Skip to main content
SpringerLink
Log in

Loss of Heterozygosity

  • Chapter
  • First Online:
Basic Concepts of Molecular Pathology

Part of the book series: Molecular Pathology Library ((MPLB,volume 2))

Abstract

The most common molecular alteration observed in human cancers,1 loss of heterozygosity (LOH), is a significant mecha-nism by which critical genes involved in growth regulation and homeostasis become inactivated, or silenced, during disease evolution. This chapter provides a review of LOH and its implications in various cancers as well as a review of LOH in nonmalignant diseases. Only 0.08% of those base pairs within the entire human genome (3 billion base pairs) vary between any two humans, and only 0.02% of those variations actually result in an expressed protein with a different amino acid as a result of the change.2 Even more remarkable, 90% of those variations are changes that are common in the population and lead to normal variation in traits among individuals; eye color, for example.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Zheng HT, Peng ZH, Li S, He L. Loss of heterozygosity analyzed by single nucleotide polymorphism array in cancer. World J Gastroenterol. 2005;11:6740–6744.

    PubMed  CAS  Google Scholar 

  2. Cecil RL, Goldman L, Ausiello DA. Cecil Textbook of Medicine. Philadelphia: Saunders Elsevier; 2007.

    Google Scholar 

  3. Knudson AG Jr. Nakahara memorial lecture. Hereditary cancer, oncogenes, and anti-oncogenes. Princess Takamatsu Symp. 1989;20:15–29.

    PubMed  Google Scholar 

  4. Fong KM, Sekido Y, Minna JD. Molecular pathogenesis of lung cancer. J Thorac Cardiovasc Surg. 1999;118:1136–1152.

    Article  PubMed  CAS  Google Scholar 

  5. Sekido Y, Fong KM, Minna JD. Progress in understanding the molecular pathogenesis of human lung cancer. Biochim Biophys Acta. 1998;1378:F21–F59.

    PubMed  CAS  Google Scholar 

  6. Pinkel D, Segraves R, Sudar D, et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet. 1998;20:207–211.

    Article  PubMed  CAS  Google Scholar 

  7. Mao X, Young BD, Lu YJ. The application of single nucleotide polymorphism microarrays in cancer research. Curr Genomics. 2007;8:219–228.

    Article  PubMed  CAS  Google Scholar 

  8. Chatterjee A, Pulido HA, Koul S, et al. Mapping the sites of putative tumor suppressor genes at 6p25 and 6p21.3 in cervical carcinoma: occurrence of allelic deletions in precancerous lesions. Cancer Res. 2001;61:2119–2123.

    PubMed  CAS  Google Scholar 

  9. Dong Z, Pang JS, Ng MH, Poon WS, Zhou L, Ng HK. Identification of two contiguous minimally deleted regions on chromosome 1p36.31-p36.32 in oligodendroglial tumours. Br J Cancer. 2004;91:1105–1111.

    Article  PubMed  CAS  Google Scholar 

  10. el-Naggar AK, Abdul-Karim FW, Hurr K, Callender D, Luna MA, Batsakis JG. Genetic alterations in acinic cell carcinoma of the parotid gland determined by microsatellite analysis. Cancer Genet Cytogenet. 1998;102:19–24.

    Article  PubMed  CAS  Google Scholar 

  11. Kim SK, Ro JY, Kemp BL, et al. Identification of two distinct tumor-suppressor loci on the long arm of chromosome 10 in small cell lung cancer. Oncogene. 1998;17:1749–1753.

    Article  PubMed  CAS  Google Scholar 

  12. Lu KH, Weitzel JN, Kodali S, Welch WR, Berkowitz RS, Mok SC. A novel 4-cM minimally deleted region on chromosome 11p15.1 associated with high grade nonmucinous epithelial ovarian carcinomas. Cancer Res. 1997;57:387–390.

    PubMed  CAS  Google Scholar 

  13. Nakamura M, Ishida E, Shimada K, et al. Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas. Lab Invest. 2005;85:165–175.

    Article  PubMed  CAS  Google Scholar 

  14. Shin JH, Kang SM, Kim YS, Shin DH, Chang J, Kim SK. Identification of tumor suppressor loci on the long arm of chromosome 5 in pulmonary large cell neuroendocrine carcinoma. Chest. 2005;128:2999–3003.

    Article  PubMed  CAS  Google Scholar 

  15. Simoneau AR, Spruck CH III, Gonzalez-Zulueta M, et al. Evidence for two tumor suppressor loci associated with proximal chromosome 9p to q and distal chromosome 9q in bladder cancer and the initial screening for GAS1 and PTC mutations. Cancer Res. 1996;56:5039–5043.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  17. Frigerio S, Padberg BC, Strebel RT, et al. Improved detection of bladder carcinoma cells in voided urine by standardized microsatellite analysis. Int J Cancer. 2007;121:329–338.

    Article  PubMed  CAS  Google Scholar 

  18. Powell CA, Klares S, O’Connor G, Brody JS. Loss of heterozygosity in epithelial cells obtained by bronchial brushing: clinical utility in lung cancer. Clin Cancer Res. 1999;5:2025–2034.

    PubMed  CAS  Google Scholar 

  19. Lindblad-Toh K, Tanenbaum DM, Daly MJ, et al. Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays. Nat Biotechnol. 2000;18:1001–1005.

    Article  PubMed  CAS  Google Scholar 

  20. Zabarovsky ER, Lerman MI, Minna JD. Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene. 2002;21:6915–6935.

    Article  PubMed  CAS  Google Scholar 

  21. Mei R, Galipeau PC, Prass C, et al. Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays. Genome Res. 2000;10:1126–1137.

    Article  PubMed  CAS  Google Scholar 

  22. Haltrich I, Kost-Alimova M, Kovacs G, et al. Multipoint interphase FISH in childhood T-acute lymphoblastic leukemia detects subpopulations that carry different chromosome 3 aberrations. Cancer Genet Cytogenet. 2007;172:54–60.

    Article  PubMed  CAS  Google Scholar 

  23. Carr J, Bown NP, Case MC, Hall AG, Lunec J, Tweddle DA. High-resolution analysis of allelic imbalance in neuroblastoma cell lines by single nucleotide polymorphism arrays. Cancer Genet Cytogenet. 2007;172:127–138.

    Article  PubMed  CAS  Google Scholar 

  24. Wogan GN. Molecular epidemiology in cancer risk assessment and prevention: recent progress and avenues for future research. Environ Health Perspect. 1992;98:167–178.

    Article  PubMed  CAS  Google Scholar 

  25. Song L, Yan W, Zhao T, et al. Mycobacterium tuberculosis infection and FHIT gene alterations in lung cancer. Cancer Lett. 2005;219:155–162.

    Article  PubMed  CAS  Google Scholar 

  26. Wu MS, Shun CT, Wang HP, et al Genetic alterations in gastric cancer: relation to histological subtypes, tumor stage, and Helicobacter pylori infection. Gastroenterology 1997;112:1457–1465.

    Article  PubMed  CAS  Google Scholar 

  27. Brooks PJ, Theruvathu JA. DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis. Alcohol. 2005;35:187–193.

    Article  PubMed  CAS  Google Scholar 

  28. Ray G, Husain SA. Oxidants, antioxidants and carcinogenesis. Indian J Exp Biol. 2002;40:1213–1232.

    PubMed  CAS  Google Scholar 

  29. Broyde S, Wang L, Zhang L, Rechkoblit O, Geacintov NE, Patel DJ. DNA adduct structure-function relationships: comparing solution with polymerase structures. Chem Res Toxicol. 2008;21:45–52.

    Article  PubMed  CAS  Google Scholar 

  30. Roos PH, Bolt HM. Cytochrome P450 interactions in human cancers: new aspects considering CYP1B1. Expert Opin Drug Metab Toxicol. 2005;1:187–202.

    Article  PubMed  CAS  Google Scholar 

  31. D’Agostino J, Zhang X, Wu H, et al. Characterization of CYP2A13*2, a variant cytochrome P450 allele previously found to be associated with decreased incidences of lung adenocarcinoma in smokers. Drug Metab Dispos. 2008;36(11):2316–2323.

    Article  PubMed  CAS  Google Scholar 

  32. Vineis P. Individual susceptibility to carcinogens. Oncogene. 2004;23:6477–6483.

    Article  PubMed  CAS  Google Scholar 

  33. Boffetta P, Hecht S, Gray N, Gupta P, Straif K. Smokeless tobacco and cancer. Lancet Oncol. 2008;9:667–675.

    Article  PubMed  Google Scholar 

  34. Halpern MT, Gillespie BW, Warner KE. Patterns of absolute risk of lung cancer mortality in former smokers. J Natl Cancer Inst. 1993;85:457–464.

    Article  PubMed  CAS  Google Scholar 

  35. Hirao T, Nelson HH, Ashok TD, et al. Tobacco smoke-induced DNA damage and an early age of smoking initiation induce chromosome loss at 3p21 in lung cancer. Cancer Res. 2001;61:612–615.

    PubMed  CAS  Google Scholar 

  36. Knoke JD, Shanks TG, Vaughn JW, Thun MJ, Burns DM. Lung cancer mortality is related to age in addition to duration and intensity of cigarette smoking: an analysis of CPS-I data. Cancer Epidemiol Biomarkers Prev. 2004;13:949–957.

    PubMed  Google Scholar 

  37. Wiencke JK, Kelsey KT. Teen smoking, field cancerization, and a “critical period” hypothesis for lung cancer susceptibility. Environ Health Perspect. 2002;110:555–558.

    PubMed  Google Scholar 

  38. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6:963–968.

    Article  PubMed  CAS  Google Scholar 

  39. Craighead JE, Mossman BT. The pathogenesis of asbestos-associated diseases. N Engl J Med. 1982;306:1446–1455.

    PubMed  CAS  Google Scholar 

  40. Both K, Henderson DW, Turner DR. Asbestos and erionite fibres can induce mutations in human lymphocytes that result in loss of heterozygosity. Int J Cancer. 1994;59:538–542.

    Article  PubMed  CAS  Google Scholar 

  41. Pylkkanen L, Wolff H, Stjernvall T, et al. Reduced Fhit protein expression and loss of heterozygosity at FHIT gene in tumours from smoking and asbestos-exposed lung cancer patients. Int J Oncol. 2002;20:285–290.

    PubMed  CAS  Google Scholar 

  42. Tug E, Tug T, Elyas H, Coskunsel M, Emri S. Tumor suppressor gene alterations in patients with malignant mesothelioma due to environmental asbestos exposure in Turkey. J Carcinog. 2006;5:23.

    Article  PubMed  Google Scholar 

  43. Safety of sodium nitrite in cured meats. http://www.medem.com/MedLB/article_detaillb.cfm?article_ID=ZZZ80XEN0IC&sub_cat = 380; 2008 Accessed 12.09.08.

  44. U.S. Department of Health and Human Services. Report on Carcinogens. 11th ed. Research Triangle Park, NC; 2005.

    Google Scholar 

  45. Go VL, Gukovskaya A, Pandol SJ. Alcohol and pancreatic cancer. Alcohol. 2005;35:205–211.

    Article  PubMed  CAS  Google Scholar 

  46. Song L, Yan W, Deng M, Song S, Zhang J, Zhao T. Aberrations in the fragile histidine triad (FHIT) gene may be involved in lung carcinogenesis in patients with chronic pulmonary tuberculosis. Tumour Biol. 2004;25:270–275.

    Article  PubMed  CAS  Google Scholar 

  47. Brenner C, Bieganowski P, Pace HC, Huebner K. The histidine triad superfamily of nucleotide-binding proteins. J Cell Physiol. 1999;181:179–187.

    Article  PubMed  CAS  Google Scholar 

  48. Girard L, Zochbauer-Muller S, Virmani AK, Gazdar AF, Minna JD. Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. Cancer Res. 2000;60:4894–4906.

    PubMed  CAS  Google Scholar 

  49. Dacic S, Ionescu DN, Finkelstein S, Yousem SA. Patterns of allelic loss of synchronous adenocarcinomas of the lung. Am J Surg Pathol. 2005;29:897–902.

    Article  PubMed  Google Scholar 

  50. Sasatomi E, Johnson LR, Aldeeb DN, et al Genetic profile of cumulative mutational damage associated with early pulmonary adenocarcinoma: bronchioloalveolar carcinoma vs. stage I invasive adenocarcinoma. Am J Surg Pathol. 2004;28:1280–1288.

    Article  PubMed  Google Scholar 

  51. Ragnarsson G, Eiriksdottir G, Johannsdottir JT, Jonasson JG, Egilsson V, Ingvarsson S. Loss of heterozygosity at chromosome 1p in different solid human tumours: association with survival. Br J Cancer. 1999;79:1468–1474.

    Article  PubMed  CAS  Google Scholar 

  52. Kurashina K, Yamashita Y, Ueno T, et al. Chromosome copy number analysis in screening for prognosis-related genomic regions in colorectal carcinoma. Cancer Sci. 2008;99(9):1835–1840.

    Article  PubMed  CAS  Google Scholar 

  53. Yang J, Du X, Lazar AJ, et al. Genetic aberrations of gastrointestinal stromal tumors. Cancer. 2008;113:1532–1543.

    Article  PubMed  CAS  Google Scholar 

  54. Pang JZ, Qin LX, Ren N, et al. Loss of heterozygosity at D8S298 is a predictor for long-term survival of patients with tumor-node-metastasis stage I of hepatocellular carcinoma. Clin Cancer Res. 2007;13:7363–7369.

    Article  PubMed  CAS  Google Scholar 

  55. Fang L, Lee SW, Aaronson SA. Comparative analysis of p73 and p53 regulation and effector functions. J Cell Biol. 1999;147:823–830.

    Article  PubMed  CAS  Google Scholar 

  56. Gupta S. Molecular steps of tumor necrosis factor receptor-mediated apoptosis. Curr Mol Med. 2001;1:317–324.

    Article  PubMed  CAS  Google Scholar 

  57. Stockhammer F, von Deimling A, Synowitz M, Blechschmidt C, van Landeghem FK. Expression of glucose transporter 1 is associated with loss of heterozygosity of chromosome 1p in oligodendroglial tumors WHO grade II. J Mol Histol. 2008; 39(5):553–560.

    Article  PubMed  CAS  Google Scholar 

  58. Wistuba II, Behrens C, Virmani AK, et al. High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res. 2000;60:1949–1960.

    PubMed  CAS  Google Scholar 

  59. Yokota J, Wada M, Shimosato Y, Terada M, Sugimura T. Loss of heterozygosity on chromosomes 3, 13, and 17 in small-cell carcinoma and on chromosome 3 in adenocarcinoma of the lung. Proc Natl Acad Sci USA. 1987;84:9252–9256.

    Article  PubMed  CAS  Google Scholar 

  60. Toledo G, Sola JJ, Lozano MD, Soria E, Pardo J. Loss of FHIT protein expression is related to high proliferation, low apoptosis and worse prognosis in non-small-cell lung cancer. Mod Pathol. 2004;17:440–448.

    Article  PubMed  CAS  Google Scholar 

  61. Ohta M, Inoue H, Cotticelli MG, et al. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell. 1996;84:587–97.

    Article  PubMed  CAS  Google Scholar 

  62. Fong KM, Biesterveld EJ, Virmani A, et al. FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. Cancer Res. 1997;57:2256–2267.

    PubMed  CAS  Google Scholar 

  63. Woenckhaus M, Grepmeier U, Wild PJ, et al. Multitarget FISH and LOH analyses at chromosome 3p in non-small cell lung cancer and adjacent bronchial epithelium. Am J Clin Pathol. 2005;123:752–761.

    Article  PubMed  CAS  Google Scholar 

  64. Zienolddiny S, Ryberg D, Arab MO, Skaug V, Haugen A. Loss of heterozygosity is related to p53 mutations and smoking in lung cancer. Br J Cancer. 2001;84:226–231.

    Article  PubMed  CAS  Google Scholar 

  65. Zanesi N, Fidanza V, Fong LY, et al. The tumor spectrum in FHIT-deficient mice. Proc Natl Acad Sci USA. 2001;98:10250–10255.

    Article  PubMed  CAS  Google Scholar 

  66. Ji L, Fang B, Yen N, Fong K, Minna JD, Roth JA. Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression. Cancer Res. 1999;59:3333–3339.

    PubMed  CAS  Google Scholar 

  67. Kuroki T, Trapasso F, Yendamuri S, et al. Allele loss and promoter hypermethylation of VHL, RAR-beta, RASSF1A, and FHIT tumor suppressor genes on chromosome 3p in esophageal squamous cell carcinoma. Cancer Res. 2003;63:3724–3728.

    PubMed  CAS  Google Scholar 

  68. Nancarrow DJ, Handoko HY, Smithers BM, et al. Genome-wide copy number analysis in esophageal adenocarcinoma using high-density single-nucleotide polymorphism arrays. Cancer Res. 2008;68:4163–4172.

    Article  PubMed  CAS  Google Scholar 

  69. Wiech T, Nikolopoulos E, Weis R, et al. Genome-wide analysis of genetic alterations in Barrett’s adenocarcinoma using single nucleotide polymorphism arrays. Lab Invest 2009;89:385–397.

    Google Scholar 

  70. Diab SG, Clark GM, Osborne CK, Libby A, Allred DC, Elledge RM. Tumor characteristics and clinical outcome of tubular and mucinous breast carcinomas. J Clin Oncol. 1999;17:1442–1448.

    PubMed  CAS  Google Scholar 

  71. Sukosd F, Kuroda N, Beothe T, Kaur AP, Kovacs G. Deletion of chromosome 3p14.2-p25 involving the VHL and FHIT genes in conventional renal cell carcinoma. Cancer Res. 2003;63:455–457.

    PubMed  Google Scholar 

  72. Toma MI, Grosser M, Herr A, et al. Loss of heterozygosity and copy number abnormality in clear cell renal cell carcinoma discovered by high-density affymetrix 10 K single nucleotide polymorphism mapping array. Neoplasia. 2008;10:634–642.

    PubMed  CAS  Google Scholar 

  73. Marsit CJ, Hasegawa M, Hirao T, et al. Loss of heterozygosity of chromosome 3p21 is associated with mutant TP53 and better patient survival in non-small-cell lung cancer. Cancer Res. 2004;64:8702–8707.

    Article  PubMed  CAS  Google Scholar 

  74. Chmara M, Wozniak A, Ochman K, et al. Loss of heterozygosity at chromosomes 3p and 17p in primary non-small cell lung cancer. Anticancer Res. 2004;24:4259–4263.

    PubMed  Google Scholar 

  75. Ho WL, Chang JW, Tseng RC, et al. Loss of heterozygosity at loci of candidate tumor suppressor genes in microdissected primary non-small cell lung cancer. Cancer Detect Prev. 2002;26:343–349.

    Article  PubMed  CAS  Google Scholar 

  76. Schwendel A, Richard F, Langreck H, et al. Chromosome alterations in breast carcinomas: frequent involvement of DNA losses including chromosomes 4q and 21q. Br J Cancer. 1998;78:806–811.

    PubMed  CAS  Google Scholar 

  77. Backsch C, Rudolph B, Kuhne-Heid R, et al. A region on human chromosome 4 (q35.-->qter) induces senescence in cell hybrids and is involved in cervical carcinogenesis. Genes Chromosomes Cancer. 2005;43:260–272.

    Article  PubMed  CAS  Google Scholar 

  78. Mitra AB, Murty VV, Li RG, Pratap M, Luthra UK, Chaganti RS. Allelotype analysis of cervical carcinoma. Cancer Res. 1994;54:4481–4487.

    PubMed  CAS  Google Scholar 

  79. Sherwood JB, Shivapurkar N, Lin WM, et al. Chromosome 4 deletions are frequent in invasive cervical cancer and differ between histologic variants. Gynecol Oncol. 2000;79:90–96.

    Article  PubMed  CAS  Google Scholar 

  80. Wang XL, Uzawa K, Imai FL, Tanzawa H. Localization of a novel tumor suppressor gene associated with human oral cancer on chromosome 4q25. Oncogene. 1999;18:823–825.

    Article  PubMed  CAS  Google Scholar 

  81. Hammoud ZT, Kaleem Z, Cooper JD, Sundaresan RS, Patterson GA, Goodfellow PJ. Allelotype analysis of esophageal adenocarcinomas: evidence for the involvement of sequences on the long arm of chromosome 4. Cancer Res. 1996;56:4499–4502.

    PubMed  CAS  Google Scholar 

  82. Rumpel CA, Powell SM, Moskaluk CA. Mapping of genetic deletions on the long arm of chromosome 4 in human esophageal adenocarcinomas. Am J Pathol. 1999;154:1329–1334.

    PubMed  CAS  Google Scholar 

  83. Sterian A, Kan T, Berki AT, et al. Mutational and LOH analyses of the chromosome 4q region in esophageal adenocarcinoma. Oncology. 2006;70:168–172.

    Article  PubMed  CAS  Google Scholar 

  84. Hurst CD, Fiegler H, Carr P, Williams S, Carter NP, Knowles MA. High-resolution analysis of genomic copy number alterations in bladder cancer by microarray-based comparative genomic hybridization. Oncogene. 2004;23:2250–2263.

    Article  PubMed  CAS  Google Scholar 

  85. Polascik TJ, Cairns P, Chang WY, Schoenberg MP, Sidransky D. Distinct regions of allelic loss on chromosome 4 in human primary bladder carcinoma. Cancer Res. 1995;55:5396–5399.

    PubMed  CAS  Google Scholar 

  86. Rosin MP, Cairns P, Epstein JI, Schoenberg MP, Sidransky D. Partial allelotype of carcinoma in situ of the human bladder. Cancer Res. 1995;55:5213–5216.

    PubMed  CAS  Google Scholar 

  87. Jiang LX, Xu J, Wang ZW, et al. Tumor suppress genes screening analysis on 4q in sporadic colorectal carcinoma. World J Gastroenterol. 2008;14:5606–5611.

    Article  PubMed  CAS  Google Scholar 

  88. Kurashina K, Yamashita Y, Ueno T, et al. Chromosome copy number analysis in screening for prognosis-related genomic regions in colorectal carcinoma. Cancer Sci. 2008;99:1835–1840.

    Article  PubMed  CAS  Google Scholar 

  89. Cho ES, Chang J, Chung KY, Shin DH, Kim YS, Kim SK. Identification of tumor suppressor loci on the long arm of chromosome 4 in primary small cell lung cancers. Yonsei Med J. 2002; 43:145–151.

    PubMed  CAS  Google Scholar 

  90. Shivapurkar N, Virmani AK, Wistuba , II, et al. Deletions of chromosome 4 at multiple sites are frequent in malignant mesothelioma and small cell lung carcinoma. Clin Cancer Res. 1999;5:17–23.

    PubMed  CAS  Google Scholar 

  91. Bluteau O, Beaudoin JC, Pasturaud P, et al. Specific association between alcohol intake, high grade of differentiation and 4q34–q35 deletions in hepatocellular carcinomas identified by high resolution allelotyping. Oncogene. 2002;21:1225–1232.

    Article  PubMed  CAS  Google Scholar 

  92. Chang J, Kim NG, Piao Z, et al. Assessment of chromosomal losses and gains in hepatocellular carcinoma. Cancer Lett. 2002;182:193–202.

    Article  PubMed  CAS  Google Scholar 

  93. Chou YH, Chung KC, Jeng LB, Chen TC, Liaw YF. Frequent allelic loss on chromosomes 4q and 16q associated with human hepatocellular carcinoma in Taiwan. Cancer Lett. 1998;123:1–6.

    Article  PubMed  CAS  Google Scholar 

  94. Rashid A, Wang JS, Qian GS, Lu BX, Hamilton SR, Groopman JD. Genetic alterations in hepatocellular carcinomas: association between loss of chromosome 4q and p53 gene mutations. Br J Cancer. 1999;80:59–66.

    Article  PubMed  CAS  Google Scholar 

  95. Takeuchi S, Seriu T, van Dongen JJ, et al. Allelotype analysis in relapsed childhood acute lymphoblastic leukemia. Oncogene. 2003;22:6970–6976.

    Article  PubMed  CAS  Google Scholar 

  96. Demopoulos K, Arvanitis DA, Vassilakis DA, Siafakas NM, Spandidos DA. MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis. J Cell Mol Med. 2002;6:215–222.

    Article  PubMed  CAS  Google Scholar 

  97. Suzuki M, Hao C, Takahashi T, et al. Aberrant methylation of SPARC in human lung cancers. Br J Cancer. 2005;92:942–948.

    Article  PubMed  CAS  Google Scholar 

  98. Sanz-Ortega J, Bryant B, Sanz-Esponera J, et al. LOH at the APC/MCC gene (5Q21) is frequent in early stages of non-small cell lung cancer. Pathol Res Pract. 1999;195:677–680.

    PubMed  CAS  Google Scholar 

  99. Yoshino I, Osoegawa A, Yohena T, et al. Loss of heterozygosity (LOH) in non-small cell lung cancer: difference between adenocarcinoma and squamous cell carcinoma. Respir Med. 2005;99: 308–312.

    Article  PubMed  Google Scholar 

  100. Brabender J, Usadel H, Danenberg KD, et al. Adenomatous polyposis coli gene promoter hypermethylation in non-small cell lung cancer is associated with survival. Oncogene. 2001;20:3 528–3532.

    Article  CAS  Google Scholar 

  101. Adams J, Cuthbert-Heavens D, Bass S, Knowles MA. Infrequent mutation of TRAIL receptor 2 (TRAIL-R2/DR5) in transitional cell carcinoma of the bladder with 8p21 loss of heterozygosity. Cancer Lett. 2005;220:137–144.

    Article  PubMed  CAS  Google Scholar 

  102. Coon SW, Savera AT, Zarbo RJ, et al. Prognostic implications of loss of heterozygosity at 8p21 and 9p21 in head and neck squamous cell carcinoma. Int J Cancer. 2004;111:206–212.

    Article  PubMed  CAS  Google Scholar 

  103. Shi Y, Chen JY, Yang J, Li B, Chen ZH, Xiao CG. DBC2 gene is silenced by promoter methylation in bladder cancer. Urol Oncol. 2008;26:465–469.

    PubMed  CAS  Google Scholar 

  104. Ye H, Pungpravat N, Huang BL, et al. Genomic assessments of the frequent loss of heterozygosity region on 8p21.3–p22 in head and neck squamous cell carcinoma. Cancer Genet Cytogenet. 2007;176:100–106.

    Article  PubMed  CAS  Google Scholar 

  105. Kurimoto F, Gemma A, Hosoya Y, et al. Unchanged frequency of loss of heterozygosity and size of the deleted region at 8p21–23 during metastasis of lung cancer. Int J Mol Med. 2001;8:89–93.

    PubMed  CAS  Google Scholar 

  106. Wistuba II, Behrens C, Virmani AK, et al. Allelic losses at chromosome 8p21–23 are early and frequent events in the pathogenesis of lung cancer. Cancer Res. 1999;59:1973–1979.

    PubMed  CAS  Google Scholar 

  107. Xu Z, Liang L, Wang H, Li T, Zhao M. HCRP1, a novel gene that is downregulated in hepatocellular carcinoma, encodes a growth-inhibitory protein. Biochem Biophys Res Commun. 2003; 311:1057–1066.

    Article  PubMed  CAS  Google Scholar 

  108. Marsit CJ, Wiencke JK, Nelson HH, et al. Alterations of 9p in squamous cell carcinoma and adenocarcinoma of the lung: association with smoking, TP53, and survival. Cancer Genet Cytogenet. 2005;162:115–121.

    Article  PubMed  CAS  Google Scholar 

  109. Virmani AK, Fong KM, Kodagoda D, et al. Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types. Genes Chromosomes Cancer. 1998;21: 308–319.

    Article  PubMed  CAS  Google Scholar 

  110. Kratzke RA, Greatens TM, Rubins JB, et al. Rb and p16INK4a expression in resected non-small cell lung tumors. Cancer Res. 1996;56:3415–3420.

    PubMed  CAS  Google Scholar 

  111. Ohtani N, Yamakoshi K, Takahashi A, Hara E. The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression. J Med Invest. 2004;51:146–153.

    Article  PubMed  Google Scholar 

  112. Sumitomo K, Shimizu E, Shinohara A, Yokota J, Sone S. Activation of RB tumor suppressor protein and growth suppression of small cell lung carcinoma cells by reintroduction of p16INK4A gene. Int J Oncol. 1999;14:1075–1080.

    PubMed  CAS  Google Scholar 

  113. Quesnel B, Preudhomme C, Fenaux P. p16ink4a gene and hematological malignancies. Leuk Lymphoma. 1996;22:11–24.

    Article  PubMed  CAS  Google Scholar 

  114. Awaya H, Takeshima Y, Amatya VJ, et al. Inactivation of the p16 gene by hypermethylation and loss of heterozygosity in adenocarcinoma of the lung. Pathol Int. 2004;54:486–489.

    Article  PubMed  CAS  Google Scholar 

  115. Hosoya Y, Gemma A, Seike M, et al. Alteration of the PTEN/MMAC1 gene locus in primary lung cancer with distant metastasis. Lung Cancer. 1999;25:87–93.

    Article  PubMed  CAS  Google Scholar 

  116. Kim SK, Su LK, Oh Y, Kemp BL, Hong WK, Mao L. Alterations of PTEN/MMAC1, a candidate tumor suppressor gene, and its homologue, PTH2, in small cell lung cancer cell lines. Oncogene. 1998;16:89–93.

    Article  PubMed  CAS  Google Scholar 

  117. Marsit CJ, Zheng S, Aldape K, et al. PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol. 2005;36:768–776.

    Article  PubMed  CAS  Google Scholar 

  118. Wikman H, Kettunen E. Regulation of the G1/S phase of the cell cycle and alterations in the RB pathway in human lung cancer. Expert Rev Anticancer Ther. 2006;6:515–530.

    Article  PubMed  CAS  Google Scholar 

  119. Arvanitis DA, Papadakis E, Zafiropoulos A, Spandidos DA. Fractional allele loss is a valuable marker for human lung cancer detection in sputum. Lung Cancer. 2003;40:55–66.

    Article  PubMed  Google Scholar 

  120. Gorgoulis VG, Zacharatos P, Kotsinas A, et al. Alterations of the p16-pRb pathway and the chromosome locus 9p21–22 in non-small-cell lung carcinomas: relationship with p53 and MDM2 protein expression. Am J Pathol. 1998;153:1749–1765.

    PubMed  CAS  Google Scholar 

  121. Hussain SP, Harris CC. p53 biological network: at the crossroads of the cellular-stress response pathway and molecular carcinogenesis. J Nippon Med Sch. 2006;73:54–64.

    Article  PubMed  CAS  Google Scholar 

  122. Pan H, Califano J, Ponte JF, et al. Loss of heterozygosity patterns provide fingerprints for genetic heterogeneity in multistep cancer progression of tobacco smoke-induced non-small cell lung cancer. Cancer Res. 2005;65:1664–1669.

    Article  PubMed  CAS  Google Scholar 

  123. von Herbay A, Arens N, Friedl W, et al. Bronchioloalveolar carcinoma: a new cancer in Peutz-Jeghers syndrome. Lung Cancer. 2005;47:283–288.

    Article  PubMed  CAS  Google Scholar 

  124. Yang TL, Su YR, Huang CS, et al. High-resolution 19p13.2–13.3 allelotyping of breast carcinomas demonstrates frequent loss of heterozygosity. Genes Chromosomes Cancer. 2004; 41:250–2546.

    Article  PubMed  CAS  Google Scholar 

  125. Sobottka SB, Haase M, Fitze G, Hahn M, Schackert HK, Schackert G. Frequent loss of heterozygosity at the 19p13.3 locus without LKB1/STK11 mutations in human carcinoma metastases to the brain. J Neuro-Oncol. 2000;49:187–195.

    Article  CAS  Google Scholar 

  126. Samara K, Zervou M, Siafakas NM, Tzortzaki EG. Microsatellite DNA instability in benign lung diseases. Respir Med. 2006;100:202–211.

    Article  PubMed  Google Scholar 

  127. King T. Idiopathic pulmonary fibrosis. In: Schwartz M, King T, eds. Interstitial Lung Disease. Ontario, Canada: Decker BC; 1998:597–644.

    Google Scholar 

  128. Uematsu K, Yoshimura A, Gemma A, et al. Aberrations in the fragile histidine triad (FHIT) gene in idiopathic pulmonary fibrosis. Cancer Res. 2001;61:8527–8533.

    PubMed  CAS  Google Scholar 

  129. Demopoulos K, Arvanitis DA, Vassilakis DA, Siafakas NM, Spandidos DA. Genomic instability on hMSH2, hMLH1, CD48 and IRF4 loci in pulmonary sarcoidosis. Int J Biol Markers. 2002;17:224–230.

    PubMed  CAS  Google Scholar 

  130. Vassilakis DA, Sourvinos G, Pantelidis P, Spandidos DA, Siafakas NM, Bouros D. Extended genetic alterations in a patient with pulmonary sarcoidosis, a benign disease. Sarcoidosis Vasc Diffuse Lung Dis. 2001;18:307–310.

    PubMed  CAS  Google Scholar 

  131. Sandford AJ, Pare PD. The genetics of asthma. The important questions. Am J Respir Crit Care Med. 2000;161:S202–S206.

    PubMed  CAS  Google Scholar 

  132. Xu J, Meyers DA, Ober C, et al Genome-wide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma. Am J Hum Genet. 2001;68:1437–1446.

    Article  PubMed  CAS  Google Scholar 

  133. Paraskakis E, Sourvinos G, Passam F, et al. Microsatellite DNA instability and loss of heterozygosity in bronchial asthma. Eur Respir J. 2003;22:951–955.

    Article  PubMed  CAS  Google Scholar 

  134. Siafakas NM, Tzortzaki EG, Sourvinos G, et al. Microsatellite DNA instability in COPD. Chest. 1999;116:47–51.

    Article  PubMed  CAS  Google Scholar 

  135. Anderson GP, Bozinovski S. Acquired somatic mutations in the molecular pathogenesis of COPD. Trends Pharmacol Sci. 2003;24:71–76.

    Article  PubMed  CAS  Google Scholar 

  136. Argos M, Kibriya MG, Jasmine F, et al. Genomewide scan for loss of heterozygosity and chromosomal amplification in breast carcinoma using single-nucleotide polymorphism arrays. Cancer Genet Cytogenet. 2008;182:69–74.

    Article  PubMed  CAS  Google Scholar 

  137. Chan CC, Collins AB, Chew EY. Molecular pathology of eyes with von Hippel-Lindau (VHL) disease: a review. Retina. 2007;27:1–7.

    Article  PubMed  Google Scholar 

  138. Simoneau AR, Spruck CH, 3rd, Gonzalez-Zulueta M, et al. Evidence for two tumor suppressor loci associated with proximal chromosome 9p to q and distal chromosome 9q in bladder cancer and the initial screening for GAS1 and PTC mutations. Cancer Res. 1996;56:5039–5043.

    PubMed  CAS  Google Scholar 

  139. Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007;170:1445–1453.

    Article  PubMed  CAS  Google Scholar 

  140. Riener MO, Nikolopoulos E, Herr A, et al Microarray comparative genomic hybridization analysis of tubular breast carcinoma shows recurrent loss of the CDH13 locus on 16q. Hum Pathol. 2008;39:1621–1629.

    Article  PubMed  CAS  Google Scholar 

  141. Hu Y, Benya RV, Carroll RE, Diamond AM. Allelic loss of the gene for the GPX1 selenium-containing protein is a common event in cancer. J Nutr. 2005;135:3021S–3024S.

    PubMed  CAS  Google Scholar 

  142. Margolin S, Lindblom A. Familial breast cancer, underlying genes, and clinical implications: a review. Crit Rev Oncog. 2006;12:75–113.

    PubMed  Google Scholar 

  143. Palacios J, Robles-Frias MJ, Castilla MA, Lopez-Garcia MA, Benitez J. The molecular pathology of hereditary breast cancer. Pathobiology. 2008;75:85–94.

    Article  PubMed  CAS  Google Scholar 

  144. Zhao J, Yart A, Frigerio S, et al. Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene. Oncogene. 2007;26:3440–3449.

    Article  PubMed  CAS  Google Scholar 

  145. Choi CH, Lee KM, Choi JJ, et al. Hypermethylation and loss of heterozygosity of tumor suppressor genes on chromosome 3p in cervical cancer. Cancer Lett. 2007;255:26–33.

    Article  PubMed  CAS  Google Scholar 

  146. Xiao YP, Wu DY, Xu L, Xin Y. Loss of heterozygosity and microsatellite instabilities of fragile histidine triad gene in gastric carcinoma. World J Gastroenterol. 2006;12:3766–3769.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Scientific & Technical Operations, Tengion, Inc., Winston-Salem, NC, USA

    Belinda J. Wagner

  2. Cell and Tissue Technologies, Becton Dickinson, Research Triangle Park, NC, USA

    Sharon C. Presnell

Authors
  1. Belinda J. Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sharon C. Presnell
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2009 Springer Science+Business Media, LLC

    About this chapter

    Cite this chapter

    Wagner, B.J., Presnell, S.C. (2009). Loss of Heterozygosity. In: Allen, T., Cagle, P.T. (eds) Basic Concepts of Molecular Pathology. Molecular Pathology Library, vol 2. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-89626-7_11

    Download citation

    • DOI: https://doi.org/10.1007/978-0-387-89626-7_11

    • Published:

    • Publisher Name: Springer, Boston, MA

    • Print ISBN: 978-0-387-89625-0

    • Online ISBN: 978-0-387-89626-7

    • eBook Packages: MedicineMedicine (R0)

    Publish with us

    Policies and ethics

    Search

    Navigation