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The Role of Mutation and Epimutation in the Development of Human Disease

  • Ashley G. Rivenbark
  • William B. Coleman
Chapter
Part of the Molecular Pathology Library book series (MPLB, volume 2)

Abstract

The paradigm of disease causation holds that disease represents the manifestation or several manifestations of an underlying process that has one or more root causes. Thus, human diseases reflect a spectrum of pathologies and mechanisms of disease pathogenesis. The general categories of disease affecting humans include (a) hereditary diseases, (b) infectious diseases, (c) inflammatory diseases, and (d) neoplastic diseases. Pathological conditions representing each of these general categories have been described for every tissue in the body. Despite the grouping of diseases by the common features of the general disease type, the pathogenesis of each of the various diseases is unique, and in some cases multiple mechanisms can give rise to a similar pathology (disease manifestation). Disease causation may be related to intrinsic factors or extrinsic factors, but many or most diseases are multifactorial, involving a combination of intrinsic and extrinsic factors. It is now well recognized that most major diseases are ultimately the result of aberrant gene expression and that susceptibility to disease is significantly influenced by patterns of gene expression in target cells or tissues for a particular type of pathology. It follows that gene mutations and other genetic alterations are important in the pathogenesis of many human diseases. Similarly, nongenetic alterations affecting the expression of key genes, called epimutations, may also contribute to the genesis of disease at many tissue sites. In this chapter, general concepts related to the molecular basis for the major disease types are reviewed. This review is not intended to be comprehensive. Rather, the current state of understanding related to the genes and molecular mechanisms (genetic and epigenetic) that contribute to illustrative diseases is described.

Keywords

Cystic Fibrosis Transmembrane Conductance Regulator Small Cell Lung Carcinoma Chromosomal Deletion Chromosomal Alteration Cystic Fibrosis Transmembrane Conductance Regulator Mutation 
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.

References

  1. 1.
    Coleman WB, Rivenbark AG. Quantitative DNA methylation analysis: the promise of high-throughput epigenomic diagnostic testing in human neoplastic disease. J Mol Diagn. 2006;8:152–156.PubMedCrossRefGoogle Scholar
  2. 2.
    Murrell A, Rakyan VK, Beck S. From genome to epigenome. Hum Mol Genet. 2005;14(Special No. 1):R3-R10.PubMedCrossRefGoogle Scholar
  3. 3.
    Fuks F. DNA methylation and histone modifications: teaming up to silence genes. Curr Opin Genet Dev. 2005;15:490-495.PubMedCrossRefGoogle Scholar
  4. 4.
    Kallioniemi A, Kallioniemi OP, Sudar D, et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science. 1992;258:818-821.PubMedCrossRefGoogle Scholar
  5. 5.
    Bignell GR, Huang J, Greshock J, et al. High-resolution analysis of DNA copy number using oligonucleotide microarrays. Genome Res. 2006;14:287-295.CrossRefGoogle Scholar
  6. 6.
    Albertson DG, Ylstra B, Segraves R, et al. Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene. Nat Genet. 2000;25:144-146.PubMedCrossRefGoogle Scholar
  7. 7.
    Jain AN, Chin K, Borresen-Dale AL, et al. Quantitative analysis of chromosomal CGH in human breast tumors associates copy number abnormalities with p53 status and patient survival. Proc Natl Acad Sci USA. 2001;98:7952-7957.PubMedCrossRefGoogle Scholar
  8. 8.
    Weiss MM, Kuipers EJ, Postma C, et al. Genomic profiling of gastric cancer predicts lymph node status and survival. Oncogene. 2003;22:1872-1879.PubMedCrossRefGoogle Scholar
  9. 9.
    Weiss MM, Snijders AM, Kuipers EJ, et al. Determination of amplicon boundaries at 20q13.2 in tissue samples of human gastric adenocarcinomas by high-resolution microarray comparative genomic hybridization. J Pathol. 2003;200:320-326.PubMedCrossRefGoogle Scholar
  10. 10.
    Schwaenen C, Nessling M, Wessendorf S, et al. Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations. Proc Natl Acad Sci USA. 2004;101:1039-1044.PubMedCrossRefGoogle Scholar
  11. 11.
    Snijders AM, Nowee ME, Fridlyand J, et al. Genome-wide-array-based comparative genomic hybridization reveals genetic homogeneity and frequent copy number increases encompassing CCNE1 in fallopian tube carcinoma. Oncogene. 2003;22:4281-4286.PubMedCrossRefGoogle Scholar
  12. 12.
    Garnis C, Coe BP, Zhang L, et al. Overexpression of LRP12, a gene contained within an 8q22 amplicon identified by high-resolution array CGH analysis of oral squamous cell carcinomas. Oncogene. 2004;23:2582-2586.PubMedCrossRefGoogle Scholar
  13. 13.
    Veltman JA, Fridlyand J, Pejavar S, et al. Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Cancer Res. 2003;63:2872-2880.PubMedGoogle Scholar
  14. 14.
    Holzmann K, Kohlhammer H, Schwaenen C, et al. Genomic DNA-chip hybridization reveals a higher incidence of genomic amplifications in pancreatic cancer than conventional comparative genomic hybridization and leads to the identification of novel candidate genes. Cancer Res. 2004;64:4428-4433.PubMedCrossRefGoogle Scholar
  15. 15.
    Berrieman HK, Ashman JN, Cowen ME, et al. Chromosomal analysis of non-small-cell lung cancer by multicolour fluorescent in situ hybridisation. Br J Cancer. 2004;90:900-905.PubMedCrossRefGoogle Scholar
  16. 16.
    Balsara BR, Sonoda G, du Manoir S, et al. Comparative genomic hybridization analysis detects frequent, often high-level, overrepresentation of DNA sequences at 3q, 5p, 7p, and 8q in human non-small cell lung carcinomas. Cancer Res. 1997;57:2116-2120.PubMedGoogle Scholar
  17. 17.
    Nowell PC, Croce CM. Chromosomal approaches to the molecular basis of neoplasia. Symp Fundam Cancer Res. 1986;39:17-29.PubMedGoogle Scholar
  18. 18.
    Grandori C, Eisenman RN. Myc target genes. Trends Biochem Sci. 1997;22:177-181.PubMedCrossRefGoogle Scholar
  19. 19.
    Hurlin PJ, Huang J. The MAX-interacting transcription factor network. Semin Cancer Biol 2006;16:265-274.PubMedCrossRefGoogle Scholar
  20. 20.
    Blackwood EM, Eisenman RN. Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. Science. 1991;251:1211-1217.PubMedCrossRefGoogle Scholar
  21. 21.
    Blackwood EM, Kretzner L, Eisenman RN. Myc and Max function as a nucleoprotein complex. Curr Opin Genet Dev. 1992;2:227-235.PubMedCrossRefGoogle Scholar
  22. 22.
    Blackwood EM, Luscher B, Kretzner L, et al. The Myc:Max protein complex and cell growth regulation. Cold Spring Harb Symp Quant Biol. 1991;56:109-117.PubMedGoogle Scholar
  23. 23.
    Gazzeri S, Brambilla E, Caron de Fromentel C, et al. p53 genetic abnormalities and myc activation in human lung carcinoma. Int J Cancer. 1994;58:24-32.PubMedCrossRefGoogle Scholar
  24. 24.
    Broers JL, Viallet J, Jensen SM, et al. Expression of c-myc in progenitor cells of the bronchopulmonary epithelium and in a large number of non-small cell lung cancers. Am J Respir Cell Mol Biol. 1993;9:33-43.PubMedGoogle Scholar
  25. 25.
    Lorenz J, Friedberg T, Paulus R, et al. Oncogene overexpression in non-small-cell lung cancer tissue: prevalence and clinicopathological significance. Clin Invest. 1994;72:156-163.CrossRefGoogle Scholar
  26. 26.
    Volm M, Drings P, Wodrich W, et al. Expression of oncoproteins in primary human non-small cell lung cancer and incidence of metastases. Clin Exp Metastasis. 1993;11:325-329.PubMedCrossRefGoogle Scholar
  27. 27.
    Wodrich W, Volm M. Overexpression of oncoproteins in non-small cell lung carcinomas of smokers. Carcinogenesis. 1993;14:1121-1124.PubMedCrossRefGoogle Scholar
  28. 28.
    Mitani S, Kamata H, Fujiwara M, et al. Analysis of c-myc DNA amplification in non-small cell lung carcinoma in comparison with small cell lung carcinoma using polymerase chain reaction. Clin Exp Med. 2001;1:105-111.PubMedCrossRefGoogle Scholar
  29. 29.
    Richardson GE, Johnson BE. The biology of lung cancer. Semin Oncol. 1993;20:105-127.PubMedGoogle Scholar
  30. 30.
    Krystal G, Birrer M, Way J, et al. Multiple mechanisms for transcriptional regulation of the myc gene family in small-cell lung cancer. Mol Cell Biol. 1988;8:3373-3381.PubMedGoogle Scholar
  31. 31.
    Johnson BE, Russell E, Simmons AM, et al. MYC family DNA amplification in 126 tumor cell lines from patients with small cell lung cancer. J Cell Biochem Suppl. 1996;24:210-217.PubMedCrossRefGoogle Scholar
  32. 32.
    Levin NA, Brzoska P, Gupta N, et al. Identification of frequent novel genetic alterations in small cell lung carcinoma. Cancer Res. 1994;54:5086-5091.PubMedGoogle Scholar
  33. 33.
    van Beers EH, Nederlof PM. Array-CGH and breast cancer. Breast Cancer Res. 2006;8:210.PubMedCrossRefGoogle Scholar
  34. 34.
    Albertson DG. Profiling breast cancer by array CGH. Breast Cancer Res Treat. 2003;78:289-298.PubMedCrossRefGoogle Scholar
  35. 35.
    Climent J, Garcia JL, Mao JH, et al. Characterization of breast cancer by array comparative genomic hybridization. Biochem Cell Biol. 2007;85:497-508.PubMedCrossRefGoogle Scholar
  36. 36.
    Jonsson G, Naylor TL, Vallon-Christersson J, et al. Distinct genomic profiles in hereditary breast tumors identified by array-based comparative genomic hybridization. Cancer Res. 2005;65: 7612-7621.PubMedGoogle Scholar
  37. 37.
    Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177-182.PubMedCrossRefGoogle Scholar
  38. 38.
    Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707-712.PubMedCrossRefGoogle Scholar
  39. 39.
    Pauletti G, Dandekar S, Rong H, et al. Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancer: a direct comparison of fluorescence in situ hybridization and immunohistochemistry. J Clin Oncol. 2000;18:3651-3664.PubMedGoogle Scholar
  40. 40.
    Perez EA, Baweja M. HER2-positive breast cancer: current treatment strategies. Cancer Invest. 2008;26:545-552.PubMedCrossRefGoogle Scholar
  41. 41.
    Oldenhuis CN, Oosting SF, Gietema JA, et al. Prognostic versus predictive value of biomarkers in oncology. Eur J Cancer. 2008;44: 946-953.PubMedCrossRefGoogle Scholar
  42. 42.
    Jahanzeb M. Adjuvant trastuzumab therapy for HER2-positive breast cancer. Clin Breast Cancer. 2008;8:324-333.PubMedCrossRefGoogle Scholar
  43. 43.
    Widakowich C, Dinh P, de Azambuja E, et al. HER-2 positive breast cancer: what else beyond trastuzumab-based therapy? Anticancer Agents Med Chem. 2008;8:488-496.PubMedGoogle Scholar
  44. 44.
    Kawanishi M, Kohno T, Otsuka T, et al. Allelotype and replication error phenotype of small cell lung carcinoma. Carcinogenesis. 1997;18:2057-2062.PubMedCrossRefGoogle Scholar
  45. 45.
    Shiseki M, Kohno T, Adachi J, et al. Comparative allelotype of early and advanced stage non-small cell lung carcinomas. Genes Chromosomes Cancer. 1996;17:71-77.PubMedCrossRefGoogle Scholar
  46. 46.
    Sato S, Nakamura Y, Tsuchiya E. Difference of allelotype between squamous cell carcinoma and adenocarcinoma of the lung. Cancer Res. 1994;54:5652-5655.PubMedGoogle Scholar
  47. 47.
    Tsuchiya E, Nakamura Y, Weng SY, et al. Allelotype of non-small cell lung carcinoma: comparison between loss of heterozygosity in squamous cell carcinoma and adenocarcinoma. Cancer Res. 1992;52:2478-2481.PubMedGoogle Scholar
  48. 48.
    Luk C, Tsao MS, Bayani J, et al. Molecular cytogenetic analysis of non-small cell lung carcinoma by spectral karyotyping and comparative genomic hybridization. Cancer Genet Cytogenet. 2001; 125:87-99.PubMedCrossRefGoogle Scholar
  49. 49.
    Lui WO, Tanenbaum DM, Larsson C. High level amplification of 1p32-33 and 2p22-24 in small cell lung carcinomas. Int J Oncol. 2001;19:451-457.PubMedGoogle Scholar
  50. 50.
    Hibi K, Takahashi T, Yamakawa K, et al. Three distinct regions involved in 3p deletion in human lung cancer. Oncogene. 1992;7: 445-449.PubMedGoogle Scholar
  51. 51.
    Brauch H, Tory K, Kotler F, et al. Molecular mapping of deletion sites in the short arm of chromosome 3 in human lung cancer. Genes Chromosomes Cancer. 1990;1:240-246.PubMedCrossRefGoogle Scholar
  52. 52.
    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
  53. 53.
    Zochbauer-Muller S, Wistuba II, Minna JD, et al. Fragile histidine triad (FHIT) gene abnormalities in lung cancer. Clin Lung Cancer. 2000;2:141-145.PubMedCrossRefGoogle Scholar
  54. 54.
    Dammann R, Schagdarsurengin U, Seidel C, et al. The tumor suppressor RASSF1A in human carcinogenesis: an update. Histol Histopathol. 2005;20:645-663.PubMedGoogle Scholar
  55. 55.
    Hosoe S, Ueno K, Shigedo Y, et al. A frequent deletion of chromosome 5q21 in advanced small cell and non-small cell carcinoma of the lung. Cancer Res. 1994;54:1787-1790.PubMedGoogle Scholar
  56. 56.
    Kinzler KW, Nilbert MC, Su LK, et al. Identification of FAP locus genes from chromosome 5q21. Science. 1991;253:661-665.PubMedCrossRefGoogle Scholar
  57. 57.
    Kinzler KW, Nilbert MC, Vogelstein B, et al. Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science. 1991;251:1366-1370.PubMedCrossRefGoogle Scholar
  58. 58.
    Groden J, Thliveris A, Samowitz W, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991;66:589-600.PubMedCrossRefGoogle Scholar
  59. 59.
    Joslyn G, Carlson M, Thliveris A, et al. Identification of deletion mutations and three new genes at the familial polyposis locus. Cell. 1991;66:601-613.PubMedCrossRefGoogle Scholar
  60. 60.
    Horii A, Nakatsuru S, Miyoshi Y, et al. Frequent somatic mutations of the APC gene in human pancreatic cancer. Cancer Res. 1992;52:6696-6698.PubMedGoogle Scholar
  61. 61.
    Fung YK, Murphree AL, T’Ang A, et al. Structural evidence for the authenticity of the human retinoblastoma gene. Science. 1987;236:1657-1661.PubMedCrossRefGoogle Scholar
  62. 62.
    Lee WH, Bookstein R, Hong F, et al. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science. 1987;235:1394-1399.PubMedCrossRefGoogle Scholar
  63. 63.
    Hensel CH, Hsieh CL, Gazdar AF, et al. Altered structure and expression of the human retinoblastoma susceptibility gene in small cell lung cancer. Cancer Res. 1990;50:3067-3072.PubMedGoogle Scholar
  64. 64.
    Xu HJ, Hu SX, Cagle PT, et al. Absence of retinoblastoma protein expression in primary non-small cell lung carcinomas. Cancer Res. 1991;51:2735-2739.PubMedGoogle Scholar
  65. 65.
    McBride OW, Merry D, Givol D. The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). Proc Natl Acad Sci USA. 1986;83:130-134.PubMedCrossRefGoogle Scholar
  66. 66.
    Yokota J, Wada M, Shimosato Y, et al. 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
  67. 67.
    Nishioka M, Kohno T, Takahashi M, et al. Identification of a 428-kb homozygously deleted region disrupting the SEZ6L gene at 22q12.1 in a lung cancer cell line. Oncogene. 2000;19:6251-6260.PubMedCrossRefGoogle Scholar
  68. 68.
    Callahan R, Cropp C, Merlo GR, et al. Genetic and molecular heterogeneity of breast cancer cells. Clin Chim Acta. 1993;217:63-73.PubMedCrossRefGoogle Scholar
  69. 69.
    Cleton-Jansen AM, Moerland EW, Kuipers-Dijkshoorn NJ, et al. At least two different regions are involved in allelic imbalance on chromosome arm 16q in breast cancer. Genes Chromosomes Cancer. 1994;9:101-107.PubMedCrossRefGoogle Scholar
  70. 70.
    Eiriksdottir G, Sigurdsson A, Jonasson JG, et al. Loss of heterozygosity on chromosome 9 in human breast cancer: association with clinical variables and genetic changes at other chromosome regions. Int J Cancer. 1995;64:378-382.PubMedCrossRefGoogle Scholar
  71. 71.
    Gudmundsson J, Barkardottir RB, Eiriksdottir G, et al. Loss of heterozygosity at chromosome 11 in breast cancer: association of prognostic factors with genetic alterations. Br J Cancer. 1995;72:696-701.PubMedGoogle Scholar
  72. 72.
    Morelli C, Sherratt T, Trabanelli C, et al. Characterization of a 4-Mb region at chromosome 6q21 harboring a replicative senescence gene. Cancer Res. 1997;57:4153-4157.PubMedGoogle Scholar
  73. 73.
    Huang H, Qian C, Jenkins RB, et al. Fish mapping of YAC clones at human chromosomal band 7q31.2: identification of YACS spanning FRA7G within the common region of LOH in breast and prostate cancer. Genes Chromosomes Cancer. 1998;21:152-159.PubMedCrossRefGoogle Scholar
  74. 74.
    Mars WM, Saunders GF. Chromosomal abnormalities in human breast cancer. Cancer Metastasis Rev. 1990;9:35-43.PubMedCrossRefGoogle Scholar
  75. 75.
    Kerangueven F, Noguchi T, Coulier F, et al. Genome-wide search for loss of heterozygosity shows extensive genetic diversity of human breast carcinomas. Cancer Res. 1997;57:5469-5474.PubMedGoogle Scholar
  76. 76.
    Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66-71.PubMedCrossRefGoogle Scholar
  77. 77.
    Wooster R, Neuhausen SL, Mangion J, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994;265:2088-2090.PubMedCrossRefGoogle Scholar
  78. 78.
    Schultz DC, Vanderveer L, Berman DB, et al. Identification of two candidate tumor suppressor genes on chromosome 17p13.3. Cancer Res. 1996;56:1997-2002.PubMedGoogle Scholar
  79. 79.
    Cleton-Jansen AM. E-cadherin and loss of heterozygosity at chromosome 16 in breast carcinogenesis: different genetic pathways in ductal and lobular breast cancer? Breast Cancer Res. 2002;4:5-8.PubMedCrossRefGoogle Scholar
  80. 80.
    Debies MT, Welch DR. Genetic basis of human breast cancer metastasis. J Mammary Gland Biol Neoplasia. 2001;6:441-451.PubMedCrossRefGoogle Scholar
  81. 81.
    Fearon ER, Cho KR, Nigro JM, et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science. 1990;247:49-56.PubMedCrossRefGoogle Scholar
  82. 82.
    Bieche I, Champeme MH, Lidereau R. Loss and gain of distinct regions of chromosome 1q in primary breast cancer. Clin Cancer Res. 1995;1:123-127.PubMedGoogle Scholar
  83. 83.
    Bieche I, Khodja A, Lidereau R. Deletion mapping in breast tumor cell lines points to two distinct tumor-suppressor genes in the 1p32-pter region, one of deleted regions (1p36.2) being located within the consensus region of LOH in neuroblastoma. Oncol Rep. 1998;5:267-272.PubMedGoogle Scholar
  84.  84.
     84. Kerangueven F, Eisinger F, Noguchi T, et al. Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions. Oncogene. 1997;14:339-347.PubMedCrossRefGoogle Scholar
  85. 85.
    Aldaz CM, Chen T, Sahin A, et al. Comparative allelotype of in situ and invasive human breast cancer: high frequency of microsatellite instability in lobular breast carcinomas. Cancer Res. 1995;55:3976-3981.PubMedGoogle Scholar
  86.  86.
     86. Radford DM, Fair KL, Phillips NJ, et al. Allelotyping of ductal carcinoma in situ of the breast: deletion of loci on 8p, 13q, 16q, 17p and 17q. Cancer Res. 1995;55:3399-3405.PubMedGoogle Scholar
  87.  87.
     87. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia [abstract]. Science. 1960;132:1497.Google Scholar
  88.  88.
     88. Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst. 1960;25:85-109.PubMedGoogle Scholar
  89.  89.
     89. Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290-293.PubMedCrossRefGoogle Scholar
  90.  90.
     90. Kakizuka A, Miller WH Jr, Umesono K, et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991;66:663-674.PubMedCrossRefGoogle Scholar
  91.  91.
     91. de The H, Lavau C, Marchio A, et al. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991;66:675-684.PubMedCrossRefGoogle Scholar
  92.  92.
     92. Miller WH, Jr., Kakizuka A, Frankel SR, et al. Reverse transcription polymerase chain reaction for the rearranged retinoic acid receptor alpha clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc Natl Acad Sci USA. 1992;89:2694-2698.PubMedCrossRefGoogle Scholar
  93.  93.
     93. Huang W, Sun GL, Li XS, et al. Acute promyelocytic leukemia: clinical relevance of two major PML-RAR alpha isoforms and detection of minimal residual disease by retrotranscriptase/polymerase chain reaction to predict relapse. Blood. 1993; 82:1264-1269.PubMedGoogle Scholar
  94.  94.
     94. Gallagher RE, Willman CL, Slack JL, et al. Association of PML-RAR alpha fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: an intergroup molecular study. Blood. 1997;90:1656-1663.PubMedGoogle Scholar
  95.  95.
     95. Vyas RC, Frankel SR, Agbor P, et al. Probing the pathobiology of response to all-trans retinoic acid in acute promyelocytic leukemia: premature chromosome condensation/fluorescence in situ hybridization analysis. Blood. 1996;87:218-226.PubMedGoogle Scholar
  96.  96.
     96. Grignani F, Fagioli M, Alcalay M, et al. Acute promyelocytic leukemia: from genetics to treatment. Blood. 1994;83:10-25.PubMedGoogle Scholar
  97.  97.
     97. Sy SM, Fan B, Lee TW, et al. Spectral karyotyping indicates complex rearrangements in lung adenocarcinoma of nonsmokers. Cancer Genet Cytogenet. 2004;153:57-59.PubMedCrossRefGoogle Scholar
  98.  98.
     98. Sy SM, Wong N, Lee TW, et al. Distinct patterns of genetic alterations in adenocarcinoma and squamous cell carcinoma of the lung. Eur J Cancer. 2004;40:1082-1094.PubMedCrossRefGoogle Scholar
  99.  99.
     99. Greenberg F. Williams syndrome. Pediatrics. 1989;84:922-923.PubMedGoogle Scholar
  100. 100.
    Osborne LR, Li M, Pober B, et al. A 1.5 million-base pair inversion polymorphism in families with Williams–Beuren syndrome. Nat Genet. 2001;29:321-325.PubMedCrossRefGoogle Scholar
  101. 101.
    Inoue K, Lupski JR. Molecular mechanisms for genomic disorders. Annu Rev Genomic Hum Genet. 2002;3:199-242.CrossRefGoogle Scholar
  102. 102.
    Gimelli G, Pujana MA, Patricelli MG, et al. Genomic inversions of human chromosome 15q11–q13 in mothers of Angelman syndrome patients with class II (BP2/3) deletions. Hum Mol Genet. 2003;12:849-858.PubMedCrossRefGoogle Scholar
  103. 103.
    Feuk L, Carson AR, Scherer SW. Structural variation in the human genome. Nat Rev Genet. 2006;7:85-97.PubMedCrossRefGoogle Scholar
  104. 104.
    Lakich D, Kazazian HH Jr, Antonarakis SE, et al. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet. 1993;5:236-241.PubMedCrossRefGoogle Scholar
  105. 105.
    Naylor J, Brinke A, Hassock S, et al. Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions. Hum Mol Genet. 1993;2:1773-1778.PubMedCrossRefGoogle Scholar
  106. 106.
    Small K, Iber J, Warren ST. Emerin deletion reveals a common X-chromosome inversion mediated by inverted repeats. Nat Genet. 1997;16:96-99.PubMedCrossRefGoogle Scholar
  107. 107.
    Timms KM, Bondeson ML, Ansari-Lari MA, et al. Molecular and phenotypic variation in patients with severe Hunter syndrome. Hum Mol Genet. 1997;6:479-486.PubMedCrossRefGoogle Scholar
  108. 108.
    Bondeson ML, Dahl N, Malmgren H, et al. Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome. Hum Mol Genet. 1995;4:615-621.PubMedCrossRefGoogle Scholar
  109. 109.
    Visser R, Shimokawa O, Harada N, et al. Identification of a 3.0-kb major recombination hotspot in patients with Sotos syndrome who carry a common 1.9-Mb microdeletion. Am J Hum Genet. 2005;76:52-67.PubMedCrossRefGoogle Scholar
  110. 110.
    Giglio S, Broman KW, Matsumoto N, et al. Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am J Hum Genet. 2001;68:874-883.PubMedCrossRefGoogle Scholar
  111. 111.
    Giglio S, Calvari V, Gregato G, et al. Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation. Am J Hum Genet. 2002;71:276-285.PubMedCrossRefGoogle Scholar
  112. 112.
    Higgs DR, Old JM, Pressley L, et al. A novel alpha-globin gene arrangement in man. Nature. 1980;284:632-635.PubMedCrossRefGoogle Scholar
  113. 113.
    Lauer J, Shen CK, Maniatis T. The chromosomal arrangement of human alpha-like globin genes: sequence homology and alpha-globin gene deletions. Cell. 1980;20:119-130.PubMedCrossRefGoogle Scholar
  114. 114.
    Vollrath D, Nathans J, Davis RW. Tandem array of human visual pigment genes at Xq28. Science. 1988;240:1669-1672.PubMedCrossRefGoogle Scholar
  115. 115.
    Nathans J, Piantanida TP, Eddy RL, et al. Molecular genetics of inherited variation in human color vision. Science. 1986; 232:203-210.PubMedCrossRefGoogle Scholar
  116. 116.
    Aradhya S, Woffendin H, Jakins T, et al. A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations. Hum Mol Genet. 2001;10:2171-2179.PubMedCrossRefGoogle Scholar
  117. 117.
    Smahi A, Courtois G, Vabres P, et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. 2000;405:466-472.PubMedCrossRefGoogle Scholar
  118. 118.
    Chance PF, Alderson MK, Leppig KA, et al. DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell. 1993;72:143-151.PubMedCrossRefGoogle Scholar
  119. 119.
    Upadhyaya M, Ruggieri M, Maynard J, et al. Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Hum Genet. 1998;102:591-597.PubMedCrossRefGoogle Scholar
  120. 120.
    Valero MC, Pascual-Castroviejo I, Velasco E, et al. Identification of de novo deletions at the NF1 gene: no preferential paternal origin and phenotypic analysis of patients. Hum Genet. 1997;99:720-726.PubMedCrossRefGoogle Scholar
  121. 121.
    Edelmann L, Pandita RK, Spiteri E, et al. A common molecular basis for rearrangement disorders on chromosome 22q11. Hum Mol Genet. 1999;8:1157-1167.PubMedCrossRefGoogle Scholar
  122. 122.
    Chen KS, Manian P, Koeuth T, et al. Homologous recombination of a flanking repeat gene cluster is a mechanism for a common contiguous gene deletion syndrome. Nat Genet. 1997;17:154-163.PubMedCrossRefGoogle Scholar
  123. 123.
    Pasternak JJ. Molecular genetics of neurological disorders. In: Pasternak JJ, ed. An Introduction to Human Molecular Genetics: Mechanisms of Inherited Diseases. Bethesda, MD: Fitzgerald Science Press, 1999:286-287.Google Scholar
  124. 124.
    Lupski JR, de Oca-Luna RM, Slaugenhaupt S, et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell. 1991;66:219-232.PubMedCrossRefGoogle Scholar
  125. 125.
    Inoue K, Osaka H, Imaizumi K, et al. Proteolipid protein gene duplications causing Pelizaeus–Merzbacher disease: molecular mechanism and phenotypic manifestations. Ann Neurol. 1999;45:624-632.PubMedCrossRefGoogle Scholar
  126. 126.
    Barbacid M. Ras genes. Annu Rev Biochem. 1987;56:779-827.PubMedCrossRefGoogle Scholar
  127. 127.
    Barbacid M. Ras oncogenes: their role in neoplasia. Eur J Clin Invest. 1990;20:225-235.PubMedCrossRefGoogle Scholar
  128. 128.
    Wittinghofer A, Scheffzek K, Ahmadian MR. The interaction of Ras with GTPase-activating proteins. FEBS Lett. 1997;410:63-67.PubMedCrossRefGoogle Scholar
  129. 129.
    Hancock JF. Ras proteins: different signals from different locations. Nat Rev Mol Cell Biol. 2003;4:373-384.PubMedCrossRefGoogle Scholar
  130. 130.
    Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3:11-22.PubMedCrossRefGoogle Scholar
  131. 131.
    Mills NE, Fishman CL, Rom WN, et al. Increased prevalence of K-ras oncogene mutations in lung adenocarcinoma. Cancer Res. 1995;55:1444-1447.PubMedGoogle Scholar
  132. 132.
    Slebos RJ, Kibbelaar RE, Dalesio O, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med. 1990;323:561-565.PubMedGoogle Scholar
  133. 133.
    Rodenhuis S, Slebos RJ, Boot AJ, et al. Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res. 1988;48:5738-5741.PubMedGoogle Scholar
  134. 134.
    Rodenhuis S, Slebos RJ. Clinical significance of ras oncogene activation in human lung cancer. Cancer Res. 1992;52:2665s-2669s.PubMedGoogle Scholar
  135. 135.
    Reynolds SH, Anna CK, Brown KC, et al. Activated protooncogenes in human lung tumors from smokers. Proc Natl Acad Sci USA. 1991;88:1085-1089.PubMedCrossRefGoogle Scholar
  136. 136.
    Suzuki Y, Orita M, Shiraishi M, et al. Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene. 1990;5:1037-1043.PubMedGoogle Scholar
  137. 137.
    Li S, Rosell R, Urban A, et al. K-ras gene point mutation: a stable tumor marker in non-small cell lung carcinoma. Lung Cancer. 1994;11:19-27.PubMedCrossRefGoogle Scholar
  138. 138.
    Feng Z, Hu W, Chen JX, et al. Preferential DNA damage and poor repair determine ras gene mutational hotspot in human cancer. J Natl Cancer Inst. 2002;94:1527-1536.PubMedGoogle Scholar
  139. 139.
    Hu W, Feng Z, Tang MS. Preferential carcinogen-DNA adduct formation at codons 12 and 14 in the human K-ras gene and their possible mechanisms. Biochemistry. 2003;42:10012-10023.PubMedCrossRefGoogle Scholar
  140. 140.
    Ahrendt SA, Decker PA, Alawi EA, et al. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer. 2001;92:1525-1530.PubMedCrossRefGoogle Scholar
  141. 141.
    Slebos RJ, Hruban RH, Dalesio O, et al. Relationship between K-ras oncogene activation and smoking in adenocarcinoma of the human lung. J Natl Cancer Inst. 1991;83:1024-1027.PubMedCrossRefGoogle Scholar
  142. 142.
    Hollstein M, Sidransky D, Vogelstein B, et al. p53 mutations in human cancers. Science. 1991;253:49-53.PubMedCrossRefGoogle Scholar
  143. 143.
    Hollstein M, Shomer B, Greenblatt M, et al. Somatic point mutations in the p53 gene of human tumors and cell lines: updated compilation. Nucleic Acids Res. 1996;24:141-146.PubMedCrossRefGoogle Scholar
  144. 144.
    Kastan MB, Onyekwere O, Sidransky D, et al. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991;51:6304-6311.PubMedGoogle Scholar
  145. 145.
    Gannon JV, Greaves R, Iggo R, et al. Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. EMBO J. 1990;9:1595-1602.PubMedGoogle Scholar
  146. 146.
    Kern SE, Kinzler KW, Baker SJ, et al. Mutant p53 proteins bind DNA abnormally in vitro. Oncogene. 1991;6:131-136.PubMedGoogle Scholar
  147. 147.
    Kern SE, Kinzler KW, Bruskin A, et al. Identification of p53 as a sequence-specific DNA-binding protein. Science. 1991;252: 1708-1711.PubMedCrossRefGoogle Scholar
  148. 148.
    Kern SE, Pietenpol JA, Thiagalingam S, et al. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science. 1992;256:827-830.PubMedCrossRefGoogle Scholar
  149. 149.
    Kramer A, Neben K, Ho AD. Centrosome replication, genomic instability and cancer. Leukemia. 2002;16:767-775.PubMedCrossRefGoogle Scholar
  150. 150.
    Wahl GM, Linke SP, Paulson TG, et al. Maintaining genetic stability through TP53 mediated checkpoint control. Cancer Surv. 1997;29:183-219.PubMedGoogle Scholar
  151. 151.
    Olivier M, Eeles R, Hollstein M, et al. The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat. 2002;19:607-614.PubMedCrossRefGoogle Scholar
  152. 152.
    Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007;28:622-629.PubMedCrossRefGoogle Scholar
  153. 153.
    Hainaut P, Hernandez T, Robinson A, et al. IARC Database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualisation tools. Nucleic Acids Res. 1998;26:205-213.PubMedCrossRefGoogle Scholar
  154. 154.
    Hainaut P, Soussi T, Shomer B, et al. Database of p53 gene somatic mutations in human tumors and cell lines: updated compilation and future prospects. Nucleic Acids Res. 1997;25:151-157.PubMedCrossRefGoogle Scholar
  155. 155.
    Hollstein M, Rice K, Greenblatt MS, et al. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res. 1994;22:3551-3555.PubMedGoogle Scholar
  156. 156.
    Petitjean A, Achatz MI, Borresen-Dale AL, et al. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene. 2007;26:2157-2165.PubMedCrossRefGoogle Scholar
  157. 157.
    Grisham JW. Molecular genetic alterations in primary hepatocellular neoplasms: Hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma. In: Coleman WB, Tsongalis GJ, eds. The Molecular Basis of Human Cancer. Totowa: Humana Press, 2002:269-346.Google Scholar
  158. 158.
    Hsu IC, Metcalf RA, Sun T, et al. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature. 1991;350: 427-428.PubMedCrossRefGoogle Scholar
  159. 159.
    Scorsone KA, Zhou YZ, Butel JS, et al. p53 mutations cluster at codon 249 in hepatitis B virus-positive hepatocellular carcinomas from China. Cancer Res. 1992;52:1635-1638.PubMedGoogle Scholar
  160. 160.
    Li D, Cao Y, He L, et al. Aberrations of p53 gene in human hepatocellular carcinoma from China. Carcinogenesis. 1993;14:169-173.PubMedCrossRefGoogle Scholar
  161. 161.
    Bressac B, Kew M, Wands J, et al. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature. 1991;350:429-431.PubMedCrossRefGoogle Scholar
  162. 162.
    Ozturk M. p53 mutation in hepatocellular carcinoma after aflatoxin exposure. Lancet. 1991;338:1356-1359.PubMedCrossRefGoogle Scholar
  163. 163.
    Soini Y, Chia SC, Bennett WP, et al. An aflatoxin-associated mutational hotspot at codon 249 in the p53 tumor suppressor gene occurs in hepatocellular carcinomas from Mexico. Carcinogenesis. 1996;17:1007-1012.PubMedCrossRefGoogle Scholar
  164. 164.
    Puisieux A, Lim S, Groopman J, et al. Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens. Cancer Res. 1991;51:6185-6189.PubMedGoogle Scholar
  165. 165.
    Oda T, Tsuda H, Scarpa A, et al. p53 gene mutation spectrum in hepatocellular carcinoma. Cancer Res. 1992;52:6358-6364.PubMedGoogle Scholar
  166. 166.
    Kress S, Jahn UR, Buchmann A, et al. p53 mutations in human hepatocellular carcinomas from Germany. Cancer Res. 1992;52: 3220-3223.PubMedGoogle Scholar
  167. 167.
    Chiba I, Takahashi T, Nau MM, et al. Mutations in the p53 gene are frequent in primary, resected non-small cell lung cancer. Lung Cancer Study Group. Oncogene. 1990;5:1603-1610.PubMedGoogle Scholar
  168. 168.
    Curiel DT, Buchhagen DL, Chiba I, et al. A chemical mismatch cleavage method useful for the detection of point mutations in the p53 gene in lung cancer. Am J Respir Cell Mol Biol. 1990;3: 405-411.PubMedGoogle Scholar
  169. 169.
    D’Amico D, Carbone D, Mitsudomi T, et al. High frequency of somatically acquired p53 mutations in small-cell lung cancer cell lines and tumors. Oncogene. 1992;7:339-346.PubMedGoogle Scholar
  170. 170.
    Robles AI, Linke SP, Harris CC. The p53 network in lung carcinogenesis. Oncogene. 2002;21:6898-6907.PubMedCrossRefGoogle Scholar
  171. 171.
    Greenblatt MS, Bennett WP, Hollstein M, et al. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855-4878.PubMedGoogle Scholar
  172. 172.
    Denissenko MF, Pao A, Tang M, et al. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 1996;274:430-432.PubMedCrossRefGoogle Scholar
  173. 173.
    Woo SL, Lidsky AS, Guttler F, et al. Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria. Nature. 1983;306:151-155.PubMedCrossRefGoogle Scholar
  174. 174.
    Kwok SC, Ledley FD, DiLella AG, et al. Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase. Biochemistry. 1985;24:556-561.PubMedCrossRefGoogle Scholar
  175. 175.
    Wang Y, DeMayo JL, Hahn TM, et al. Tissue- and development-specific expression of the human phenylalanine hydroxylase/chloramphenicol acetyltransferase fusion gene in transgenic mice. J Biol Chem. 1992;267:15105-15110.PubMedGoogle Scholar
  176. 176.
    Scriver CR. The PAH gene, phenylketonuria, and a paradigm shift. Hum Mutat. 2007;28:831-845.PubMedCrossRefGoogle Scholar
  177. 177.
    DiLella AG, Kwok SC, Ledley FD, et al. Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene. Biochemistry. 1986;25:743-749.PubMedCrossRefGoogle Scholar
  178. 178.
    Konecki DS, Wang Y, Trefz FK, et al. Structural characterization of the 5′ regions of the human phenylalanine hydroxylase gene. Biochemistry. 1992;31:8363-8368.PubMedCrossRefGoogle Scholar
  179. 179.
    Farrell PM, Rosenstein BJ, White TB, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr. 2008;153:S4-S14.PubMedCrossRefGoogle Scholar
  180. 180.
    Davis PB. Cystic fibrosis: new perceptions, new strategies. Hosp Pract (Off Ed). 1992;27:79-83, 87-78, 93-74 passim.Google Scholar
  181. 181.
    Davies JC, Alton EW, Bush A. Cystic fibrosis. BMJ. 2007;335:1255-1259.PubMedCrossRefGoogle Scholar
  182. 182.
    Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245:1066-1073.PubMedCrossRefGoogle Scholar
  183. 183.
    Gadsby DC, Vergani P, Csanady L. The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature. 2006;440:477-483.PubMedCrossRefGoogle Scholar
  184. 184.
    Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. Cystic Fibrosis Foundation Consensus Panel. J Pediatr. 1998;132:589-595.PubMedCrossRefGoogle Scholar
  185. 185.
    Zielenski J, Tsui LC. Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet. 1995;29:777-807.PubMedCrossRefGoogle Scholar
  186. 186.
    Mickle JE, Cutting GR. Genotype-phenotype relationships in cystic fibrosis. Med Clin North Am. 2000;84:597-607.PubMedCrossRefGoogle Scholar
  187. 187.
    Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67:117-133.PubMedCrossRefGoogle Scholar
  188. 188.
    Quinton PM. Chloride impermeability in cystic fibrosis. Nature. 1983;301:421-422.PubMedCrossRefGoogle Scholar
  189. 189.
    Du K, Sharma M, Lukacs GL. The DeltaF508 cystic fibrosis mutation impairs domain–domain interactions and arrests post-translational folding of CFTR. Nat Struct Mol Biol. 2005;12:17-25.PubMedCrossRefGoogle Scholar
  190. 190.
    Tomashefski JF Jr, Crystal RG, Wiedemann HP, et al. The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: findings of the Death Review Committee of the national registry for individuals with Severe Deficiency of Alpha-1 Antitrypsin. Hum Pathol. 2004;35:1452-1461.PubMedCrossRefGoogle Scholar
  191. 191.
    Lieberman J, Winter B, Sastre A. Alpha 1-antitrypsin Pi-types in 965 COPD patients. Chest. 1986;89:370-373.PubMedCrossRefGoogle Scholar
  192. 192.
    Stoller JK, Aboussouan LS. Alpha 1-antitrypsin deficiency. Lancet. 2005;365:2225-2236.PubMedCrossRefGoogle Scholar
  193. 193.
    Lomas DA, Mahadeva R. Alpha 1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest. 2002;110:1585-1590.PubMedGoogle Scholar
  194. 194.
    DeMeo DL, Silverman EK. Alpha 1-antitrypsin deficiency. 2: Genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax. 2004;59:259-264.PubMedCrossRefGoogle Scholar
  195. 195.
    Lomas DA, Evans DL, Finch JT, et al. The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature. 1992;357:605-607.PubMedCrossRefGoogle Scholar
  196. 196.
    Ogushi F, Fells GA, Hubbard RC, et al. Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase. J Clin Invest. 1987;80:1366-1374.PubMedCrossRefGoogle Scholar
  197. 197.
    Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042-2054.PubMedCrossRefGoogle Scholar
  198. 198.
    Baylin S. DNA methylation and epigenetic mechanisms of carcinogenesis. Dev Biol. 2001;106:85-87.Google Scholar
  199. 199.
    Baylin SB, Herman JG, Graff JR, et al. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res. 1998;72:141-196.PubMedCrossRefGoogle Scholar
  200. 200.
    Momparler RL. Cancer epigenetics. Oncogene. 2003;22:6479-6483.PubMedCrossRefGoogle Scholar
  201. 201.
    Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet. 1999;21:163-167.PubMedCrossRefGoogle Scholar
  202. 202.
    Tsou JA, Hagen JA, Carpenter CL, et al. DNA methylation analysis: a powerful new tool for lung cancer diagnosis. Oncogene. 2002;21:5450-5461.PubMedCrossRefGoogle Scholar
  203. 203.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.PubMedCrossRefGoogle Scholar
  204. 204.
    Baylin SB, Ohm JE. Epigenetic gene silencing in cancer: a mechanism for early oncogenic pathway addiction. Nat Rev Cancer. 2006;6:107-116.PubMedCrossRefGoogle Scholar
  205. 205.
    Toyooka S, Toyooka KO, Maruyama R, et al. DNA methylation profiles of lung tumors. Mol Cancer Ther. 2001;1:61-67.PubMedGoogle Scholar
  206. 206.
    Tanaka R, Wang D, Morishita Y, et al. Loss of function of p16 gene and prognosis of pulmonary adenocarcinoma. Cancer. 2005;103:608-615.PubMedCrossRefGoogle Scholar
  207. 207.
    Shapiro GI, Park JE, Edwards CD, et al. Multiple mechanisms of p16INK4A inactivation in non-small cell lung cancer cell lines. Cancer Res. 1995;55:6200-6209.PubMedGoogle Scholar
  208. 208.
    Sanchez-Cespedes M, Decker PA, Doffek KM, et al. Increased loss of chromosome 9p21 but not p16 inactivation in primary non-small cell lung cancer from smokers. Cancer Res. 2001;61:2092-2096.PubMedGoogle Scholar
  209. 209.
    Liu Y, Lan Q, Siegfried JM, et al. Aberrant promoter methylation of p16 and MGMT genes in lung tumors from smoking and never-smoking lung cancer patients. Neoplasia. 2006;8:46-51.PubMedCrossRefGoogle Scholar
  210. 210.
    Tsou JA, Shen LY, Siegmund KD, et al. Distinct DNA methylation profiles in malignant mesothelioma, lung adenocarcinoma, and non-tumor lung. Lung Cancer. 2005;47:193-204.PubMedCrossRefGoogle Scholar
  211. 211.
    Zhu WG, Srinivasan K, Dai Z, et al. Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21(Cip1) promoter. Mol Cell Biol. 2003;23:4056-4065.PubMedCrossRefGoogle Scholar
  212. 212.
    Soria JC, Rodriguez M, Liu DD, et al. Aberrant promoter methylation of multiple genes in bronchial brush samples from former cigarette smokers. Cancer Res. 2002;62:351-355.PubMedGoogle Scholar
  213. 213.
    Lai JC, Cheng YW, Chiou HL, et al. Gender difference in estrogen receptor alpha promoter hypermethylation and its prognostic value in non-small cell lung cancer. Int J Cancer. 2005;117:974-980.PubMedCrossRefGoogle Scholar
  214. 214.
    Chen Y, Huhn D, Knosel T, et al. Downregulation of connexin 26 in human lung cancer is related to promoter methylation. Int J Cancer. 2005;113:14-21.PubMedCrossRefGoogle Scholar
  215. 215.
    Wistuba II, Gazdar AF, Minna JD. Molecular genetics of small cell lung carcinoma. Semin Oncol. 2001;28:3-13.PubMedCrossRefGoogle Scholar
  216. 216.
    Miyamoto K, Asada K, Fukutomi T, et al. Methylation-associated silencing of heparan sulfate d-glucosaminyl 3-O-sulfotransferase-2 (3-OST-2) in human breast, colon, lung and pancreatic cancers. Oncogene. 2003;22:274-280.PubMedCrossRefGoogle Scholar
  217. 217.
    Du Y, Carling T, Fang W, et al. Hypermethylation in human cancers of the RIZ1 tumor suppressor gene, a member of a histone/protein methyltransferase superfamily. Cancer Res. 2001;61:8094-8099.PubMedGoogle Scholar
  218. 218.
    Xu XL, Wu LC, Du F, et al. Inactivation of human SRBC, located within the 11p15.5-p15.4 tumor suppressor region, in breast and lung cancers. Cancer Res. 2001;61:7943-7949.PubMedGoogle Scholar
  219. 219.
    Dammann R, Takahashi T, Pfeifer GP. The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas. Oncogene. 2001;20:3563-3567.PubMedCrossRefGoogle Scholar
  220. 220.
    Osada H, Tatematsu Y, Yatabe Y, et al. Frequent and histological type-specific inactivation of 14-3-3sigma in human lung cancers. Oncogene. 2002;21:2418-2424.PubMedCrossRefGoogle Scholar
  221. 221.
    Fukasawa M, Kimura M, Morita S, et al. Microarray analysis of promoter methylation in lung cancers. J Hum Genet. 2006;51:368-374.PubMedCrossRefGoogle Scholar
  222. 222.
    Bai AH, Tong JH, To KF, et al. Promoter hypermethylation of tumor-related genes in the progression of colorectal neoplasia. Int J Cancer. 2004;112:846-853.PubMedCrossRefGoogle Scholar
  223. 223.
    Petko Z, Ghiassi M, Shuber A, et al. Aberrantly methylated CDKN2A, MGMT, and MLH1 in colon polyps and in fecal DNA from patients with colorectal polyps. Clin Cancer Res. 2005;11:1203-1209.PubMedGoogle Scholar
  224. 224.
    Sharma G, Mirza S, Prasad CP, et al. Promoter hypermethylation of p16(INK4A), p14(ARF), CyclinD2 and Slit2 in serum and tumor DNA from breast cancer patients. Life Sci. 2007;80:1873-1881.PubMedCrossRefGoogle Scholar
  225. 225.
    Krassenstein R, Sauter E, Dulaimi E, et al. Detection of breast cancer in nipple aspirate fluid by CpG island hypermethylation. Clin Cancer Res. 2004;10:28-32.PubMedCrossRefGoogle Scholar
  226. 226.
    Perry AS, Foley R, Woodson K, et al. The emerging roles of DNA methylation in the clinical management of prostate cancer. Endocr Relat Cancer. 2006;13:357-377.PubMedCrossRefGoogle Scholar
  227. 227.
    Hoque MO, Topaloglu O, Begum S, et al. Quantitative methylation-specific polymerase chain reaction gene patterns in urine sediment distinguish prostate cancer patients from control subjects. J Clin Oncol. 2005;23:6569-6575.PubMedCrossRefGoogle Scholar
  228. 228.
    Ha PK, Califano JA. Promoter methylation and inactivation of tumour-suppressor genes in oral squamous-cell carcinoma. Lancet Oncol. 2006;7:77-82.PubMedCrossRefGoogle Scholar
  229. 229.
    Duenas-Gonzalez A, Lizano M, Candelaria M, et al. Epigenetics of cervical cancer. An overview and therapeutic perspectives. Mol Cancer. 2005;4:38.PubMedCrossRefGoogle Scholar
  230. 230.
    Balch C, Huang TH, Brown R, et al. The epigenetics of ovarian cancer drug resistance and resensitization. Am J Obstet Gynecol. 2004;191:1552-1572.PubMedCrossRefGoogle Scholar
  231. 231.
    van Doorn R, Gruis NA, Willemze R, et al. Aberrant DNA methylation in cutaneous malignancies. Semin Oncol. 2005;32:479-487.PubMedCrossRefGoogle Scholar
  232. 232.
    Kuroki T, Tajima Y, Kanematsu T. Role of hypermethylation on carcinogenesis in the pancreas. Surg Today. 2004;34:981-986.PubMedCrossRefGoogle Scholar
  233. 233.
    Debinski W, Gibo D, Mintz A. Epigenetics in high-grade astrocytomas: opportunities for prevention and detection of brain tumors. Ann N Y Acad Sci. 2003;983:232-242.PubMedCrossRefGoogle Scholar
  234. 234.
    Claus R, Almstedt M, Lubbert M. Epigenetic treatment of hematopoietic malignancies: in vivo targets of demethylating agents. Semin Oncol. 2005;32:511-520.PubMedCrossRefGoogle Scholar
  235. 235.
    Kay PH, Spagnolo DV, Taylor J, et al. DNA methylation and developmental genes in lymphomagenesis – more questions than answers? Leuk Lymphoma. 1997;24:211-220.PubMedGoogle Scholar
  236. 236.
    Chou JL, Rozmahel R, Tsui LC. Characterization of the promoter region of the cystic fibrosis transmembrane conductance regulator gene. J Biol Chem. 1991;266:24471-24476.PubMedGoogle Scholar
  237. 237.
    Yoshimura K, Nakamura H, Trapnell BC, et al. The cystic fibrosis gene has a “housekeeping”-type promoter and is expressed at low levels in cells of epithelial origin. J Biol Chem. 1991;266:9140-9144.PubMedGoogle Scholar
  238. 238.
    Denamur E, Chehab FF. Methylation status of CpG sites in the mouse and human CFTR promoters. DNA Cell Biol. 1995;14:811-815.PubMedCrossRefGoogle Scholar
  239. 239.
    Koh J, Sferra TJ, Collins FS. Characterization of the cystic fibrosis transmembrane conductance regulator promoter region. Chromatin context and tissue-specificity. J Biol Chem. 1993;268:15912-15921.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Ashley G. Rivenbark
    • 1
  • William B. Coleman
    • 2
  1. 1.UNC Lineberger Comprehensive Cancer CenterDepartment of Biochemistry and Biophysics, University of North Carolina School of MedicineChapel HillUSA
  2. 2.Department of Pathology and Laboratory MedicineUNC Lineberger Comprehensive Cancer Center, University of North Carolina School of MedicineChapel HillUSA

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