Overview of Genetic Diagnosis in Cancer

Bruce R. Korf1, Fady M. Mikhail1

1 University of Alabama at Birmingham, Birmingham, Alabama
Publication Name:  Current Protocols in Human Genetics
Unit Number:  Unit 10.1
DOI:  10.1002/cphg.36
Online Posting Date:  April, 2017
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library


Both cytogenetic and molecular genetic studies can contribute to the management of patients with cancer. In some cases, genetic markers are specific to particular tumor types and are useful in diagnosis. This can be helpful in distinguishing histologically similar tumors that may respond differently to treatment and can sometimes be of prognostic value. Genetic markers can also be tools for following the response of a tumor to therapy, providing a sensitive means to detect relapse. This introductory unit considers some of the types of genetic changes that occur in association with malignancies, as well as major approaches used in their detection. © 2017 by John Wiley & Sons, Inc.

Keywords: cancer; diagnosis; oncogene; tumor suppressor gene

PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • Oncogenes
  • Tumor Suppressor Genes
  • Other Gene Rearrangements in Cancer
  • Prospects for Molecular Genetic Diagnosis and Cancer Therapy
  • Conclusion
  • Acknowledgments
  • Literature Cited
  • Tables
PDF or HTML at Wiley Online Library


PDF or HTML at Wiley Online Library



Literature Cited

Literature Cited
  Alizadeh, A. A., Eisen, M. B., Davis, R. E., Ma, C., Lossos, I. S., … Staudt, L. M. (2000). Distinct types of diffuse large B‐cell lymphoma identified by gene expression profiling. Nature, 403, 503–511. doi: 10.1038/35000501.
  Bea, S., Zettl, A., Wright, G., Salaverria, I., Jehn, P., Moreno, V., … Lymphoma/Leukemia Molecular Profiling Project. (2005). Diffuse large B‐cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene‐expression‐based survival prediction. Blood, 106, 3183–3190. doi: 10.1182/blood‐2005‐04‐1399.
  Bonner, T. I., Oppermann, H., Seeburg, P., Kerby, S. B., Gunnell, M. A., Young, A. C., … Rapp, U. R. (1986). The complete coding sequence of the human raf oncogene and the corresponding structure of the c‐raf‐1 gene. Nucleic Acids Research, 14, 1009–1015. doi: 10.1093/nar/14.2.1009.
  Brookes, S., Smith, R., Casey, G., Dickson, C., & Peters, G. (1989). Sequence organization of the human int‐2 gene and its expression in teratocarcinoma cells. Oncogene, 4, 429–436.
  Chen, Z., & Sandberg, A. A. (2002). Molecular cytogenetic aspects of hematological malignancies: Clinical implications. American Journal of Medical Genetics, 115, 130–141. doi: 10.1002/ajmg.10689.
  Chissoe, S. L., Bodenteich, A., Wang, Y‐F., Wang, Y‐P., Burian, D., Clifton, S. W., … Roe, B. A. (1995). Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation. Genomics, 27, 67–82. doi: 10.1006/geno.1995.1008.
  Chmielecki J., & Meyerson M. (2014). DNA sequencing of cancer: What have we learned? Annual Review of Medicine, 65, 63–79. doi: 10.1146/annurev‐med‐060712‐200152.
  Cowell, J. K. (1982). Double minutes and homogeneously staining regions: Gene amplification in mammalian cells. Annual Review of Genetics, 16, 21–59. doi: 10.1146/annurev.ge.16.120182.000321.
  Dawson M. A., & Kouzarides T. (2012). Cancer epigenetics: From mechanism to therapy. Cell, 150, 12–27. doi: 10.1016/j.cell.2012.06.013.
  Dimmock, D. (2013). Whole genome sequencing: A considered approach to clinical implementation. Current Protocols in Human Genetics, 77, 9.22.1–9.22.7. doi: 10.1002/0471142905.hg0922s77.
  Doucas, V., Brockes, J. P., Yaniv, M., de The, H., & Dejean, A. (1993). The PML‐retinoic acid receptor alpha translocation converts the receptor from an inhibitor to a retinoic acid‐dependent activator of transcription factor AP‐1. Proceedings of the National Academy of Sciences of the United States of America, 90, 9345–9349. doi: 10.1073/pnas.90.20.9345.
  Druker, B. J., Sawyers, C. L., Capdeville, R., Ford, J. M., Baccarani, M., & Goldman, J. M. (2001). Chronic myelogenous leukemia. Hematology 2002, 87–112.
  Eccles, S. A. (2001). The role of c‐erbB‐2/HER2/neu in breast cancer progression and metastasis. Journal of Mammary Gland Biology and Neoplasia, 6, 393–406. doi: 10.1023/A:1014730829872.
  Forozan, F., Karhu, R., Kononen, J., Kallioniemi, A., & Kallioniemi, O. P. (1997). Genome screening by comparative genomic hybridization. Trends in Genetics., 13, 405–409. doi: 10.1016/S0168‐9525(97)01244‐4.
  Greco, A., Villa, R., & Pierotti, M. A. (1996). Genomic organization of the human NTRK1 gene. Oncogene, 13, 2463–2466.
  Greenman, C., Stephens, P., Smith, R., Dalgliesh, G. L., Hunter, C., Bignell, G., … Stratton, M. R. (2007). Patterns of somatic mutation in human cancer genomes. Nature, 446, 153–158. doi: 10.1038/nature05610.
  Hampe, A., Shamoon, B. M., Gobet, M., Sherr, C. J., & Galibert, F. (1989). Nucleotide sequence and structural organization of the human FMS proto‐oncogene. Oncogene Research, 4, 9–17.
  Hirota, S., Isozaki, K., Moriyama, Y., Hashimoto, K., Nishida, T., Ishiguro, S., … Kitamura, Y. (1998). Gain‐of‐function mutations of c‐kit in human gastrointestinal stromal tumors. Science, 279, 577–580. doi: 10.1126/science.279.5350.577.
  Irby, R. B., Mao, W., Coppola, D., Kang, J., Loubeau, J. M., Trudeau, W., … Yeatman, T. J. (1999). Activating SRC mutation in a subset of advanced human colon cancers. Nature Genetics., 21, 187–190. doi: 10.1038/5971.
  Jeffers, M., Schmidt, L., Nakaigawa, N., Webb, C. P., Weirich, G., Kishida, T., … Vande Woude, G. F. (1997). Activating mutations for the Met tyrosine receptor in human cancer. Proceedings of The National Academy of Sciences of the United States of America., 94, 11445–11450. doi: 10.1073/pnas.94.21.11445.
  Joos, S., Granzow, M., Holtgreve‐Grez, H., Siebert, R., Harder, L., Martin‐Subero, J. I., … Jauch, A. (2003). Hodgkin's lymphoma cell lines are characterized by frequent aberrations on chromosomes 2p and 9p including REL and JAK2. International Journal of Cancer, 103, 489–495. doi: 10.1002/ijc.10845.
  Knoll, J. H. M., & Lichter, P. (2005). In situ hybridization to metaphase chromosomes and interphase nuclei. Current Protocols in Human Genetics, 45, 4.3.1–4.3.31. doi: 10.1002/0471142905.hg0403s45.
  Kruidering, M. (2002). N‐MYC overexpression and neuroblastomas. Trends in Pharmacological Sciences, 23, 452. doi: 10.1016/S0165‐6147(02)02117‐X.
  Landis, C. A., Masters, S. B., Spada, A., Pace, A. M., Bourne, H. R., & Vallar, L. (1989). GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature, 340, 692–696. doi: 10.1038/340692a0.
  Langer, C. J. (2004). Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: Focus on NSCLC. International Journal of Radiation Oncology Biology Physics, 58, 991–1002. doi: 10.1016/j.ijrobp.2003.09.099.
  Liu, B., Nicolaides, N. C., Markowitz, S., Willson, J. K., Parsons, R. E., Jen, J., … Vogelstein, B. (1995). Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nature Genetics, 9, 48–55. doi: 10.1038/ng0195‐48.
  Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., … Haber, D. A. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non‐small‐cell lung cancer to gefitinib. The New England Journal of Medicine, 305, 1163–1167. doi: 10.1056/NEJMoa040938.
  Macleod, K. (2000). Tumor suppressor genes. Current Opinion in Genetics & Development, 10, 81–93. doi: 10.1016/S0959‐437X(99)00041‐6.
  Marsden, V. S., O'Connor, L., O'Reilly, L. A., Silke, J., Metcalf, D., Ekert, P. G., … Strasser, A. (2002). Apoptosis initiated by Bcl‐2‐regulated caspase activation independently of the cytochrome c/Apaf‐1/caspase‐9 apoptosome. Nature, 419, 634–637. doi: 10.1038/nature01101.
  Meldrum, C., Doyle, M. A., & Tothill, R. W. (2011). Next‐generation sequencing for cancer diagnostics: A practical perspective. The Clinical Biochemist. Reviews, 32, 177–195.
  Metzker, M. L. (2010). Sequencing technologies—the next generation. Nature Reviews Genetics, 11, 31–46. doi: 10.1038/nrg2626.
  Mody, R. J., Wu, Y. M., Lonigro, R. J., Cao, X., Roychowdhury, S., Vats, P., … Chinnaiyan, A. M. (2015). Integrative clinical sequencing in the management of refractory or relapsed cancer in youth. JAMA, 314, 913–925. doi: 10.1001/jama.2015.10080.
  Muller, A., & Fishel, R. (2002). Mismatch repair and the hereditary non‐polyposis colorectal cancer syndrome (HNPCC). Cancer Investigation., 20, 102–109. doi: 10.1081/CNV‐120000371.
  Nakata, Y., Shetzline, S., Sakashita, C., Kalota, A., Rallapalli, R., Rudnick, S. I., … Gewirtz, A. M. (2007). c‐Myb contributes to G2/M cell cycle transition in human hematopoietic cells by direct regulation of cyclin B1 expression. Molecular and Cell Biology of Human Diseases Series, 27, 2048–2058. doi: 10.1128/MCB.01100‐06.
  Nau, M. M., Brooks, B. J., Battey, J., Sausville, E., Gazdar, A. F., Kirsch, I. R., … Minna, J. D. (1985). L‐myc, a new myc‐related gene amplified and expressed in human small cell lung cancer. Nature, 318, 69–73. doi: 10.1038/318069a0.
  Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L., & Vogelstein, B. (1992). Amplification of a gene encoding a p53‐associated protein in human sarcomas. Nature, 358, 80–83. doi: 10.1038/358080a0.
  Paez, J. G., Janne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., … Meyerson, M. (2004). EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science, 304, 1497–1500. doi: 10.1126/science.1099314.
  Pasini, B., Ceccherini, I., & Romeo, G. (1996). RET mutations in human disease. Trends in Genetics, 12, 138–144. doi: 10.1016/0168‐9525(96)10012‐3.
  Pasqualucci, L., Neumeister, P., Goossens, T., Nanjangud, G., Chaganti, R. S. K., Kuppers, R., & Dalla‐Favera, R. (2001). Hypermutation of multiple proto‐oncogenes in B‐cell diffuse large‐cell lymphomas. Nature, 412, 341–346. doi: 10.1038/35085588.
  Pegram, M. D., Konecny, G., & Slamon, D. J. (2000). The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of herceptin (trastuzumab) therapy for breast cancer. Cancer Treatment and Research, 103, 57–75. doi: 10.1007/978‐1‐4757‐3147‐7_4.
  Pinkel, D. (1994). Visualizing tumour amplification. Nature Genetics, 8, 107–108. doi: 10.1038/ng1094‐107.
  Robbins, K. C., Antoniades, H. N., Devare, S. G., Hunkapiller, M. W., & Aaronson, S. A. (1983). Structural and immunological similarities between simian sarcoma virus gene product(s) and human platelet‐derived growth factor. Nature, 305, 605–608. doi: 10.1038/305605a0.
  Roy, L., Guilhot, J., Krahnke, T., Guerci‐Bresler, A., Druker, B. J., Larson, R. A., O'Brien, S., … Guilhot, F. (2006). Survival advantage from imatinib compared with the combination interferon‐alpha plus cytarabine in chronic‐phase chronic myelogenous leukemia: Historical comparison between two phase 3 trials. Blood, 108, 1478–1484. doi: 10.1182/blood‐2006‐02‐001495.
  Sakamoto, H., Mori, M., Taira, M., Yoshida, T., Matsukawa, S., Shimizu, K., … Sugimura, T. (1986). Transforming gene from human stomach cancers and a noncancerous portion of stomach mucosa. Proceedings of the National Academy of Sciences of the United States of America, 83, 3997–4001. doi: 10.1073/pnas.83.11.3997.
  Schubbert, S., Shannon, K., & Bollag, G. (2007). Hyperactive Ras in developmental disorders and cancer. Nature Reviews. Cancer, 7, 295–308. doi: 10.1038/nrc2109.
  Schwab, M., Alitalo, K., Klempnauer, K. H., Varmus, H. E., Bishop, J. M., Gilbert, F., Brodeur, G., … Trent, J. (1983). Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature, 305, 245–248. doi: 10.1038/305245a0.
  Sharma, S., Kelly, T. K., & Jones, P. A. (2010). Epigenetics in cancer. Carcinogenesis, 31, 27–36. doi: 10.1093/carcin/bgp220.
  Sholl, L. M., Longtine, J., & Kuo, F. C. 2017. Molecular analysis of gene rearrangements and mutations in acute leukemias and myeloid neoplasms, 92, 10.4.1–10.4.49. doi: 10.1002/cphg.31.
  Sibilia, M., Fleischmann, A., Behrens, A., Stingl, L., Carroll, J., Watt, F. M., … Wagner, E. F. (2000). The EGF receptor provides an essential survival signal for SOS‐dependent skin tumor development. Cell, 102, 211–220. doi: 10.1016/S0092‐8674(00)00026‐X.
  Slamon, D. J., Godolphin, W., Jones, L. A., Holt, J. A., Wong, S. G., Keith, D. E., … Press, M. F. (1989). Studies of the HER‐2/neu proto‐oncogene in human breast and ovarian cancer. Science, 244, 707–712. doi: 10.1126/science.2470152.
  Sodroski, J. G., Goh, W. C., & Haseltine, W. A. (1984). Transforming potential of a human protooncogene (c‐fps/fes) locus. Proceedings of the National Academy of Sciences of the United States of America, 81, 3039–3043. doi: 10.1073/pnas.81.10.3039.
  Taub, R., Kirsch, I., Morton, C., Lenoir, G., Swan, D., Tronick, S., … Leder, P. (1982). Translocation of the c‐myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proceedings of the National Academy of Sciences of the United States of America, 79, 7837–7841. doi: 10.1073/pnas.79.24.7837.
  Thibodeau, S. N., Bren, G., & Schaid, D. (1993). Microsatellite instability in cancer of the proximal colon. Science, 260, 816–819. doi: 10.1126/science.8484122.
  van Riggelen, J., Buchwalter, G., Soto, U., De‐Castro Arce, J., Hausen, H. Z., Wasylyk, B., & Rosl, F. (2005). Loss of net as repressor leads to constitutive increased c‐fos transcription in cervical cancer cells. The Journal of Biological Chemistry, 280, 3286–3294. doi: 10.1074/jbc.M409915200.
  Vogt, P. K. (2001). Jun, the oncoprotein. Oncogene, 20, 2365–2377. doi: 10.1038/sj.onc.1204443.
  Wasson, J. C., & Brodeur, G. M. (2001). Molecular analysis of gene amplification in tumors. Current Protocols in Human Genetics, 2, 10.5.1–10.5.18. doi: 10.1002/0471142905.hg1005s02.
  Young, D., Waitches, G., Birchmeier, C., Fasano, O., & Wigler, M. (1984). Isolation and characterization of a new cellular oncogene encoding a protein with multiple transmembrane domains. Cell, 45, 711–719. doi: 10.1016/0092‐8674(86)90785‐3.
  Zahir, F. R., & Marra, M. A. (2015). Use of Affymetrix arrays in the diagnosis of gene copy‐number variation. Current Protocols in Human Genetics, 85, 8.13.1–8.13.13. doi: 10.1002/0471142905.hg0813s85.
PDF or HTML at Wiley Online Library