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 DNACNVs 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).



Balavenkatraman KK, Jandt E, Friedrich K et al. (2006) DEP‐1 protein tyrosine phosphatase inhibits proliferation and migration of colon carcinoma cells and is upregulated by protective nutrients. Oncogene 25: 6319–6324.

Bartos JD, Gaile DP, McQuaid DE et al. (2007) aCGH local copy number aberrations associated with overall copy number genomic instability in colorectal cancer: coordinate involvement of the regions including BCR and ABL. Mutation Research 615: 1–11.

Bastepe M, Fröhlich LF, Linglart A et al. (2005) Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Nature Genetics 37: 25–27.

Bennett KL Mester J and Eng C (2011) Germline epigenetic regulation of KILLIN in Cowden and Cowden‐like syndrome. JAMA 304: 2724–2731.

Berger AH and Pandolfi PP (2011) Haplo‐insufficiency: a driving force in cancer. Journal of Pathology 223: 137–146.

Bodmer W and Bonilla C (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nature Genetics 40: 695–701.

Bodmer W and Tomlinson I (2010) Rare genetic variants and the risk of cancer. Current Opinion in Genetics & Development 20: 262–267.

Chotalia M, Smallwood SA, Ruf N et al. (2009) Transcription is required for establishment of germline methylation marks at imprinted genes. Genes & Development 23: 105–117.

Conrad DF and Hurles ME (2007) The population genetics of structural variation. Nature Genetics 39: S30–S36.

Conrad DF, Pinto D, Redon R et al. (2009) Origins and functional impact of copy number variation in the human genome. Nature 464: 704–712.

de Hoog CL, Foster LJ and Mann M (2004) RNA and RNA binding proteins participate in early stages of cell spreading through spreading initiation centers. Cell 117: 649–662.

Falk RE and Casas KA (2007) Chromosome 2q37 deletion: clinical and molecular aspects. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 145C: 357–371.

Fearnhead NS, Wilding JL, Winney B et al. (2004) Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas. Proceedings of the National Academy of Sciences of the USA 101: 15992–15997.

Frayling IM, Beck NE, Ilyas M et al. (1998) The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history. Proceedings of the National Academy of Sciences of the USA 95: 10722–10727.

Friend SH, Bernards R, Rogelj S et al. (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323: 643–646.

Garber JE and Offit K (2005) Hereditary cancer predisposition syndromes. Journal of Clinical Oncology 23: 276–292.

Gudmundsson J, Johannesdottir G, Bergthorsson JT et al. (1995) Different tumour types from BRCA2 carriers show wild‐type chromosome deletions on 13q12‐q13. Cancer Research 55: 4830–4832.

Hanks S, Coleman K, Reid S et al. (2004) Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genetics 36: 1159–1161.

Hasle H, Clemmensen IH and Mikkelsen M (2000) Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 355: 165–169.

Hazan RB, Kang L, Roe S et al. (1997) Vinculin is associated with the E‐cadherin adhesion complex. Journal of Biological Chemistry 272: 32448–32453.

Herrera L, Kakati S, Gibas L et al. (1986) Gardner syndrome in a man with an interstitial deletion of 5q. American Journal of Medical Genetics 25: 473–476.

Hitchins MP, Rapkins RW, Kwok CT et al. (2011) Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer‐affected family is linked to a single nucleotide variant within the 5′UTR. Cancer Cell 20: 200–213.

Houlston RS, Cheadle J, Dobbins SE et al. (2010) Meta‐analysis of three genome‐wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nature Genetics 42: 973–977.

Isidor B, Le Cunff M, Boceno M et al. (2008) Complex constitutional subtelomeric 1p36.3 deletion/duplication in a mentally retarded child with neonatal neuroblastoma. European Journal of Medical Genetics 51: 679–684.

Iuliano R, Le Pera I, Cristofaro C et al. (2004) The tyrosine phosphatase PTPRJ/DEP‐1 genotype affects thyroid carcinogenesis. Oncogene 23: 8432–8438.

Jaeger E, Webb E, Howarth K et al. (2008) Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nature Genetics 40: 26–28.

Janssens AC, Gwinn M, Bradley LA et al. (2008) A critical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalize health interventions. American Journal of Human Genetics 82: 593–599.

Keane MM, Lowrey GA, Ettenberg SA et al. (1996) The protein tyrosine phosphatase DEP‐1 is induced during differentiation and inhibits growth of breast cancer cells. Cancer Research 56: 4236–4243.

Kempers MJ, Kuiper RP, Ockeloen CW et al. (2011) Risk of colorectal and endometrial cancers in EPCAM deletion‐positive Lynch syndrome: a cohort study. Lancet Oncology 12: 49–55.

Kingsmore SF, Lindquist IE, Mudge J et al. (2008) Genome‐wide association studies: progress and potential for drug discovery and development. Nature Reviews Drug Discovery 7: 221–230.

van der Klift H, Wijnen J, Wagner A et al. (2005) Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Genes, Chromosomes and Cancer 44: 123–138.

Knudson AG (1971) Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the USA 68: 820–823.

Korbel JO, Urban AE, Affourtit JP et al. (2007) Paired‐end mapping reveals extensive structural variation in the human genome. Science 318: 420–426.

Kosinski C, Li VS, Chan AS et al. (2007) Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proceedings of the National Academy of Sciences of the USA 104: 15418–15423.

Koufos A, Hansen MF, Lampkin BC et al. (1984) Loss of alleles at loci on human chromosome 11 during genesis of Wilms’ tumour. Nature 309: 170–172.

Kovalenko M, Denner K, Sandström J et al. (2000) Site‐selective dephosphorylation of the platelet‐derived growth factor beta‐receptor by the receptor‐like protein‐tyrosine phosphatase DEP‐1. Journal of Biological Chemistry 275: 16219–16226.

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

Kuiper RP, Vreede L, Venkatachalam R et al. (2009) The tumor suppressor gene FBXW7 is disrupted by a constitutional t(3;4)(q21;q31) in a patient with renal cell cancer. Cancer Genetics and Cytogenetics 195: 105–111.

Latif F, Tory K, Gnarra J et al. (1993) Identification of the von Hippel‐Lindau disease tumor suppressor gene. Science 260: 1317–1320.

Levy DB, Smith KJ, Beazer‐Barclay Y et al. (1994) Inactivation of both APC alleles in human and mouse tumours. Cancer Research 54: 5953–5958.

Lewis A, Segditsas S, Deheragoda M et al. (2010) Severe polyposis in Apc(1322 T) mice is associated with submaximal Wnt signalling and increased expression of the stem cell marker Lgr5. Gut 59: 1680–1686.

Lichtenstein P, Holm NV, Verkasalo PK et al. (2000) Environmental and heritable factors in the causation of cancer‐analyses of cohorts of twins from Sweden, Denmark, and Finland. New England Journal of Medicine 343: 78–85.

Ligtenberg MJL, 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.

Lipkin SM, Rozek LS, Rennert G et al. (2004) The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. Nature Genetics 36: 694–699.

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.

Lopez‐Correa C, Brems H, Lázaro C et al. (1999) Molecular studies in 20 submicroscopic neurofibromatosis type 1 gene deletions. Human Mutation 14: 387–393.

Lucci‐Cordisco E, Zollino M, Baglioni S et al. (2005) A novel microdeletion syndrome with loss of the MSH2 locus and hereditary non‐polyposis colorectal cancer. Clinical Genetics 67: 178–182.

Luo L, Shen GQ, Stiffler KA et al. (2006) Loss of heterozygosity in human aberrant crypt foci (ACF), a putative precursor of colon cancer. Carcinogenesis 27: 1153–1159.

Manolio TA, Collins FS, Cox NJ et al. (2009) Finding the missing heritability of complex diseases. Nature 461: 747–753.

McCarroll SA, Kuruvilla FG, Korn JM et al. (2008) Integrated detection and population‐genetic analysis of SNPs and copy number variation. Nature Genetics 40: 1166–1174.

McDermott U, Downing JR and Stratton MR (2011) Genomics and the continuum of cancer care. New England Journal of Medicine 364: 340–350.

McMullan DJ, Bonin M, Hehir‐Kwa JY et al. (2009) Molecular karyotyping of patients with unexplained mental retardation by SNP arrays: a multicenter study. Human Mutation 30: 1082–1092.

Meijers‐Heijboer H, van den Ouweland A, Klijn J et al. (2002) Low‐penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature Genetics 31: 55–59.

Nguyen D‐Q, Webber C and Ponting CP (2006) Bias of selection on human copy‐number variants. PLoS Genetics 2: e20. doi:10.1371/journal.pgen.0020020.

Östman A, Yang Q and Tonks NK (1994) Expression of DEP‐1, a receptor‐like protein‐tyrosine‐phosphatase, is enhanced with increasing cell density. Proceedings of the National Academy of Sciences of the USA 91: 9680–9684.

Petrij‐Bosch A, Peelen T, van Vliet M et al. (1997) BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nature Genetics 17: 341–345.

Rahman N, Seal S, Thompson D et al. (2007) PALB2, which encodes a BRCA2‐interacting protein, is a breast cancer susceptibility gene. Nature Genetics 39: 165–167.

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

Ruivenkamp CA, van Wezel T, Zanon C et al. (2002) Ptprj is a candidate for the mouse colon‐cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nature Genetics 31: 295–300.

Seal S, Thompson D, Renwick A et al. (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low penetrance breast cancer susceptibility alleles. Nature Genetics 38: 1239–1241.

Shibata T, Shimoyama Y, Gotoh M et al. (1997) Identification of human cadherin‐14, a novel neurally specific type II cadherin, by protein interaction cloning. Journal of Biological Chemistry 272: 5236–5240.

Smith SA, Easton DF, Evans DG et al. (1992) Allele losses in the region 17q12‐21 in familial breast and ovarian cancer involve the wildtype chromosome. Nature Genetics 2: 128–131.

Stoffel EM and Chittenden A (2010) Genetic testing for hereditary colorectal cancer: challenges in identifying, counseling, and managing high‐risk patients. Gastroenterology 139: 1436–1441.

Tenesa A, Farrington SM, Prendergast JG et al. (2008) Genome‐wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nature Genetics 40: 631–637.

Thean LF, Loi C, Ho KS et al. (2010) Genome‐wide scan identifies a copy number variable region at 3q26 that regulates PPM1L in APC mutation‐negative familial colorectal cancer patients. Genes, Chromosomes and Cancer 49: 99–106.

Tomlinson IP, Carvajal‐Carmona LG, Dobbins SE et al. (2011) Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genetics 7(6): e1002105.

Tory K, Brauch H, Linehan M et al. (1989) Specific genetic change in tumours associated with von Hippel‐Lindau disease. Journal of the National Cancer Institute 81: 1097–1101.

Trapasso F, Yendamuri S, Dumon KR et al. (2004) Restoration of receptor‐type protein tyrosine phosphatase eta function inhibits human pancreatic carcinoma cell growth in vitro and in vivo. Carcinogenesis 25: 2107–2114.

Tsuchiya KD, Wiesner G, Cassidy SB et al. (1998) Deletion 10q23.2‐q23.33 in a patient with gastrointestinal juvenile polyposis and other features of a Cowden‐like syndrome. Genes, Chromosomes and Cancer 21: 113–118.

Tufarelli C, Stanley JA, Garrick D et al. (2003) Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nature Genetics 34: 157–165.

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.

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

Weiss EE, Kroemker M, Rüdiger AH et al. (1998) Vinculin is part of the cadherin‐catenin junctional complex: complex formation between alpha‐catenin and vinculin. Journal of Cell Biology 141: 755–764.

Wood LD, Parsons DW, Jones S et al. (2007) The genomic landscapes of human breast and colorectal cancers. Science 318: 1108–1113.

Yu H, Hawash K, Picker J et al. (2012) A recurrent 1.71 Mb genomic imbalance at 2q13 increases the risk of developmental delay and dysmorphism. Clinical Genetics 81: 257–264.

Further Reading

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

Colnaghi R, Carpenter G, Volker M and O'Driscoll M (2011) The consequences of structural genomic alterations in humans: genomic disorders, genomic instability and cancer. Seminars in Cell & Developmental Biology 22: 875–885.

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

Fletcher O and Houlston RS (2010) Architecture of inherited susceptibility to common cancer. Nature Reviews Cancer 10: 353–361.

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

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

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

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
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]