Loss of Heterozygosity

  • Belinda J. Wagner
  • Sharon C. Presnell
Part of the Molecular Pathology Library book series (MPLB, volume 2)


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.


Chronic Obstructive Pulmonary Disease Tumor Suppressor Gene Idiopathic Pulmonary Fibrosis Smokeless Tobacco Idiopathic Pulmonary Fibrosis Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 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.PubMedGoogle Scholar
  2. 2.
    Cecil RL, Goldman L, Ausiello DA. Cecil Textbook of Medicine. Philadelphia: Saunders Elsevier; 2007.Google Scholar
  3. 3.
    Knudson AG Jr. Nakahara memorial lecture. Hereditary cancer, oncogenes, and anti-oncogenes. Princess Takamatsu Symp. 1989;20:15–29.PubMedGoogle Scholar
  4. 4.
    Fong KM, Sekido Y, Minna JD. Molecular pathogenesis of lung cancer. J Thorac Cardiovasc Surg. 1999;118:1136–1152.PubMedCrossRefGoogle Scholar
  5. 5.
    Sekido Y, Fong KM, Minna JD. Progress in understanding the molecular pathogenesis of human lung cancer. Biochim Biophys Acta. 1998;1378:F21–F59.PubMedGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 7.
    Mao X, Young BD, Lu YJ. The application of single nucleotide polymorphism microarrays in cancer research. Curr Genomics. 2007;8:219–228.PubMedCrossRefGoogle Scholar
  8. 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.PubMedGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 16.
    Vogelstein B, Fearon ER, Kern SE, et al. Allelotype of colorectal carcinomas. Science. 1989;244:207–211.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 27.
    Brooks PJ, Theruvathu JA. DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis. Alcohol. 2005;35:187–193.PubMedCrossRefGoogle Scholar
  28. 28.
    Ray G, Husain SA. Oxidants, antioxidants and carcinogenesis. Indian J Exp Biol. 2002;40:1213–1232.PubMedGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 30.
    Roos PH, Bolt HM. Cytochrome P450 interactions in human cancers: new aspects considering CYP1B1. Expert Opin Drug Metab Toxicol. 2005;1:187–202.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 32.
    Vineis P. Individual susceptibility to carcinogens. Oncogene. 2004;23:6477–6483.PubMedCrossRefGoogle Scholar
  33. 33.
    Boffetta P, Hecht S, Gray N, Gupta P, Straif K. Smokeless tobacco and cancer. Lancet Oncol. 2008;9:667–675.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 38.
    Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6:963–968.PubMedCrossRefGoogle Scholar
  39. 39.
    Craighead JE, Mossman BT. The pathogenesis of asbestos-associated diseases. N Engl J Med. 1982;306:1446–1455.PubMedGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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. 44.
    U.S. Department of Health and Human Services. Report on Carcinogens. 11th ed. Research Triangle Park, NC; 2005.Google Scholar
  45. 45.
    Go VL, Gukovskaya A, Pandol SJ. Alcohol and pancreatic cancer. Alcohol. 2005;35:205–211.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 47.
    Brenner C, Bieganowski P, Pace HC, Huebner K. The histidine triad superfamily of nucleotide-binding proteins. J Cell Physiol. 1999;181:179–187.PubMedCrossRefGoogle Scholar
  48. 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.PubMedGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. 53.
    Yang J, Du X, Lazar AJ, et al. Genetic aberrations of gastrointestinal stromal tumors. Cancer. 2008;113:1532–1543.PubMedCrossRefGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar
  55. 55.
    Fang L, Lee SW, Aaronson SA. Comparative analysis of p73 and p53 regulation and effector functions. J Cell Biol. 1999;147:823–830.PubMedCrossRefGoogle Scholar
  56. 56.
    Gupta S. Molecular steps of tumor necrosis factor receptor-mediated apoptosis. Curr Mol Med. 2001;1:317–324.PubMedCrossRefGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar
  58. 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.PubMedGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. 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.PubMedCrossRefGoogle Scholar
  61. 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.PubMedCrossRefGoogle Scholar
  62. 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.PubMedGoogle Scholar
  63. 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.PubMedCrossRefGoogle Scholar
  64. 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.PubMedCrossRefGoogle Scholar
  65. 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.PubMedCrossRefGoogle Scholar
  66. 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.PubMedGoogle Scholar
  67. 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.PubMedGoogle Scholar
  68. 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.PubMedCrossRefGoogle Scholar
  69. 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. 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.PubMedGoogle Scholar
  71. 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.PubMedGoogle Scholar
  72. 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.PubMedGoogle Scholar
  73. 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.PubMedCrossRefGoogle Scholar
  74. 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.PubMedGoogle Scholar
  75. 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.PubMedCrossRefGoogle Scholar
  76. 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.PubMedGoogle Scholar
  77. 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.PubMedCrossRefGoogle Scholar
  78. 78.
    Mitra AB, Murty VV, Li RG, Pratap M, Luthra UK, Chaganti RS. Allelotype analysis of cervical carcinoma. Cancer Res. 1994;54:4481–4487.PubMedGoogle Scholar
  79. 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.PubMedCrossRefGoogle Scholar
  80. 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.PubMedCrossRefGoogle Scholar
  81. 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.PubMedGoogle Scholar
  82. 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.PubMedGoogle Scholar
  83. 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.PubMedCrossRefGoogle Scholar
  84. 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.PubMedCrossRefGoogle Scholar
  85. 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.PubMedGoogle Scholar
  86. 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.PubMedGoogle Scholar
  87. 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.PubMedCrossRefGoogle Scholar
  88. 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.PubMedCrossRefGoogle Scholar
  89. 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.PubMedGoogle Scholar
  90. 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.PubMedGoogle Scholar
  91. 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.PubMedCrossRefGoogle Scholar
  92. 92.
    Chang J, Kim NG, Piao Z, et al. Assessment of chromosomal losses and gains in hepatocellular carcinoma. Cancer Lett. 2002;182:193–202.PubMedCrossRefGoogle Scholar
  93. 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.PubMedCrossRefGoogle Scholar
  94. 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.PubMedCrossRefGoogle Scholar
  95. 95.
    Takeuchi S, Seriu T, van Dongen JJ, et al. Allelotype analysis in relapsed childhood acute lymphoblastic leukemia. Oncogene. 2003;22:6970–6976.PubMedCrossRefGoogle Scholar
  96. 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.PubMedCrossRefGoogle Scholar
  97. 97.
    Suzuki M, Hao C, Takahashi T, et al. Aberrant methylation of SPARC in human lung cancers. Br J Cancer. 2005;92:942–948.PubMedCrossRefGoogle Scholar
  98. 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.PubMedGoogle Scholar
  99. 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.PubMedCrossRefGoogle Scholar
  100. 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.CrossRefGoogle Scholar
  101. 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.PubMedCrossRefGoogle Scholar
  102. 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.PubMedCrossRefGoogle Scholar
  103. 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.PubMedGoogle Scholar
  104. 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.PubMedCrossRefGoogle Scholar
  105. 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.PubMedGoogle Scholar
  106. 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.PubMedGoogle Scholar
  107. 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.PubMedCrossRefGoogle Scholar
  108. 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.PubMedCrossRefGoogle Scholar
  109. 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.PubMedCrossRefGoogle Scholar
  110. 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.PubMedGoogle Scholar
  111. 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.PubMedCrossRefGoogle Scholar
  112. 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.PubMedGoogle Scholar
  113. 113.
    Quesnel B, Preudhomme C, Fenaux P. p16ink4a gene and hematological malignancies. Leuk Lymphoma. 1996;22:11–24.PubMedCrossRefGoogle Scholar
  114. 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.PubMedCrossRefGoogle Scholar
  115. 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.PubMedCrossRefGoogle Scholar
  116. 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.PubMedCrossRefGoogle Scholar
  117. 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.PubMedCrossRefGoogle Scholar
  118. 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.PubMedCrossRefGoogle Scholar
  119. 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.PubMedCrossRefGoogle Scholar
  120. 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.PubMedGoogle Scholar
  121. 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.PubMedCrossRefGoogle Scholar
  122. 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.PubMedCrossRefGoogle Scholar
  123. 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.PubMedCrossRefGoogle Scholar
  124. 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.PubMedCrossRefGoogle Scholar
  125. 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.CrossRefGoogle Scholar
  126. 126.
    Samara K, Zervou M, Siafakas NM, Tzortzaki EG. Microsatellite DNA instability in benign lung diseases. Respir Med. 2006;100:202–211.PubMedCrossRefGoogle Scholar
  127. 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. 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.PubMedGoogle Scholar
  129. 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.PubMedGoogle Scholar
  130. 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.PubMedGoogle Scholar
  131. 131.
    Sandford AJ, Pare PD. The genetics of asthma. The important questions. Am J Respir Crit Care Med. 2000;161:S202–S206.PubMedGoogle Scholar
  132. 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.PubMedCrossRefGoogle Scholar
  133. 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.PubMedCrossRefGoogle Scholar
  134. 134.
    Siafakas NM, Tzortzaki EG, Sourvinos G, et al. Microsatellite DNA instability in COPD. Chest. 1999;116:47–51.PubMedCrossRefGoogle Scholar
  135. 135.
    Anderson GP, Bozinovski S. Acquired somatic mutations in the molecular pathogenesis of COPD. Trends Pharmacol Sci. 2003;24:71–76.PubMedCrossRefGoogle Scholar
  136. 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.PubMedCrossRefGoogle Scholar
  137. 137.
    Chan CC, Collins AB, Chew EY. Molecular pathology of eyes with von Hippel-Lindau (VHL) disease: a review. Retina. 2007;27:1–7.PubMedCrossRefGoogle Scholar
  138. 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.PubMedGoogle Scholar
  139. 139.
    Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007;170:1445–1453.PubMedCrossRefGoogle Scholar
  140. 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.PubMedCrossRefGoogle Scholar
  141. 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.PubMedGoogle Scholar
  142. 142.
    Margolin S, Lindblom A. Familial breast cancer, underlying genes, and clinical implications: a review. Crit Rev Oncog. 2006;12:75–113.PubMedGoogle Scholar
  143. 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.PubMedCrossRefGoogle Scholar
  144. 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.PubMedCrossRefGoogle Scholar
  145. 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.PubMedCrossRefGoogle Scholar
  146. 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.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Belinda J. Wagner
    • 1
  • Sharon C. Presnell
    • 2
  1. 1.Scientific & Technical OperationsTengion, Inc.Winston-SalemUSA
  2. 2.Cell and Tissue TechnologiesBecton DickinsonResearch Triangle ParkUSA

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