Germline Copy Number Variation and Cancer Risk

Abstract

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.