Skip to main content
SpringerLink
Log in

The Molecular Pathobiology of Malignant Process and Molecular Diagnostic Testing for Cancer

  • Chapter
  • First Online:
Practical Oncologic Molecular Pathology

Part of the book series: Practical Anatomic Pathology ((PAP))

Abstract

Cancer is recognized as a genetic disease resulting from alterations of genes or other genetic elements involved in cellular activities including proliferation, differentiation, apoptosis, maintenance of genetic stability, and cellular metabolism and intercellular interactions. The structural organization of genetic material into chromosomes, the major types of genes, and genetic regulatory processes related to cancer development are reviewed in this introductory chapter in the viewpoint of molecular oncology, focusing on the important genes and alterations related to the diagnosis, classification, disease monitoring, and targeted therapy of cancer. Frequent types of genetic abnormalities related to cancer development are explained from a molecular pathologist’s perspective and in relation to the methods used in the clinical diagnostic laboratories for the detection of cancer-related mutations and other genetic alterations. The concept of noncoding RNA and its potential role in tumorigenesis are discussed. The general principles of classifying genetic abnormalities and standardized nomenclature of mutations are introduced based on the national guidelines and consensus. Selected cases are presented to illustrate how the molecular test results are interpreted to help understand the pathobiology of cancer, and how these results can facilitate the final diagnosis and provide critical information for clinical management.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Cavalcante GC, et al. A cell’s fate: an overview of the molecular biology and genetics of apoptosis. Int J Mol Sci. 2019;20(17):4133.

    Article  PubMed Central  CAS  Google Scholar 

  2. Raab MS, et al. Multiple myeloma. Lancet. 2009;374(9686):324–39.

    Article  PubMed  Google Scholar 

  3. Pertea M. The human transcriptome: an unfinished story. Genes (Basel). 2012;3(3):344–60.

    Article  CAS  Google Scholar 

  4. Ghittoni R, et al. The biological properties of E6 and E7 oncoproteins from human papillomaviruses. Virus Genes. 2010;40(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  5. Snyder MW, et al. Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin. Cell. 2016;164(1–2):57–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Issa JP. CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004;4(12):988–93.

    Article  CAS  PubMed  Google Scholar 

  7. Kang GH. Four molecular subtypes of colorectal cancer and their precursor lesions. Arch Pathol Lab Med. 2011;135(6):698–703.

    Article  PubMed  Google Scholar 

  8. Malta TM, et al. Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications. Neuro-Oncology. 2018;20(5):608–20.

    Article  CAS  PubMed  Google Scholar 

  9. Audia JE, Campbell RM. Histone modifications and cancer. Cold Spring Harb Perspect Biol. 2016;8(4):a019521.

    Article  PubMed  PubMed Central  Google Scholar 

  10. West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124(1):30–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. McCabe MT, et al. Targeting histone methylation in cancer. Cancer J. 2017;23(5):292–301.

    Article  CAS  PubMed  Google Scholar 

  12. Narita T, Weinert BT, Choudhary C. Functions and mechanisms of non-histone protein acetylation. Nat Rev Mol Cell Biol. 2019;20(3):156–74.

    Article  CAS  PubMed  Google Scholar 

  13. Ye D, Xiong Y, Guan KL. The mechanisms of IDH mutations in tumorigenesis. Cell Res. 2012;22(7):1102–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Birney E, et al. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007;447(7146):799–816.

    Article  CAS  PubMed  Google Scholar 

  15. Lee Y, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425(6956):415–9.

    Article  CAS  PubMed  Google Scholar 

  16. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Eichhorn SW, et al. mRNA destabilization is the dominant effect of mammalian microRNAs by the time substantial repression ensues. Mol Cell. 2014;56(1):104–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Beermann J, et al. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev. 2016;96(4):1297–325.

    Article  CAS  PubMed  Google Scholar 

  19. Drula R, et al. MicroRNAs from liquid biopsy derived extracellular vesicles: recent advances in detection and characterization methods. Cancers (Basel). 2020;12(8):2009.

    Article  CAS  Google Scholar 

  20. Zhou H, Neelakantan D, Ford HL. Clonal cooperativity in heterogenous cancers. Semin Cell Dev Biol. 2017;64:79–89.

    Article  PubMed  Google Scholar 

  21. DeCordova S, et al. Molecular heterogeneity and immunosuppressive microenvironment in glioblastoma. Front Immunol. 2020;11:1402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stanta G, Bonin S. A practical approach to tumor heterogeneity in clinical research and diagnostics. Pathobiology. 2018;85(1–2):7–17.

    Article  CAS  PubMed  Google Scholar 

  23. Ellsworth RE, et al. Molecular heterogeneity in breast cancer: state of the science and implications for patient care. Semin Cell Dev Biol. 2017;64:65–72.

    Article  CAS  PubMed  Google Scholar 

  24. Uhlen M, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357(6352):eaan2507.

    Article  PubMed  CAS  Google Scholar 

  25. Bozic I, et al. Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci U S A. 2010;107(43):18545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Vogelstein B, et al. Cancer genome landscapes. Science. 2013;339(6127):1546–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tessema M, et al. Common cancer-driver mutations and their association with abnormally methylated genes in lung adenocarcinoma from never-smokers. Lung Cancer. 2018;123:99–106.

    Article  PubMed  Google Scholar 

  28. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8.

    Article  CAS  PubMed  Google Scholar 

  29. Spencer SL, et al. Modeling somatic evolution in tumorigenesis. PLoS Comput Biol. 2006;2(8):e108.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Amaral PP, et al. The eukaryotic genome as an RNA machine. Science. 2008;319(5871):1787–9.

    Article  CAS  PubMed  Google Scholar 

  31. Li MM, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19(1):4–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nishida N, et al. Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma. Hepatology. 2008;47(3):908–18.

    Article  CAS  PubMed  Google Scholar 

  33. Yang Y, et al. Recurrently deregulated lncRNAs in hepatocellular carcinoma. Nat Commun. 2017;8:14421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jung G, et al. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol. 2020;17(2):111–30.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ono M, Kuwano M. Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to Gefitinib and other EGFR-targeting drugs. Clin Cancer Res. 2006;12(24):7242–51.

    Article  CAS  PubMed  Google Scholar 

  36. Martinelli E, et al. Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives. Ann Oncol. 2020;31(1):30–40.

    Article  CAS  PubMed  Google Scholar 

  37. Reckamp KL. Targeted therapy for patients with metastatic non-small cell lung Cancer. J Natl Compr Cancer Netw. 2018;16(5s):601–4.

    Article  Google Scholar 

  38. Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol. 2018;12(1):3–20.

    Article  PubMed  Google Scholar 

  39. Dulgar O, Kutuk T, Eroglu Z. Mechanisms of resistance to BRAF-targeted melanoma therapies. Am J Clin Dermatol. 2020;22:1.

    Article  Google Scholar 

  40. den Dunnen JT, et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat. 2016;37(6):564–9.

    Article  CAS  Google Scholar 

  41. Ogino S, et al. Standard mutation nomenclature in molecular diagnostics: practical and educational challenges. J Mol Diagn. 2007;9(1):1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. MacArthur JAL, et al. Locus reference genomic: reference sequences for the reporting of clinically relevant sequence variants. Nucleic Acids Res. 2014;42(Database issue):D873–8.

    Article  CAS  PubMed  Google Scholar 

  43. Wakeling MN, et al. Misannotation of multiple-nucleotide variants risks misdiagnosis. Wellcome Open Res. 2019;4:145.

    Article  PubMed  Google Scholar 

  44. Wang Q, et al. Landscape of multi-nucleotide variants in 125,748 human exomes and 15,708 genomes. Nat Commun. 2020;11(1):2539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sepulveda AR, et al. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn. 2017;19(2):187–225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Stolze B, et al. Comparative analysis of KRAS codon 12, 13, 18, 61, and 117 mutations using human MCF10A isogenic cell lines. Sci Rep. 2015;5:8535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jancik S, et al. Clinical relevance of KRAS in human cancers. J Biomed Biotechnol. 2010;2010:150960.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Grothey A. EGFR antibodies in colorectal cancer: where do they belong? J Clin Oncol. 2010;28(31):4668–70.

    Article  PubMed  Google Scholar 

  49. Hecht JR, et al. Extended RAS analysis for anti-epidermal growth factor therapy in patients with metastatic colorectal cancer. Cancer Treat Rev. 2015;41(8):653–9.

    Article  CAS  PubMed  Google Scholar 

  50. De Roock W, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11(8):753–62.

    Article  PubMed  CAS  Google Scholar 

  51. Karapetis CS, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65.

    Article  CAS  PubMed  Google Scholar 

  52. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396(6712):643–9.

    Article  CAS  PubMed  Google Scholar 

  53. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med. 2009;361(25):2449–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tsang AH, et al. Current and future molecular diagnostics in colorectal cancer and colorectal adenoma. World J Gastroenterol. 2014;20(14):3847–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tejpar S, Van Cutsem E. Molecular and genetic defects in colorectal tumorigenesis. Best Pract Res Clin Gastroenterol. 2002;16(2):171–85.

    Article  CAS  PubMed  Google Scholar 

  56. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–67.

    Article  CAS  PubMed  Google Scholar 

  57. Wong TN, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518(7540):552–5.

    Article  CAS  PubMed  Google Scholar 

  58. Oliveira AM, et al. Aneurysmal bone cyst: a neoplasm driven by upregulation of the USP6 oncogene. J Clin Oncol. 2006;24(1):e1; author reply e2.

    Article  PubMed  Google Scholar 

  59. Oliveira AM, et al. Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes. Oncogene. 2005;24(21):3419–26.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine, Geisinger Health, Danville, PA, USA

    Yi Ding

  2. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Linsheng Zhang

Authors
  1. Yi Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linsheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Linsheng Zhang .

Editor information

Editors and Affiliations

  1. Department of Laboratory Medicine, Geisinger Health, Danville, PA, USA

    Yi Ding

  2. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Linsheng Zhang

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ding, Y., Zhang, L. (2021). The Molecular Pathobiology of Malignant Process and Molecular Diagnostic Testing for Cancer. In: Ding, Y., Zhang, L. (eds) Practical Oncologic Molecular Pathology. Practical Anatomic Pathology. Springer, Cham. https://doi.org/10.1007/978-3-030-73227-1_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-73227-1_1

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-73226-4

  • Online ISBN: 978-3-030-73227-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation