Germline Genomic Copy Number Variation Contribution to Cancer Predisposition


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.

Keywords: structural variation; CNV; cancer predisposition; germline alterations; next‐generation sequencing

Figure 1.

Different classes of pathogenic events involving CNV. Three different genomic regions are represented as coloured bars in the chromosome ideograms (blue, red and green). (a) Normal copy number: the three specific genomic regions presenting normal diploid copy number (one copy at each of the homologue chromosomes); (b) duplication: one of the loci (red) is duplicated, resulting in three copies of the genomic segment; (c) deletion: one of the loci (red) is lost, resulting in only one copy of the genomic segment; (d) compound heterozygote variants: concurrent CNV and mutation in homologous locus: one allele was already deleted and, subsequently, the remaining allele is inactivated by point mutation (yellow thunder bolt); (e) CNV‐based epimutation: partial deletion of a locus leading to methylation of the promoter and consequent silencing (crossed arrow) of a gene located downstream.

Figure 2.

Examples of submicroscopic germline CNVs detected using the array‐CGH technique (comparative genomic hybridisation based on microarrays; images adapted from the Genomic Workbench software, Agilent Technologies). (a) Deletion at 22q11.11: upper panel shows the array‐CGH profile of the entire chromosome 22, with probes (filled black dots) ordered from 22qcen to 22qter; the position of the deletion is marked as a red bar in the chromosome 22 ideogram, and the corresponding region is detailed underneath. (b) Duplication at 8p12: upper panel shows the array‐CGH profile of the entire chromosome 8, with probes ordered from 8p to 8q; the position of the duplication is marked as a red bar in the chromosome 8 ideogram, and the corresponding region is detailed underneath.

Figure 3.

Complex patterns of CNV. Three different genomic regions are represented as coloured bars in the chromosome ideograms (blue, red and green); three examples of complex CNVs are showed: (a) one of the loci (red) is triplicated in one of the homologues, resulting in four copies of the genomic segment; (b) one of the loci (green) is triplicated in one of the homologue and absent in the other, resulting in a copy number change identical to a tandem duplication (3 copies); (c) one of the loci (red) is triplicated in one homologue, and other locus (green) is triplicated in the other homologue chromosome resulting in two regions with multiple copies.



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Silva, Amanda Gonçalves, Rodrigues, Tatiane Cristina, Pearson, Peter Lees, Rosenberg, Carla, and Krepischi, Ana Cristina Victorino(Sep 2013) Germline Genomic Copy Number Variation Contribution to Cancer Predisposition. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025028]