Germline Genomic Copy Number Variation Contribution to Cancer Predisposition

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.

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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References

Abecasis GR, Auton A, Brooks LD et al. (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491: 56–65.

Al‐Sukhni W, Joe S, Lionel AC et al. (2012) Identification of germline genomic copy number variation in familial pancreatic cancer. Human Genetics 131: 1481–1494.

Cazier JB and Tomlinson I (2010) General lessons from large‐scale studies to identify human cancer predisposition genes. Journal of Pathology 220: 255–262.

Clifford RJ, Zhang J, Meerzaman DM et al. (2010) Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma. Hepatology 52: 2034–2043.

Conrad DF, Pinto D, Redon R et al. (2010) Origins and functional impact of copy number variation in the human genome. Nature 464: 704–712.

De Voer RM, Hoogerbrugge N and Kuiper RP (2011) Spindle-assembly checkpoint and gastrointestinal cancer. The New England Journal of Medicine 364: 1279–1280.

Diskin SJ, Hou C, Glessner JT et al. (2009) Copy number variation at 1q21.1 associated with neuroblastoma. Nature 459: 987–991.

Duan J, Zhang JG, Deng HW and Wang YP (2013) Comparative studies of copy number variation detection methods for next‐generation sequencing technologies. PLoS One 8: e59128.

Duclos A, Charbonnier F, Chambon P et al. (2011) Pitfalls in the use of DGV for CNV interpretation. American Journal of Medical Genetics Part A 155A: 2593–2596.

Fanciulli M, Norsworthy PJ, Petretto E et al. (2007) FCGR3B copy number variation is associated with susceptibility to systemic, but not organ‐specific, autoimmunity. Nature Genetics 39: 721–723.

Fanciulli M, Petretto E and Aitman TJ (2010) Gene copy number variation and common human disease. Clinical Genetics 77: 201–213.

Gamazon ER, Huang RS, Dolan ME and Cox NJ (2011) Copy number polymorphisms and anticancer pharmacogenomics. Genome Biology 12: R46.

Gonzalez E, Kulkarni H, Bolivar H et al. (2005) The influence of CCL3L1 gene‐containing segmental duplications on HIV‐1/AIDS susceptibility. Science 307: 1434–1440.

Hitchins MP (2010) Inheritance of epigenetic aberrations (constitutional epimutations) in cancer susceptibility. Advances in Genetics 70: 201–243.

Iafrate AJ, Feuk L, Rivera MN et al. (2004) Detection of large‐scale variation in the human genome. Nature Genetics 36: 949–951.

Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nature Reviews Genetics 13: 484–492.

Kim HN, Kim NY, Yu L et al. (2012) Association of GSTT1 polymorphism with acute myeloid leukemia risk is dependent on smoking status. Leukemia & Lymphoma 53(4): 681–687.

Kovacs ME, Papp J, Szentirmay Z, Otto S and Olah E (2009) Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Human Mutation 30: 197–203.

Krepischi AC, Achatz MI, Santos EM et al. (2012a) Germline DNA copy number variation in familial and early‐onset breast cancer. Breast Cancer Research 14: R24.

Krepischi AC, Pearson PL and Rosenberg C (2012b) Germline copy number variations and cancer predisposition. Future Oncology 8: 441–450.

Kuiper RP, Ligtenberg MJ, Hoogerbrugge N and Geurts van KA (2010) Germline copy number variation and cancer risk. Current Opinion in Genetics and Development .20(3): 282–289.

Ligtenberg MJ, Kuiper RP, Chan TL et al. (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nature Genetics 41: 112–117.

Liu W, Sun J, Li G et al. (2009) Association of a germ‐line copy number variation at 2p24.3 and risk for aggressive prostate cancer. Cancer Research 69: 2176–2179.

McKinney C, Merriman ME, Chapman PT et al. (2008) Evidence for an influence of chemokine ligand 3‐like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis. Annals of the Rheumatic Diseases 67: 409–413.

Mileyko Y, Joh RI and Weitz JS (2008) Small‐scale copy number variation and large‐scale changes in gene expression. Proceedings of the National Academy of Sciences of the USA 105: 16659–16664.

Mills RE, Walter K, Stewart C et al. (2011) Mapping copy number variation by population‐scale genome sequencing. Nature 470: 59–65.

Nguyen DQ, Webber C and Ponting CP (2006) Bias of selection on human copy‐number variants. PLoS Genetics 2: e20.

Niessen RC, Hofstra RM, Westers H et al. (2009) Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes, Chromosomes and Cancer 48: 737–744.

Norskov MS, Frikke‐Schmidt R, Bojesen SE et al. (2011) Copy number variation in glutathione‐S‐transferase T1 and M1 predicts incidence and 5‐year survival from prostate and bladder cancer, and incidence of corpus uteri cancer in the general population. Pharmacogenomics Journal 11: 292–299.

Peltomaki P and Vasen H (2004) Mutations associated with HNPCC predisposition – update of ICG‐HNPCC/INSiGHT mutation database. Disease Markers 20: 269–276.

Pollack JR, Sorlie T, Perou CM et al. (2002) Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proceedings of the National Academy of Sciences of the USA 99: 12963–12968.

Pylkas K, Vuorela M, Otsukka M et al. (2012) Rare copy number variants observed in hereditary breast cancer cases disrupt genes in estrogen signaling and TP53 tumor suppression network. PLoS Genetics 8: e1002734.

Rodriguez‐Revenga L, Mila M, Rosenberg C, Lamb A and Lee C (2007) Structural variation in the human genome: the impact of copy number variants on clinical diagnosis. Genetics in Medicine 9: 600–606.

Sebat J, Lakshmi B, Troge J et al. (2004) Large‐scale copy number polymorphism in the human genome. Science 305: 525–528.

Shlien A and Malkin D (2010) Copy number variations and cancer susceptibility. Current Opinion in Oncology 22: 55–63.

Shlien A, Tabori U, Marshall CR et al. (2008) Excessive genomic DNA copy number variation in the Li‐Fraumeni cancer predisposition syndrome. Proceedings of the National Academy of Sciences of the USA 105: 11264–11269.

Silva AG, Achatz IM, Krepischi AC, Pearson PL and Rosenberg C (2012) Number of rare germline CNVs and TP53 mutation types. Orphanet Journal of Rare Diseases 7: 101.

Speleman F, Kumps C, Buysse K et al. (2008) Copy number alterations and copy number variation in cancer: close encounters of the bad kind. Cytogenetic and Genome Research 123: 176–182.

Stankiewicz P and Lupski JR (2010) Structural variation in the human genome and its role in disease. Annual Review of Medicine 61: 437–455.

Stranger BE, Forrest MS, Dunning M et al. (2007) Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315: 848–853.

Tang MH, Varadan V, Kamalakaran S et al. (2012) Major chromosomal breakpoint intervals in breast cancer co‐localize with differentially methylated regions. Frontiers in Oncology 2: 197.

Tse KP, Su WH, Yang ML et al. (2011) A gender‐specific association of CNV at 6p21.3 with NPC susceptibility. Human Molecular Genetics 20: 2889–2896.

Tuzun E, Sharp AJ, Bailey JA et al. (2005) Fine‐scale structural variation of the human genome. Nature Genetics 37: 727–732.

Venkatachalam R, Ligtenberg MJ, Hoogerbrugge N et al. (2010) Germline epigenetic silencing of the tumor suppressor gene PTPRJ in early‐onset familial colorectal cancer. Gastroenterology 139: 2221–2224.

Venkatachalam R, Verwiel ET, Kamping EJ et al. (2011) Identification of candidate predisposing copy number variants in familial and early‐onset colorectal cancer patients. International Journal of Cancer 129: 1635–1642.

Walker LC, Krause L, Spurdle AB and Waddell N (2012) Germline copy number variants are not associated with globally acquired copy number changes in familial breast tumours. Breast Cancer Research and Treatment 134: 1005–1011.

Waszak SM, Hasin Y, Zichner T et al. (2010) Systematic inference of copy‐number genotypes from personal genome sequencing data reveals extensive olfactory receptor gene content diversity. PLoS Computational Biology 6: e1000988.

Woods MO, Williams P, Careen A et al. (2007) A new variant database for mismatch repair genes associated with Lynch syndrome. Human Mutation 28: 669–673.

Yoshihara K, Tajima A, Adachi S et al. (2011) Germline copy number variations in BRCA1‐associated ovarian cancer patients. Genes, Chromosomes and Cancer 50: 167–177.

Further Reading

Feuk L, Carson AR and Scherer SW (2006) Structural variation in the human genome. Nature Reviews Genetics 7: 85–97.

Francke U (1976) Retinoblastoma and chromosome 13. Birth Defects Original Article Series 12(7): 131–134. Historical report of the identification of a chromosome alteration mapping RB1 and relating to cancer predisposition.

Hitchins M, Williams R, Cheong K et al. (2005) MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 129: 1392–1399.

Redon R, Ishikawa S, Fitch KR et al. (2006) Global variation in copy number in the human genome. Nature 444: 444–454.

Scherer SW, Lee C, Birney E et al. (2007) Challenges and standards in integrating surveys of structural variation. Nature Genetics 39: S7–S15.

Zhao Y, Marotta M, Eichler EE, Eng C and Tanaka H (2009) Linkage disequilibrium between two high‐frequency deletion polymorphisms: implications for association studies involving the glutathione‐S transferase (GST) genes. PLoS Genetics 5: e1000472.

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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. http://www.els.net [doi: 10.1002/9780470015902.a0025028]