Incipient Events in Human Carcinogenesis: A Concept of Forerunner Genes

  • Bogdan Czerniak
Part of the TTME book series (TTME, volume 2)


Many common epithelial human cancers start as in situ expansions of cells, which exhibit almost normal phenotype. Such expansions form large plaques involving the affected mucosal membrane and are antecedent to the development of dysplasia or carcinoma in situ. Here we describe a whole-organ genomic mapping strategy to identify specific chromosomal regions involved in the development of early intraurothelial lesions in human bladder carcinogenesis. High resolution mapping of one such regions containing the model tumor suppressor RB1 provided evidence supporting the existence of a new class of genes termed forerunner (FR) genes. These genes map near tumor suppressors and provide a critical driving force for the early clonal expansion of neoplastic cells. The FR genes are related to tumor suppressors as they contribute to tumor development by their loss of function but their inactivation occurs prior to that of tumor suppressors such as RB1 in tumorigenesis.


Bladder cancer Carcinogenesis Whole-organ genetic mapping Forerunner genes Hyperplasia In situ neoplasia Loss of heterozygosity (LOH) Polymorphism Genetic instability Homologous recombination 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Weinberg, R. A., (Ed.) (2006) The Biology of Cancer, Garland Science, New York.Google Scholar
  2. 2.
    Fearon, E. R., and Vogelstein, B. (1990) A genetic model for colorectal tumorigenesis, Cell 61, 759–767.CrossRefPubMedGoogle Scholar
  3. 3.
    Hanahan, D., and Weinberg, R. A. (2000) The hallmarks of cancer, Cell 100, 57–70.CrossRefPubMedGoogle Scholar
  4. 4.
    Ross, R. K., Jones, P. A., and Yu, M. C. (1996) Bladder cancer epidemiology and pathogenesis, Semin Oncol 23, 536–545.PubMedGoogle Scholar
  5. 5.
    Sidransky, D., and Messing, E. (1992) Molecular genetics and biochemical mechanisms in bladder cancer: oncogenes, tumor suppressor genes, and growth factors, Urol Clin North Am 19, 629–639.PubMedGoogle Scholar
  6. 6.
    Simoneau, A. R., and Jones, P. A. (1994) Bladder cancer: the molecular progression to invasive disease, World J Urol 12, 89–95.CrossRefPubMedGoogle Scholar
  7. 7.
    Baselga, J., and Norton, L. (2002) Focus on breast cancer, Cancer Cell 1, 319–322.CrossRefPubMedGoogle Scholar
  8. 8.
    Minna, J. D., Roth, J. A., and Gazdar, A. F. (2002) Focus on lung cancer, Cancer Cell 1, 49–52.CrossRefPubMedGoogle Scholar
  9. 9.
    Isaacs, W., De Marzo, A., and Nelson, W. G. (2002) Focus on prostate cancer, Cancer Cell 2, 113–116.CrossRefPubMedGoogle Scholar
  10. 10.
    Ellenson, L. H., and Wu, T. C. (2004) Focus on endometrial and cervical cancer, Cancer Cell 5, 533–538.CrossRefPubMedGoogle Scholar
  11. 11.
    Carethers, J. M. (1996) The cellular and molecular pathogenesis of colorectal cancer, Gastroenterol Clin N Am 25, 737–754.CrossRefGoogle Scholar
  12. 12.
    Ilyas, M., Straub, J., Tomlinson, I. P., and Bodmer, W. F. (1999) Genetic pathways in colorectal and other cancers, Eur J Cancer 35, 335–351.CrossRefPubMedGoogle Scholar
  13. 13.
    Watanabe, T., and Muto, T. (2000) Colorectal carcinogenesis based on molecular biology of early colorectal cancer, with special reference to nonpolypoid (superficial) lesions, World J Surg 24, 1091–1097.CrossRefPubMedGoogle Scholar
  14. 14.
    Henson D.E., and Albores-Saavedra, J., (Eds.) (2001) Pathology of Incipient Neoplesia, Oxford University Press, New York.Google Scholar
  15. 15.
    Lee, S., Jeong, J., Majewski, T., Scherer, S. E., Kim, M. S., Tuziak, T., Tang, K. S., Baggerly, K., Grossman, H. B., Zhou, J. H., Shen, L., Bondaruk, J., Ahmed, S. S., Samanta, S., Spiess, P., Wu, X., Filipek, S., McConkey, D., Bar-Eli, M., Issa, J. P., Benedict, W. F., and Czerniak, B. (2007) Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia, Proc Natl Acad Sci USA 104, 13732–13737.CrossRefPubMedGoogle Scholar
  16. 16.
    Majewski, T., Lee, S., Jeong, J., Yoon, D.-S., Kram, A., Kim, M.-S., Tuziak, T., Bondaruk, J., Lee, S., Park, W.-S., Tang, K. S., Chung, W., Shen, L., Ahmed, S. S., Johnston, D. A., Grossman, H. B., Zhou, J.-H., Harris, R. A., Snyder, C., Filipek, S., Narod, S. A., Watson, P., Lynch, H. T., Gazdar, A., Baggerly, K., Issa, J.-P., Benedict, W. F., Scherer, S. E., Czerniak, B. (2007) Understanding the development of human bladder cancer by using a whole-organ genomic mapping strategy, Lab Invest, 2008.Google Scholar
  17. 17.
    Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., and Thun, M. J. (2007) Cancer statistics, 2007, CA Cancer J Clin 57, 43–66.Google Scholar
  18. 18.
    Dinney, C. P., McConkey, D. J., Millikan, R. E., Wu, X., Bar-Eli, M., Adam, L., Kamat, A. M., Siefker-Radtke, A. O., Tuziak, T., Sabichi, A. L., Grossman, H. B., Benedict, W. F., and Czerniak, B. (2004) Focus on bladder cancer, Cancer Cell 6, 111–116.CrossRefPubMedGoogle Scholar
  19. 19.
    Spiess, P. E., and Czerniak, B. (2006) Dual-track pathway of bladder carcinogenesis: practical implications, Arch Pathol Lab Med 130, 844–852.PubMedGoogle Scholar
  20. 20.
    Koss, L. G., Tiamson, E. M., and Robbins, M. A. (1974) Mapping cancerous and precancerous bladder changes: a study of the urothelium in ten surgically removed bladders, Jama 227, 281–286.CrossRefPubMedGoogle Scholar
  21. 21.
    Koss, L. G., Nakanishi, I., and Freed, S. Z. (1977) Nonpapillary carcinoma in situ and atypical hyperplasia in cancerous bladders: further studies of surgically removed bladders by mapping, Urology 9, 442–455.CrossRefPubMedGoogle Scholar
  22. 22.
    Koss, L. G. (1979) Mapping of the urinary bladder: its impact on the concepts of bladder cancer, Hum Pathol 10, 533–548.PubMedCrossRefGoogle Scholar
  23. 23.
    Collins, F. S. (1995) Positional cloning moves from perditional to traditional, Nat Genet 9, 347–350.CrossRefPubMedGoogle Scholar
  24. 24.
    Collins, F. S. (1992) Positional cloning: let’s not call it reverse anymore, Nat Genet 1, 3–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Czerniak, B., Li, L., Chaturvedi, V., Ro, J. Y., Johnston, D. A., Hodges, S., and Benedict, W. F. (2000) Genetic modeling of human urinary bladder carcinogenesis, Genes Chrom Cancer 27, 392–402.CrossRefPubMedGoogle Scholar
  26. 26.
    Chaturvedi, V., Li, L., Hodges, S., Johnston, D., Ro, J. Y., Logothetis, C., von Eschenbach, A. C., Batsakis, J. G., and Czerniak, B. (1997) Superimposed histologic and genetic mapping of chromosome 17 alterations in human urinary bladder neoplasia, Oncogene 14, 2059–2070.CrossRefPubMedGoogle Scholar
  27. 27.
    Czerniak, B., Chaturvedi, V., Li, L., Hodges, S., Johnston, D., Roy, J. Y., Luthra, R.,Logothetis, C., von Eschenbach, A. C., Grossman, H. B., Benedict, W. F., and Batsakis, J. G. (1999) Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer, Oncogene 18, 1185–1196.CrossRefPubMedGoogle Scholar
  28. 28.
    Yoon, D. S., Li, L., Zhang, R. D., Kram, A., Ro, J. Y., Johnston, D., Grossman, H. B., Scherer, S., and Czerniak, B. (2001) Genetic mapping and DNA sequence-based analysis of deleted regions on chromosome 16 involved in progression of bladder cancer from occult preneoplastic conditions to invasive disease, Oncogene 20, 5005–5014.CrossRefPubMedGoogle Scholar
  29. 29.
    Kram, A., Li, L., Zhang, R. D., Yoon, D. S., Ro, J. Y., Johnston, D., Grossman, H. B., Scherer, S., and Czerniak, B. (2001) Mapping and genome sequence analysis of chromosome 5 regions involved in bladder cancer progression, Lab Invest 81, 1039–1048.PubMedGoogle Scholar
  30. 30.
    Tuziak, T., Jeong, J., Majewski, T., Kim, M. S., Steinberg, J., Wang, Z., Yoon, D. S., Kuang, T. C., Baggerly, K., Johnston, D., and Czerniak, B. (2005) High-resolution whole-organ mapping with SNPs and its significance to early events of carcinogenesis, Lab Invest 85, 689–701.CrossRefPubMedGoogle Scholar
  31. 31.
    Kim, M. S., Jeong, J., Majewski, T., Kram, A., Yoon, D. S., Zhang, R. D., Li, J. Z., Ptaszynski, K., Kuang, T. C., Zhou, J. H., Sathyanarayana, U. G., Tuziak, T., Johnston, D. A., Grossman, H. B., Gazdar, A. F., Scherer, S. E., Benedict, W. F., and Czerniak, B. (2006) Evidence for alternative candidate genes near RB1 involved in clonal expansion of in situ urothelial neoplasia, Lab Invest 86, 175–190.CrossRefPubMedGoogle Scholar
  32. 32.
    Bishop J. M., and Weinberg, R. A., (Eds.) (1996) Molecular Oncology, Scientific American, New York.Google Scholar
  33. 33.
    Purandare, S. M., and Patel, P. I. (1997) Recombination hot spots and human disease, Genome Res 7, 773–786.PubMedGoogle Scholar
  34. 34.
    Mabuchi, H., Fujii, H., Calin, G., Alder, H., Negrini, M., Rassenti, L., Kipps, T. J., Bullrich, F., and Croce, C. M. (2001) Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia, Cancer Res 61, 2870–2877.PubMedGoogle Scholar
  35. 35.
    Solomou, E. E., Sfikakis, P. P., Kotsi, P., Papaioannou, M., Karali, V., Vervessou, E.,Hoffbrand, A. V., and Panayiotidis, P. (2003) 13q deletion in chronic lymphocytic leukemia: characterization of E4.5, a novel chromosome condensation regulator-like guanine nucleotide exchange factor, Leukemia Lymphoma 44, 1579–1585.CrossRefPubMedGoogle Scholar
  36. 36.
    Latil, A., Morant, P., Fournier, G., Mangin, P., Berthon, P., and Cussenot, O. (2002) CHC1-L, a candidate gene for prostate carcinogenesis at 13q14.2, is frequently affected by loss of heterozygosity and underexpressed in human prostate cancer, Int J Cancer 99, 689–696.CrossRefPubMedGoogle Scholar
  37. 37.
    Kong, A., Gudbjartsson, D. F., Sainz, J., Jonsdottir, G. M., Gudjonsson, S. A., Richardsson, B., Sigurdardottir, S., Barnard, J., Hallbeck, B., Masson, G., Shlien, A., Palsson, S. T., Frigge, M. L., Thorgeirsson, T. E., Gulcher, J. R., and Stefansson, K. (2002) A high-resolution recombination map of the human genome, Nat Genet 31, 241–247.PubMedGoogle Scholar
  38. 38.
    Grover, D., Mukerji, M., Bhatnagar, P., Kannan, K., and Brahmachari, S. K. (2004) Alu repeat analysis in the complete human genome: trends and variations with respect to genomic composition, Bioinformatics 20, 813–817.CrossRefPubMedGoogle Scholar
  39. 39.
    Albrecht, P., Bode, J., Buiting, K., Prashanth, A. K., and Lohmann, D. R. (2004) Recurrent deletion of a region containing exon 24 of the RB1 gene caused by non-homologous recombination between a LINE-1HS and MER21B element, J Med Genet 41, e122.CrossRefPubMedGoogle Scholar
  40. 40.
    Yi, J. M., Kim, H. M., and Kim, H. S. (2006) Human endogenous retrovirus HERV-H family in human tissues and cancer cells: expression, identification, and phylogeny, Cancer Lett 231, 228–239.CrossRefPubMedGoogle Scholar
  41. 41.
    Redon, R., Ishikawa, S., Fitch, K. R., Feuk, L., Perry, G. H., Andrews, T. D., Fiegler, H., Shapero, M. H., Carson, A. R., Chen, W., Cho, E. K., Dallaire, S., Freeman, J. L., Gonzalez, J. R., Gratacos, M., Huang, J., Kalaitzopoulos, D., Komura, D., MacDonald, J. R., Marshall, C. R., Mei, R., Montgomery, L., Nishimura, K., Okamura, K., Shen, F., Somerville, M. J., Tchinda, J., Valsesia, A., Woodwark, C., Yang, F., Zhang, J., Zerjal, T., Zhang, J., Armengol, L., Conrad, D. F., Estivill, X., Tyler-Smith, C., Carter, N. P., Aburatani, H., Lee, C., Jones, K. W., Scherer, S. W., and Hurles, M. E. (2006) Global variation in copy number in the human genome, Nature 444, 444–454.CrossRefPubMedGoogle Scholar
  42. 42.
    Fleischer, A., Ayllon, V., Dumoutier, L., Renauld, J. C., and Rebollo, A. (2002) Proapoptotic activity of ITM2B(s), a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2, Oncogene 21, 3181–3189.CrossRefPubMedGoogle Scholar
  43. 43.
    Foulds, L., (Ed.) (1969) Neoplastic Development: The Natural History of Cancer, Academic Press, New York.Google Scholar
  44. 44.
    Nowell, P. C. (1976) The clonal evolution of tumor cell populations, Science 194, 23–28.CrossRefPubMedGoogle Scholar
  45. 45.
    Peiffer, D. A., Le, J. M., Steemers, F. J., Chang, W., Jenniges, T., Garcia, F., Haden, K., Li, J., Shaw, C. A., Belmont, J., Cheung, S. W., Shen, R. M., Barker, D. L., and Gunderson, K. L. (2006) High-resolution genomic profiling of chromosomal aberrations using Infinium whole-genome genotyping, Genome Res 16, 1136–1148.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Bogdan Czerniak
    • 1
  1. 1.Department of Pathology, Nathan W. Lassiter Distinguished Chair in Urology, Department of PathologyThe University of Texas, MD Anderson Cancer CenterHoustonUSA

Personalised recommendations