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. 2007 May 1;4(3):151–163. doi: 10.1111/j.1582-4934.2000.tb00113.x

Comprehensive genetic analysis of cancer cells

Nicholas C Popescu 1,✉
PMCID: PMC6741355  PMID: 12167284

Abstract

Human cancer is viewed as a disorder of genes originating from the progeny of a single cell that has accumulated multiple genetic alterations. The genetic alterations include point mutation, chromosomal rearrangements and imbalances. Amplifications primarily involve oncogenes whose overexpression leads to growth deregulation, while deletions commonly target tumor suppressor genes that control cell cycle checkpoints and DNA repair mechanisms. With the advent of molecular cytogenetics procedures for global detection of genomic imbalances and for multicolor visualization of structural chromosome changes, as well as the completion of human genome mapping and the development of microarray technology for serial gene expression analysis of the entire genomes, a significant progress has been made in uncovering the molecular basis of cancer. The major challenge in cancer biology is to decipher the molecular anatomy of various cancers and to identify cancer‐related genes that now comprise only a fraction of human genes. The complete genetic anatomy of specific cancers would allow a better understanding of the role of genetic alterations in carcinogenesis, provide diagnostic and prognostic markers and discriminate between cells at different stages of progression toward malignancy. This review highlights current technologies that are available to explore cancer cells and outlines their application to investigations in human hepatocellular carcinoma.

Keywords: cancer genetics, oncogenes, tumor suppressor genes, genomic alteratons, molecular cytogenetics spectral karyotyping, comparative genomic hybridization, expression microarray

References

  • 1. Childs R., Chernoff A., Contentin N., Bahceci E., Schrump D., Leitman S., Read E. J., Tisdale J., Dunbar C., Linehan W. M., Young N. S., Barrett A. J., Regression of metastatic renal‐cell carcinoma after nonmyeloablative allogeneic peripheral‐blood stem‐cell transplantation. N. Engl. J. Med., 343: 750–758, 2000. [DOI] [PubMed] [Google Scholar]
  • 2. Casperson T., Zech L., Johansson C., Differential banding of alkylating fluorochomes in human chromosomes. Exp. Cell Res., 60: 315–319, 1970. [DOI] [PubMed] [Google Scholar]
  • 3. Pinkel D., Straume, T. , Gray, I. W. , Cytogenetic analysis using quantitative, high sensitivity, fluorescence hybridization. Proc. Natl. Acad. Sci. USA, 83: 2934–2938, 1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Bishop J. M., The molecular genetics of cancer. Science, 235: 305–311, 1987. [DOI] [PubMed] [Google Scholar]
  • 5. Fearon E. R., Vogelstein B., A genetic model for colorectal tumorigenesis. Cell, 61: 759–767, 1990. [DOI] [PubMed] [Google Scholar]
  • 6. Croce C. M., Nowell P. C., Molecular basis of human B cell neoplasia. Blood, 65: 1–7, 1985. [PubMed] [Google Scholar]
  • 7. Knudson A. G., Antioncogenes and human cancer. Proc. Natl. Acad. Sci. USA, 90: 10914–10921, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Mitelman F., Mertens F., Johansson B., A breakpoint map of recurrent chromosomal rearrangements in human neoplasia. Nat. Genet., 15 Spec No: 417–474, 1997. [DOI] [PubMed] [Google Scholar]
  • 9. Rabbitts T. H., Chromosomal translocations in human cancer. Nature, 372: 143–149, 1994. [DOI] [PubMed] [Google Scholar]
  • 10. Rowley J. D., Molecular cytogenetics: Rosetta stone for understanding cancer–twenty‐ninth G. H. A. Clowes memorial award lecture. Cancer Res., 50: 3816–3825, 1990. [PubMed] [Google Scholar]
  • 11. Sandberg A., The chromosomes in human cancer and leukemia. New York , NY : Elsevier Science, 1990. [Google Scholar]
  • 12. Strausberg R. L., Dahl C. A., Klausner R. D., New opportunities for uncovering the molecular basis of cancer. Nature Genet., 15 Spec No: 415–416, 1997. [DOI] [PubMed] [Google Scholar]
  • 13. Popescu N. C., Zimonjic D. B., Molecular cytogenetic characterization of cancer cell alterations. Cancer Genet. Cytogenet., 93: 10–21, 1997. [DOI] [PubMed] [Google Scholar]
  • 14. Schröck E., du Manoir, S. , Veldman T., Schoell B., Wienberg J., Ferguson‐Smith M. A., Ning Y., Ledbetter D. H., Bar‐Am I., Soenksen D., Garini Y., Ried T., Multicolor spectral karyotyping of human chromosomes. Science, 273: 494–497, 1966. [DOI] [PubMed] [Google Scholar]
  • 15. Kallioniemi A., Kallioniemi O. P., Sudar D., Rutovitz D., Gray J. W., Waldman F., Pinkel D., Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science, 258: 818–821, 1992. [DOI] [PubMed] [Google Scholar]
  • 16. Knutsen T., Ried T., SKY: A comprehensive diagnostic and research tool: A review of the first 300 published cases. J. Assoc. Genetic Technologists, 26: 3–15, 2000. [Google Scholar]
  • 17. Bentz M., Plesch A., Stilgenbauer S., Dohner H., Lichter P., Minimal sizes of deletions detected by comparative genomic hybridization. Genes Chromosomes Cancer, 21: 172–175, 1998. [PubMed] [Google Scholar]
  • 18. Knuutila S., Bjorkqvist A. M., Autio K., Tarkkanen M., Wolf M., Monni O., Szymanska J., Larramendy M. L., Tapper J., Pere H., El‐Rifai W., Hemmer S., Wasenius V. M., Vidgren V., Zhu Y., DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies. Am. J. Pathol., 152: 1107–1123, 1998. [PMC free article] [PubMed] [Google Scholar]
  • 19. Zitzelsberger H., Lehmann L., Werner M., Bauchinger M., Comparative genomic hybridisation for the analysis of chromosomal imbalances in solid tumours and haematological malignancies. Histochem. Cell. Biol., 108: 403–417, 1997. [DOI] [PubMed] [Google Scholar]
  • 20. Solinas‐Toldo S., Lampel S., Stilgenbauer S., Nickolenko J., Benner A., Dohner H., Cremer T., Lichter P., Matrix‐based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer, 20: 399–407, 1997. [PubMed] [Google Scholar]
  • 21. Pinkel D., Segraves R., Sudar D., Clark S., Poole I., Kowbel D., Collins C., Kuo W. L., Chen C., Zhai Y., Dairkee S. H., Ljung B. M., Gray J. W., Albertson D. G., High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat. Genet., 20: 207–211, 1998. [DOI] [PubMed] [Google Scholar]
  • 22. Kononen J., Bubendorf L., Kallioniemi A., Barlund M., Schraml P., Leighton S., Torhorst J., Mihatsch M. J., Sauter G., Kallioniemi O. P., Tissue microarrays for high‐throughput molecular profiling of tumor specimens. Nat. Med., 4: 844–847, 1998. [DOI] [PubMed] [Google Scholar]
  • 23. Schena M., Shalon D., Heller R., Chai A., Brown P. O., Davis R. W., Parallel human genome analysis: microarray‐based expression monitoring of 1000 genes. Proc. Natl. Acad. Sci. USA, 93: 10614–10619, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Kurian K. M., Watson C. J., Wyllie A. H., DNA chip technology. J. Pathol., 187: 267–271, 1999. [DOI] [PubMed] [Google Scholar]
  • 25. Young R. A., Biomedical discovery with DNA arrays. Cell, 102: 9–15, 2000. [DOI] [PubMed] [Google Scholar]
  • 26. Hegde P., Qi R., Abernathy K., Gay C., Dharap S., Gaspard R., Hughes J. E., Snesrud E., Lee N., Quackenbush J., A concise guide to cDNA microarray analysis. Biotechniques, 29: 548–554, 2000. [DOI] [PubMed] [Google Scholar]
  • 27. Golub T. R., Slonim D. K., Tamayo P., Huard C., Gaasenbeek M., Mesirov J. P., Coller H., Loh M. L., Downing J. R., Caligiuri M. A., Bloomfield C. D., Lander E. S., Molecular classification of cancer: Class Discovery and class prediction by gene expression monitoring. Science, 286: 531–537, 1999. [DOI] [PubMed] [Google Scholar]
  • 28. Alizadeh A. A., Eisen M. B., Davis R. E., Ma C., Lossos I. S., Rosenwald A., Boldrick J. C., Sabet H., Tran T., Yu X., Powell J. I., Yang L., Marti G. E., Moore T., Hudson, J. Jr. , Lu, L. , Lewis D. B., Tibshirani R., Sherlock G., Chan W. C., Greiner T. C., Weisenburger D. D., Armitage J. O., Warnke R., Levy R., Wyndham W., Grever M. R., Byrd J. C., Botstein D., Brown P. O., Staudt L. M., Distinct types of diffuse large B‐cell lymphoma identified by gene expression profiling. Nature, 403: 503–511, 2000. [DOI] [PubMed] [Google Scholar]
  • 29. Bittner M., Meltzer P., Chen Y., Jiang Y., Seftor E., Hendrix M., Radmacher M., Simon R., Yakhini Z., Ben‐Dor A., Sampas N., Dougherty E., Wang E., Marincola F., Gooden C., Lueders J., Glatfelter A., Pollock P., Carpten J., Gillanders Leja, D. , Dietrich K, Beaudry C., Berens M., Alberts D., Sondak V., Hayward N., Trent J., Molecular classification of cutaneous. malignant melanoma by gene expression profiling. Nature, 406: 536–54, 2000. [DOI] [PubMed] [Google Scholar]
  • 30. Marx J., Medicine. DNA arrays reveal cancer in its many forms. News focus. Science, 289: 1670–1672, 2000. [DOI] [PubMed] [Google Scholar]
  • 31. Kraus M. H., Popescu N. C., Amsbaugh S. C., King C. R., Overexpression of the Egf receptor‐related protooncogene Erbb‐2 in human mammary tumor cell lines by different molecular mechanisms. Embo. J., 6: 605–610, 1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Slamon D. J., Clark G. M., Wong S. G., Levin W. J., Ullrich A., McGuire W. L., Human breast cancer: correlation of relapse and survival with amplification of the HER‐2/neu oncogene. Science, 235: 177–182, 1987. [DOI] [PubMed] [Google Scholar]
  • 33. Pegram M. D., Lipton A., Hayes D. F., Weber B. L., Baselga J. M., Tripathy D., Baly D., Baughman S. A., Twaddell T., Glaspy J. A., Slamon D. J., Phase II study of receptor‐enhanced chemosensitivity using recombinant humanized anti‐p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu‐overexpressing metastatic breast cancer refractory to chemotherapy treatment. J. Clin. Oncol., 16: 2659–2671, 1998. [DOI] [PubMed] [Google Scholar]
  • 34. Macville M., Schrock E., Padilla‐Nash H., Keck C. L., Ghadimi M. B., Zimonjic D. B., Popescu N. C., Ried T., Comprehensive and definitive molecular cytogenetic characterization of Hela cells by spectral karyotyping. Cancer Res., 59: 141–150, 1999. [PubMed] [Google Scholar]
  • 35. Forozan F., Mahlamaki E. H., Monni O., Chen Y., Veldman R., Jiang Y., Gooden G. C., Ethier S. P., Kallioniemi A., Kallioniemi O. P., Comparative genomic hybridization analysis of 38 breast cancer cell lines: a basis for interpreting complementary DNA microarray data. Cancer Res., 60: 4519–4525, 2000. [PubMed] [Google Scholar]
  • 36. Harris C. C., Hepatocellular carcinogenesis: recent advances and speculations. Cancer Cells, 2: 146–148, 1990. [PubMed] [Google Scholar]
  • 37. Simonetti R. G., Camma C., Fiorello F., Politi F., D'Amico G., Pagliaro L., Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig. Dis. Sci., 36: 962–972, 1991. [DOI] [PubMed] [Google Scholar]
  • 38. Keck C. L., Zimonjic D. B., Yuan B. Z., Thorgeirsson S. S., Popescu N. C., Nonrandom breakpoints of unbalanced chromosome translocations in human hepatocellular carcinoma cell lines. Cancer Genet. Cytogenet., 111: 37–44, 1999. [DOI] [PubMed] [Google Scholar]
  • 39. Lowichik A., Schneider N. R., Tonk V., Ansari M. Q., Timmons C. F., Report of a complex karyotype in recurrent metastatic fibrolamellar hepatocellular carcinoma and a review of hepatocellular carcinoma cytogenetics. Cancer Genet. Cytogenet., 88: 170–174, 1996. [DOI] [PubMed] [Google Scholar]
  • 40. Nowell P. C., Croce C. M., Chromosomes, genes and cancer. Am. J. Pathol., 125: 7–16, 1986. [PMC free article] [PubMed] [Google Scholar]
  • 41. Ohta M., Inoue H., Cotticelli M. G., Kastury K., Baffa R., Palazzo J., Siprashvili Z., Mori M., McCue P., Druck T., Croce C. M., The FHIT gene, spanning the chromosome 3p14. 2 fragile site and renal carcinomaassociated t (3;8) breakpoint, is abnormal in digestive tract cancers. Cell, 84: 587–597, 1996. [DOI] [PubMed] [Google Scholar]
  • 42. Huebner K., Hadaczek P., Siprashvili Z., Druck T., Croce C. M., The FHIT gene, a multiple tumor suppressor gene encompassing the carcinogen sensitive chromosome fragile site, FRA3B. Biochim. Biophys. Acta., 1332: M65–70, 1997. [DOI] [PubMed] [Google Scholar]
  • 43. Siprashvili Z., Sozzi G., Barnes L. D., McCue P., Robinson A. K., Eryomin V., Sard L., Tagliabue E., Greco A., Fusetti L., Schwartz G., Pierotti M. A., Croce C. M., Huebner K., Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc. Natl. Acad. Sci. USA, 94: 13771–13776, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Zimonjic D. B., Druck T., Ohta M., Kastury K., Croce C. M., Popescu N. C., Huebner K., Positions of chromosome 3p14. 2 fragile sites (FRA3B) within the FHIT gene. Cancer Res., 57: 1166–1170, 1997. [PubMed] [Google Scholar]
  • 45. Yuan B. Z., Keck‐Waggoner C. L., Zimonjic D. B., Thorgeirsson S. S., Popescu N. C., Alterations of FHIT gene in hepatocellular carcinoma. Cancer Res., 60: 1049–1053, 2000. [PubMed] [Google Scholar]
  • 46. Sozzi, G. , Sard, L. , De Gregorio, L. , Marchetti, A. , Musso, K. , Buttitta, F. , Tornielli, S. , Pellegrini, S. , Veronese, M. L. , Manenti, G. , Incarbone, M. , Chella, A. , Angeletti, C. A. , Pastorino, U. , Huebner, K. , Bevilaqua, G. , Pilotti, S. , Croce, C. M. , Pierotti, M. A. , Association between cigarette smoking and FHIT gene alterations in lung cancer. Cancer Res., 57: 2121–2123, 1997. [PubMed] [Google Scholar]
  • 47. Popescu N. C., Chromosome fragility and instability in human cancer. Crit. Rev. Oncog., 5: 121–140, 1994. [DOI] [PubMed] [Google Scholar]
  • 48. Zimonjic D. B., Keck, C. L. , Thorgeirsson, S. S. , Popescu N. C., Novel recurrent genetic imbalances in human hepatocellular carcinoma cell lines identified by comparative genomic hybridization. Hepatology, 29: 1208–1214, 1999. [DOI] [PubMed] [Google Scholar]
  • 49. Yuan B. Z., Miller M. J., Keck C. L., Zimonjic D. B., Thorgeirsson S. S., Popescu N. C., Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC‐1) homologous to rat RhoGAP. Cancer Res., 58: 2196–2199, 1998. [PubMed] [Google Scholar]
  • 50. Khosravi‐Far R., Campbell S., Rossman K. L., Der C. J., Increasing complexity of Ras signal transduction: involvement of Rho family proteins. Adv. Cancer. Res., 69: 59–105, 1997. [DOI] [PubMed] [Google Scholar]
  • 51. Quilliam L. A., Khosravi‐Far R., Huff S. Y., Der C. J., Guanine nucleotide exchange factors: activators of the Ras superfamily of proteins. Bioessays, 17: 395–404, 1995. [DOI] [PubMed] [Google Scholar]
  • 52. Wang D. Z., Nur E. K. M. S., Tikoo A., Montague W., Maruta H., The GTPase and Rho GAP domains of p190, a tumor suppressor protein that binds the M (r) 120, 000 Ras GAP, independently function as anti‐Ras tumor suppressors. Cancer Res., 57: 2478–2484, 1997. [PubMed] [Google Scholar]
  • 53. Qin L. X., Tang Z. Y., Sham J. S., Ma Z. C., Ye S. L., Zhou X. D., Wu Z. Q., Trent J. M., Guan X. Y., The association of chromosome 8p deletion and tumor metastasis in human hepatocellular carcinoma. Cancer Res., 59: 5662–5665, 1999. [PubMed] [Google Scholar]
  • 54. Chinen K., Isomura M., Izawa K., Fujiwara Y., Ohata H., Iwamasa T., Nakamura Y., Isolation of 45 exon‐like fragments from 8p22→p21. 3, a region that is commonly deleted in hepatocellular, colorectal, and non‐small cell lung carcinomas. Cytogenet. Cell. Genet., 75: 190–196, 1996. [DOI] [PubMed] [Google Scholar]
  • 55. Ishii H., Baffa R., Numata S. I., Murakumo Y., Rattan S., Inoue H., Mori M., Fidanza V., Alder H., Croce C. M., The FEZ1 gene at chromosome 8p22 encodes a leucine‐zipper protein, and its expression is altered in multiple human tumors. Proc. Natl. Acad. Sci. USA, 96: 3928–3933, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Bissonnette R. P., Echeverri F., Mahboubi A., Green D. R., Apoptotic cell death induced by c‐myc is inhibited by bcl‐2. Nature, 359: 552–554, 1992. [DOI] [PubMed] [Google Scholar]

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