Loss of Heterozygosity

Kylie L Gorringe, Cancer Genomics Program, Melbourne, Victoria, Australia

Published online: September 2016

DOI: 10.1002/9780470015902.a0026643

Abstract

Loss of heterozygosity (LOH) is a genetic event frequently observed in many cancer types. The loss of one allele of a genetic locus can have multiple possible functional effects including haploinsufficiency, loss of gene expression and being the second ‘hit’ that unmasks a recessive tumour suppressor gene. LOH can be caused by mitotic errors, chromothripsis, gene conversion and inappropriate repair of DNA (deoxyribonucleic acid) breaks. The methods for detecting LOH are evolving from single locus assays such as microsatellite analysis, to accurate and sensitive genome‐wide assays including single‐nucleotide polymorphism arrays and massively parallel DNA sequencing. LOH is an important tool to aid in the discovery of novel tumour suppressor genes and now is gaining importance as a biomarker for clinical decision making in certain contexts.

Key Concepts

  • Loss of heterozygosity is a common genetic event in cancer whereby one allele is lost, leading to part of the genome appearing homozygous in the tumour where heterozygous in matching normal DNA.
  • Allelic imbalance is different from LOH: both alleles are still present but are in different numbers of copies.
  • Regions of LOH can be copy number neutral or show copy number loss.
  • Whole‐chromosome LOH can be caused by mitotic nondisjunction.
  • Defects in homologous recombination repair lead to increased levels of LOH in cancer.
  • The two‐hit hypothesis describes the inactivation of both copies of a recessive tumour suppressor gene in cancer; LOH can be one such hit.
  • Haplo‐insufficiency is where a gene cannot perform its function normally when present as only one copy and is a likely reason for selection of some LOH events.

Keywords: loss of heterozygosity; polymorphism; chromosome instability; tumour suppressor gene; cancer genomics

Figure 1. Mechanisms of LOH (loss of heterozygosity) formation. Most of the causes of LOH shown here lead to loss of chromosomal material (loss LOH), but some can lead to copy number neutral LOH (neutral LOH). Note that although not shown here, a reduplication of the retained chromosome can occur at any time including before the LOH event and can lead to neutral LOH for any of the loss LOH mechanisms. Blue and red chromosomes are homologous, and other colours represent DNA (deoxyribonucleic acid) from other chromosomes.
Figure 2. Common methods of LOH detection. Microsatellite analysis by PCR (polymerase chain reaction) was one of the earliest methods of detection. Shown are a heterozygous locus (Het) with both alleles retained in the tumour, a heterozygous locus with the larger allele lost (LOH) in the tumour (with some remaining signal from contaminating normal DNA, arrowhead) and a homozygous (Hom) and therefore uninformative locus. N, normal DNA; T, tumour DNA. SNP (single nucleotide polymorphism) arrays measure the overall copy number (red dots and blue line), the genotype at each locus (green bars, heterozygous; pink bars, homozygous) and the allele‐specific copy number (red and green lines). Areas of loss LOH (CNL‐LOH), neutral LOH (CNN‐LOH) and allelic imbalance are indicated. In a next‐generation sequencing approach, reads from exome data are binned together along the chromosome and the depth‐of‐coverage (DCC) ratio is calculated. The top panel shows the overall copy number, and the bottom panel shows the B‐allele frequency (number of reads supporting the ‘B’ allele divided by the total number of reads for an SNP). Areas of loss and LOH (CNL‐LOH) are shown in red.
Figure 3. Functional consequences of LOH. Chromosomes shown in blue and protein (or RNA, ribonucleic acid) products in red or purple (different colours indicate products of different genes). White areas in products indicate change in function, from somewhat to highly deleterious. Arrows indicate LOH event, leading to either copy number loss LOH (single chromosome) or copy number neutral LOH (two chromosomes). X: pathogenic mutation. A, B: different alleles, either somatic or germline.
close

References

Abkevich V, Timms KM, Hennessy BT, et al. (2012) Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. British Journal of Cancer 107 (10): 1776–1782.

Agnelli L, Mosca L, Fabris S, et al. (2009) A SNP microarray and FISH‐based procedure to detect allelic imbalances in multiple myeloma: an integrated genomics approach reveals a wide gene dosage effect. Genes, Chromosomes & Cancer 48 (7): 603–614.

Amarasinghe KC, Li J, Hunter SM, et al. (2014) Inferring copy number and genotype in tumour exome data. BMC Genomics 15: 732.

Aziz A, Baxter EJ, Edwards C, et al. (2013) Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions. Journal of Clinical Investigation 123 (5): 2169–2182.

Baylin SB, Herman JG, Graff JR, et al. (1998) Alterations in DNA methylation: a fundamental aspect of neoplasia. Advances in Cancer Research 72: 141–196.

Birkbak NJ, Eklund AC, Li Q, et al. (2011) Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Research 71 (10): 3447–3452.

Bolognesi C, Forcato C, Buson G, et al. (2016) Digital sorting of pure cell populations enables unambiguous genetic analysis of heterogeneous formalin‐fixed paraffin‐embedded tumors by next generation sequencing. Scientific Reports 6: 20944.

Cavenee WK, Dryja TP, Phillips RA, et al. (1983) Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305 (5937): 779–784.

Cliby W, Ritland S, Hartmann L, et al. (1993) Human epithelial ovarian cancer allelotype. Cancer Research 53 (10 Suppl): 2393–2398.

Davis L and Maizels N (2014) Homology‐directed repair of DNA nicks via pathways distinct from canonical double‐strand break repair. Proceedings of the National Academy of Sciences of the United States of America 111 (10): E924–E932.

Davoli T, Xu AW, Mengwasser KE, et al. (2013) Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell 155 (4): 948–962.

Dracopoli NC and Fogh J (1983) Loss of heterozygosity in cultured human tumor cell lines. Journal of the National Cancer Institute 70 (1): 83–87.

Eluri S, Brugge WR, Daglilar ES, et al. (2015) The presence of genetic mutations at key loci predicts progression to esophageal adenocarcinoma in Barrett's esophagus. American Journal of Gastroenterology 110 (6): 828–834.

Esteller M, Silva JM, Dominguez G, et al. (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. Journal of the National Cancer Institute 92 (7): 564–569.

Fehrmann RS, Karjalainen JM, Krajewska M, et al. (2015) Gene expression analysis identifies global gene dosage sensitivity in cancer. Nature Genetics 47 (2): 115–125.

Fujimori M, Tokino T, Hino O, et al. (1991) Allelotype study of primary hepatocellular carcinoma. Cancer Research 51 (1): 89–93.

Gartler SM (1968) Apparent Hela cell contamination of human heteroploid cell lines. Nature 217 (5130): 750–751.

Gorringe KL, Ramakrishna M, Williams LH, et al. (2009) Are there any more ovarian tumor suppressor genes? A new perspective using ultra high‐resolution copy number and loss of heterozygosity analysis. Genes, Chromosomes & Cancer 48 (10): 931–942.

Gronseth CM, McElhone SE, Storer BE, et al. (2015) Prognostic significance of acquired copy‐neutral loss of heterozygosity in acute myeloid leukemia. Cancer 121 (17): 2900–2908.

Ha G, Roth A, Lai D, et al. (2012) Integrative analysis of genome‐wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple‐negative breast cancer. Genome Research 22 (10): 1995–2007.

Hanahan D and Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144 (5): 646–674.

Hu N, Clifford RJ, Yang HH, et al. (2010) Genome wide analysis of DNA copy number neutral loss of heterozygosity (CNNLOH) and its relation to gene expression in esophageal squamous cell carcinoma. BMC Genomics 11: 576.

Isakoff SJ, Mayer EL, He L, et al. (2015) TBCRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple‐negative breast cancer. Journal of Clinical Oncology 33 (17): 1902–1909.

Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America 68 (4): 820–823.

Kugoh H, Ohira T and Oshimura M (2015) Studies of tumor suppressor genes via chromosome engineering. Cancers (Basel) 8 (1: pii: E4).

Lech G, Slotwinski R, Slodkowski M, et al. (2016) Colorectal cancer tumour markers and biomarkers: recent therapeutic advances. World Journal of Gastroenterology 22 (5): 1745–1755.

Lin YF, Li LH, Lin CH, et al. (2016) Selective retention of an inactive allele of the DKK2 tumor suppressor gene in hepatocellular carcinoma. PLoS Genetics 12 (5): e1006051.

Mayrhofer M, Kultima HG, Birgisson H, et al. (2014) 1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II‐III colon cancer. BMC Cancer 14: 872.

Millet C, Ausiannikava D, Le Bihan T, et al. (2015) Cell populations can use aneuploidy to survive telomerase insufficiency. Nature Communications 6: 8664.

Morita R, Ishikawa J, Tsutsumi M, et al. (1991) Allelotype of renal cell carcinoma. Cancer Research 51 (3): 820–823.

Newman S, Howarth KD, Greenman CD, et al. (2013) The relative timing of mutations in a breast cancer genome. PLoS One 8 (6): e64991.

Nigro JM, Baker SJ, Preisinger AC, et al. (1989) Mutations in the p53 gene occur in diverse human tumour types. Nature 342 (6250): 705–708.

Ogiwara H, Kohno T, Nakanishi H, et al. (2008) Unbalanced translocation, a major chromosome alteration causing loss of heterozygosity in human lung cancer. Oncogene 27 (35): 4788–4797.

Pedersen BS and De S (2013) Loss of heterozygosity preferentially occurs in early replicating regions in cancer genomes. Nucleic Acids Research 41 (16): 7615–7624.

Presneau N, Manderson EN and Tonin PN (2003) The quest for a tumor suppressor gene phenotype. Current Molecular Medicine 3 (7): 605–629.

Ryland GL, Doyle MA, Goode D, et al. (2015) Loss of heterozygosity: what is it good for? BMC Medical Genomics 8: 45.

Sato T, Tanigami A, Yamakawa K, et al. (1990) Allelotype of breast cancer: cumulative allele losses promote tumor progression in primary breast cancer. Cancer Research 50 (22): 7184–7189.

Stephens PJ, Greenman CD, Fu B, et al. (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144 (1): 27–40.

Stirewalt DL, Pogosova‐Agadjanyan EL, Tsuchiya K, et al. (2014) Copy‐neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML. Blood Cancer Journal 4: e208.

Teh MT, Blaydon D, Chaplin T, et al. (2005) Genomewide single nucleotide polymorphism microarray mapping in basal cell carcinomas unveils uniparental disomy as a key somatic event. Cancer Research 65 (19): 8597–8603.

Thiagalingam S, Laken S, Willson JK, et al. (2001) Mechanisms underlying losses of heterozygosity in human colorectal cancers. Proceedings of the National Academy of Sciences of the United States of America 98 (5): 2698–2702.

Tomlinson IP, Lambros MB and Roylance RR (2002) Loss of heterozygosity analysis: practically and conceptually flawed? Genes, Chromosomes & Cancer 34 (4): 349–353.

Torres EM, Sokolsky T, Tucker CM, et al. (2007) Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317 (5840): 916–924.

Vogelstein B, Fearon ER, Kern SE, et al. (1989) Allelotype of colorectal carcinomas. Science 244 (4901): 207–211.

Wang ZC, Birkbak NJ, Culhane AC, et al. (2012) Profiles of genomic instability in high‐grade serous ovarian cancer predict treatment outcome. Clinical Cancer Research 18 (20): 5806–5815.

Weller M, Stupp R, Hegi ME, et al. (2012) Personalized care in neuro‐oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro‐Oncology 14 (Suppl 4: iv100‐108).

William WN Jr, Papadimitrakopoulou V, Lee JJ, et al. (2016) Erlotinib and the risk of oral cancer: the Erlotinib Prevention of Oral Cancer (EPOC) randomized clinical trial. JAMA Oncology 2 (2): 209–216.

Yuen ST, Chan TL, Ho JW, et al. (2002) Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC‐related cancers. Oncogene 21 (49): 7585–7592.

Zack TI, Schumacher SE, Carter SL, et al. (2013) Pan‐cancer patterns of somatic copy number alteration. Nature Genetics 45 (10): 1134–1140.

Zhang L, Poh CF, Williams M, et al. (2012) Loss of heterozygosity (LOH) profiles – validated risk predictors for progression to oral cancer. Cancer Prevention Research (Philadelphia, Pa.) 5 (9): 1081–1089.

Further Reading

Daniel FI, Cherubini K, Yurgel LS, et al. (2011) The role of epigenetic transcription repression and DNA methyltransferases in cancer. Cancer 117 (4): 677–687.

Grade M, Difilippantonio MJ and Camps J (2015) Patterns of chromosomal aberrations in solid tumors. Recent Results in Cancer Research 200: 115–142.

Heyer WD, Ehmsen KT and Liu J (2010) Regulation of homologous recombination in eukaryotes. Annual Review of Genetics 44: 113–139.

Knudson AG (2001) Two genetic hits (more or less) to cancer. Nature Reviews. Cancer 1 (2): 157–162.

Storchova Z and Kloosterman WP (2016) The genomic characteristics and cellular origin of chromothripsis. Current Opinion in Cell Biology 40: 106–113.

Walsh CS (2015) Two decades beyond BRCA1/2: homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy. Gynecologic Oncology 137 (2): 343–350.

Watkins JA, Irshad S, Grigoriadis A, et al. (2014) Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Research 16 (3): 211.

Related Sub-Topics:

DNA Damage and Repair | Cancer Genetics | DNA Structure and Function
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Loss of Heterozygosity
 
How to Cite close
Gorringe, Kylie L(Sep 2016) Loss of Heterozygosity. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026643]