Uniparental Disomy in Cancer – A New Tool in Molecular Cancer


The cancer genome project has attempted to provide the complete landscape of existing mutations in tumours, but sequencing the whole genome for all tumour types is a challenging goal. Recently a novel form of abnormality in various cancers, acquired uniparental disomy (aUPD), has been revealed. aUPD regions may pinpoint the mutated genes for next generation sequencing. Therefore, identifying the aUPD regions can help to identify novel candidate genes for mutation analysis instead of randomly sequencing the genome, may help to distinguish driver genes from passenger, lead to the discovery of novel therapeutic targets and provide important prognostic information, which may thus lead to important clinical applications.

Key Concepts:

  • Acquired uniparental disomy is a novel form of abnormality in cancer.

  • The regions of acquired uniparental disomy pinpoint homozygously mutated or methylated genes.

  • Homozygously mutated genes in aUPD regions may be tumourā€suppressor or oncogenes.

  • Homozygously mutated genes in aUPD regions may be involved in tumourigenesis.

  • aUPD regions may correlate with outcome of disease, so can be of use as prognostic marker.

Keywords: acquired uniparental disomy; genome; mutation; solid tumours; leukaemia; myeloproliferative neoplasia; lymphoma

Figure 1.

Illustration depicts the normal chromosome, numeric (monosomy and trisomy) and structural (losses and gains) chromosomal rearrangements, and (UPD) identified by (SNP) array analysis (on the left panel) and illustration of homologous chromosomes in somatic cells (i.e. red chromosome represents maternal and blue chromosome represents paternal one or vice versa) (on the right panel). In the upper area of each panel, the blue line represents the average copy number signal intensity of the SNPs on the array. In the lower panel, the green and red lines show the relative signal intensity for individual homologous identified by using the AsCNAR software. (a) Depicts normal chromosome with no gains or losses, (b) loss of one copy and (c) trisomy, the gain of one copy resulting from a nondisjunction error in mitotic division. In this scenario, the cell harbours two copies of this particular chromosome from one parent, and the third homologous chromosome is from the other parent. Therefore, this change is not called uniparental disomy. aUPD, in which one copy is lost and the remaining is duplicated ((d) and (f)), or triplicate (e); therefore, all of them come from the same parent for this specific chromosome. Mechanism underlying UPD (f).



Bagrintseva K, Schwab R, Kohl T M et al. (2004) Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3‐ITD‐transformed hematopoietic cells. Blood 103: 2266–2275. DOI: 10.1182/blood‐2003‐05‐1653.

Baxter E J, Scott L M, Campbell P J et al. (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365: 1054–1061. DOI: 10.1016/S0140‐6736(05)71142‐9.

Cavenee W K, Dryja T P, Phillips R A et al. (1983) Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305: 779–784. DOI: 10.1038/305779a0.

Chaligne R, Tonetti C, Besancenot R et al. (2008) New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S‐phase transition. Leukemia 22: 1557–1566. DOI: 10.1038/leu.2008.137.

De Keersmaecker K and Cools J (2006) Chronic myeloproliferative disorders: a tyrosine kinase tale. Leukemia 20: 200–205. DOI: 10.1038/sj.leu.2404064.

Dunbar A J, Gondek L P, O'Keefe C L et al. (2008) 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c‐Cbl, in myeloid malignancies. Cancer Research 68: 10349–10357. DOI: 10.1158/0008‐5472.CAN‐08‐2754.

Engel E (1980) A new genetic concept: uniparental disomy and its potential effect, isodisomy. American Journal of Medical Genetics 6: 137–143.

Fitzgibbon J, Smith L L, Raghavan M et al. (2005) Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias. Cancer Research 65: 9152–9154.

Flotho C, Steinemann D, Mullighan C G et al. (2007) Genome‐wide single‐nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11. Oncogene 26: 5816–5821. DOI: 10.1038/sj.onc.1210361.

Frohling S, Scholl C, Levine R L et al. (2007) Identification of driver and passenger mutations of FLT3 by high‐throughput DNA sequence analysis and functional assessment of candidate alleles. Cancer Cell 12: 501–513. DOI: 10.1016/j.ccr.2007.11.005.

Gondek L P, Tiu R, O'Keefe C L et al. (2008) Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS‐derived AML. Blood 111: 1534–1542. DOI: 10.1182/blood‐2007‐05‐092304.

Grand F H, Hidalgo‐Curtis C E, Ernst T et al. (2009) Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 113: 6182–6192. DOI: 10.1182/blood‐2008‐12‐194548.

Gupta M, Raghavan M, Gale RE et al. (2008) Novel regions of acquired uniparental disomy discovered in acute myeloid leukemia. Genes Chromosomes and Cancer 47: 729–739. DOI: 10.1002/gcc.20573.

James C, Ugo V, Le Couedic JP et al. (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434: 1144–1148. DOI: 10.1038/nature03546.

Jankowska AM, Szpurka H, Tiu RV et al. (2009) Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood 113: 6403–6410. DOI: 10.1182/blood‐2009‐02‐205690.

Karow A, Steinemann D, Gohring G et al. (2007) Clonal duplication of a germline PTPN11 mutation due to acquired uniparental disomy in acute lymphoblastic leukemia blasts from a patient with Noonan syndrome. Leukemia 21: 1303–1305. DOI: 10.1038/sj.leu.2404651.

Kato M, Sanada M, Kato I et al. (2009) Frequent inactivation of A20 in B‐cell lymphomas. Nature 459: 712–716. DOI: 10.1038/nature07969.

Keilholz U, Menssen HD, Gaiger A et al. (2005) Wilms’ tumour gene 1 (WT1) in human neoplasia. Leukemia 19: 1318–1323. DOI: 10.1038/sj.leu.2403817.

Knapper S (2007) FLT3 inhibition in acute myeloid leukaemia. British Journal of Haematology 138: 687–699. DOI: 10.1111/j.1365‐2141.2007.06700.x.

Langemeijer SM, Kuiper RP, Berends M et al. (2009) Acquired mutations in TET2 are common in myelodysplastic syndromes. Nature Genetics 41: 838–842. DOI: 10.1038/ng.391.

Lee BH, Williams IR, Anastasiadou E et al. (2005) FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model. Oncogene 24: 7882–7892. DOI: 10.1038/sj.onc.1208933.

Lehmann S, Ogawa S, Raynaud SD et al. (2008) Molecular allelokaryotyping of early stage, untreated chronic lymphocytic leukemia. Cancer 112: 1296–1305. DOI: 10.1002/cncr.23270.

Loh ML, Vattikuti S, Schubbert S et al. (2004) Mutations in PTPN11 implicate the SHP‐2 phosphatase in leukemogenesis. Blood 103: 2325–2331. DOI: 10.1182/blood‐2003‐09‐3287.

Lutterbach B and Hiebert S W (2000) Role of the transcription factor AML‐1 in acute leukemia and hematopoietic differentiation. Gene 245: 223–235. DOI: 10.1016/S0378‐1119(00)00014‐7.

O'shea D, O'Riain C, Gupta M et al. (2009) Regions of acquired uniparental disomy at diagnosis of follicular lymphoma are associated with both overall survival and risk of transformation. Blood 113: 2298–2301. DOI: 10.1182/blood‐2008‐08‐174953.

Plo I, Nakatake M, Malivert L et al. (2008) JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders. Blood 112: 1402–1412. DOI: 10.1182/blood‐2008‐01‐134114.

Raghavan M, Smith LL, Lillington DM et al. (2008) Segmental uniparental disomy is a commonly acquired genetic event in relapsed acute myeloid leukemia. Blood 112: 814–821. DOI: 10.1182/blood‐2008‐01‐132431.

Renneville A, Roumier C, Biggio V et al. (2008) Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia 22: 915–931. DOI: 10.1038/leu.2008.19.

Roumier C, Lejeune‐Dumoulin S, Renneville A et al. (2006) Cooperation of activating Ras/rtk signal transduction pathway mutations and inactivating myeloid differentiation gene mutations in M0 AML: a study of 45 patients. Leukemia 20: 433–436. DOI: 10.1038/sj.leu.2404097.

Sanada M, Suzuki T, Shih L Y et al. (2009) Gain‐of‐function of mutated C‐CBL tumour suppressor in myeloid neoplasms. Nature 460: 904–908. DOI: 10.1038/nature08240.

Scully R, Chen J, Plug A et al. (1997) Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88: 265–275. DOI: 10.1016/S0092‐8674(00)81847‐4.

Serrano E, Carnicer M J, Orantes V et al. (2008) Uniparental disomy may be associated with microsatellite instability in acute myeloid leukemia (AML) with a normal karyotype. Leukemia and Lymphoma 49: 1178–1183. DOI: 10.1080/10428190802035941.

Song WJ, Sullivan MG, Legare RD et al. (1999) Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nature Genetics 23: 166–175.

Szpurka H, Gondek L P, Mohan S R et al. (2008) UPD1p indicates the presence of MPL W515L mutation in RARS‐T, a mechanism analogous to UPD9p and JAK2 V617F mutation. Leukemia. 23: 610–614.

Tahiliani M, Koh KP, Shen Y et al. (2009) Conversion of 5‐methylcytosine to 5‐hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324: 930–935. DOI: 10.1126/science.1170116.

Tartaglia M, Niemeyer CM, Shannon KM and Loh ML (2004) SHP‐2 and myeloid malignancies. Current Opinion in Hematology 11: 44–50.

Thien CB and Langdon WY (2005) Negative regulation of PTK signalling by Cbl proteins. Growth Factors 23: 161–167. DOI: 10.1080/08977190500153763.

Tiu RV, Gondek LP, O'Keefe CL et al. (2009) New lesions detected by single nucleotide polymorphism array‐based chromosomal analysis have important clinical impact in acute myeloid leukemia. Journal of Clinical Oncology 27: 5219–5226. DOI: 10.1200/JCO.2009.21.9840.

Verma A, Kambhampati S, Parmar S and Platanias LC (2003) Jak family of kinases in cancer. Cancer Metastasis Review 22: 423–434. DOI: 10.1023/A:1023805715476.

Wouters BJ, Sanders MA, Lugthart S et al. (2007) Segmental uniparental disomy as a recurrent mechanism for homozygous CEBPA mutations in acute myeloid leukemia. Leukemia 21: 2382–2384. DOI: 10.1038/sj.leu.2404795.

Xing S, Wanting TH, Zhao W et al. (2008) Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice. Blood 111: 5109–5117. DOI: 10.1182/blood‐2007‐05‐091579.

Yamamoto G, Nannya Y, Kato M et al. (2007) Highly sensitive method for genomewide detection of allelic composition in nonpaired, primary tumor specimens by use of affymetric single‐nucleotide‐polymorphism genotyping microarrays. American Journal of Human Genetics 81: 114–126. DOI: 10.1086/518809.

Yanada M, Matsuo K, Suzuki T, Kiyoi H and Naoe T (2005) Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta‐analysis. Leukemia 19: 1345–1349. DOI: 10.1038/sj.leu.2403838.

Yin D, Ogawa S, Kawamata N et al. (2009) High‐resolution genomic copy number profiling of glioblastoma multiforme by single nucleotide polymorphism DNA microarray. Molecular Cancer Research 7: 665–677.

Further Reading

Tuna M, Knuutila S and Mills GB (2009) Uniparental disomy in cancer. Trends in Molecular Medicine 15(3): 120–128. DOI: 10.1016/j.molmed.2009.01.005.

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

* Required Field

How to Cite close
Tuna, Musaffe, and Amos, Christopher I(May 2010) Uniparental Disomy in Cancer – A New Tool in Molecular Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022430]