Germline Copy Number Variation and Cancer Risk


Cancer is usually considered to be an acquired disease caused by the progressive accumulation of somatic deoxyribonucleic acid (DNA) changes. It is clear, however, that inherited factors may also play a significant role in the initiation of this disease. Some of these factors represent loss‐of‐function mutations in tumour suppressor genes, resulting in an increased cancer risk among carriers. Such an increased risk may also be attributed to the presence of multiple polymorphic variants such as single nucleotide polymorphisms (SNPs), each of which may convey a mild effect upon cancer susceptibility. DNA copy number variation (CNV) and other structural variations in the human genome are increasingly recognised as an alternative source of genetic variation that may influence cancer risk. Specifically, rare CNVs may affect important cancer‐associated genes and/or pathways and, thus, provide an explanation for moderate‐ to high‐risk cancer families. Therefore, it is anticipated that the identification of rare germline CNVs in unexplained familial and early onset cancer patients will contribute to our understanding of cancer predisposition and development.

Key Concepts:

  • Copy number variation (CNV) is a common form of normal variation affecting a significant proportion of the human genome.

  • CNVs frequently encompass annotated genes.

  • Disruption and/or silencing of critical genes located in rare CNVs may result in increased risk of disease, including cancer.

  • Genome‐wide copy number analysis can be used as a strategy to identify novel moderate‐ to high‐penetrant cancer predisposing genes and/or mechanisms.

  • Discovery of cancer‐predisposing CNVs may reveal new cancer syndromes that exhibit additional clinical features.

Keywords: copy number variation; cancer predisposition; colorectal cancer; cancer syndromes

Figure 1.

Genetic contribution to cancer risk. Based on current knowledge, the susceptibility to develop cancer is influenced by many genetic factors that vary in penetrance (Y‐axis) and frequency (X‐axis), indicated by the grey shaded region. Mutations in high penetrant genes, like APC, BRCA1/2 and RB1, occur at very low frequencies and have been found by positional cloning and linkage‐based approaches. A large number of common risk factors with low relative risk have recently been identified by genome‐wide association studies in many common types of cancer. It has been hypothesised that a significant proportion of the ‘missing heritability’ is attributable to rare variants with intermediate penetrances, which have been difficult to identify by conventional gene discovery approaches. We anticipate that the candidate DNA CNVs identified by our alternative strategy should be considered as rare variants with moderate penetrances. Modified from Manolio et al. .

Figure 2.

Strategy to identify novel germline CNVs and to establish their causal relationship with cancer susceptibility. For explanation, see text.

Figure 3.

Novel genes involved in colorectal cancer (CRC) susceptibility. Genome‐wide copy number analysis in carefully selected unexplained cases at risk for hereditary CRC resulted in the identification of novel rare germline CNVs involved in CRC predisposition. Based on existing literature, six genes identified by our approach were known to play a role in CRC susceptibility (light grey circle), (early) CRC development (white circle) or could be functionally linked to known CRC‐associated pathways (dark grey circle).



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Further Reading

Brennan K and Flanagan JM (2012) Epigenetic epidemiology for cancer risk: harnessing germline epigenetic variation. Methods in Molecular Biology 863: 439–465.

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Venkatachalam R, Ligtenberg MJ, Hoogerbrugge N et al. (2010) The epigenetics of (hereditary) colorectal cancer. Cancer Genetics and Cytogenetics 203: 1–6.

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de Voer, Richarda M, Venkatachalam, Ramprasath, van Kessel, Ad Geurts, and Kuiper, Roland P(Jun 2012) Germline Copy Number Variation and Cancer Risk. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023854]