mendelian fashion or occur de novo . Germline CNVs play an important role in a range of human pathologies through several mechanisms, mainly affecting gene dosage or function. Nearly half of the approximately 100 Mendelian cancer predisposition genes were also reported as rare pathogenic germline CNVs. Next‐generation sequencing (NGS) combined with automated high throughput data analysis is the most promising approach for elucidating the contribution of both CNVs and point mutations to cancer predisposition.