Tumour Formation: Number of Mutations Required

Lindsay D Butcher, Baylor University, Waco, Texas, USA
C Richard Boland, Baylor Research Institute and Baylor University Medical Center, Dallas, Texas, USA

Published online: October 2012

DOI: 10.1002/9780470015902.a0006050.pub2

Cancer is a genetic disease, and occurs through the progressive accumulation of activating alterations to growth-promoting oncogenes, and inactivating alterations to tumour suppressor genes. The rate of accumulation of these alterations may be accelerated by a variety of processes that cause genetic instability. There are several key ‘pathways’ involved in the evolution of a tumour, and the alterations may occur at any point in each pathway. Each tumour develops its own unique constellation of genetic alterations, and tumours are genetically distinct between tumour types, and within individual tumours of one type. The focus of this review is on colorectal cancer, but the concepts are broadly applicable to many types of tumours.

Key Concepts:

  • Cancer is a disease caused by genetic alterations.
  • Oncogenes are normal cellular genes altered by point mutations, amplification or changes in the regulation of gene expression that result in an increase cell growth, survival, ability to invade, or other tumour-related cell behaviours.
  • Tumour suppressor genes normally restrain a cell's ability to grow or invade, and inactivation is involved in tumourigenesis.
  • Epigenetic alterations, such as deoxyribonucleic acid (DNA) methylation, play a role in carcinogenesis.
  • Most solid tumours evolve through progressive multistep carcinogenesis that is mediated by the accumulation of altered genes. This is why tumours may be found at various stages of development.
  • The genes involved in tumour formation are tissue-specific.
  • The landscape of altered genes is heterogeneous among a group of tumours from one specific tissue or organ.
  • Genetic alterations may be heterogeneous throughout individual tumours.
  • Some tumours have a very large number of genetic alterations (chromosomal rearrangements, point mutations and DNA methylation), and others have many fewer alterations.

Keywords: oncogene; tumour suppressor gene; microsatellite instability; chromosomal instability; DNA methylation; multistep carcinogenesis

Figure 1. Types of mutations.
Figure 2. Methylation of CpG islands.
Figure 3. Histone modification.
Figure 4. Development of therapeutic resistance.
Figure 5. Multistep colorectal carcinogenesis.
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 References
    Bishop JM (1991) Molecular themes in oncogenesis. Cell 64: 235–242.
    Boland CR and Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138: 2073–2087.
    Boland CR, Sato J, Appelman HD, Bresalier RS and Feinberg AP (1995) Microallelotyping defines the sequence and tempo of allelic losses at tumor suppressor gene loci during colorectal cancer progression. Nature Medicine 1: 902–909.
    Campbell PJ, Yachida S, Mudie LJ et al. (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467: 1109–1113.
    De Klein A, Van Kessel AG, Grosveld G et al. (1982) A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 300: 765–767.
    Diaz LA, Williams RT, Wu J et al. (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486(7404): 537–540.
    Ducasse M and Brown MA (2006) Epigenetic aberrations and cancer. Molecular Cancer 5: 60.
    Duval A and Hamelin R (2002) Mutations at coding repeat sequences in mismatch repair-deficient human cancer: toward a new concept of target genes for instability. Cancer Research 62: 2447–2454.
    Fatemi M, Pao MM, Jeong S et al. (2005) Footprinting of mammalian promoters: use of a CpG DNA methyltransferase revealing nucleosome positions at a single molecule level. Nucleic Acids Research 33(20): e176.
    Fearon ER and Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61: 759–767.
    Garcia-Closas M, Malats N, Real FX et al. (2006) Genetic variations in the nucleotide excision repair pathway and bladder cancer risk. Cancer Epidemiology, Biomarkers and Prevention 15(3): 536–542.
    Gerlinger M, Rowan AJ, Horswell S et al. (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New England Journal of Medicine 366(10): 883–892.
    Goel A and Boland CR (2012) Epigenetics of colorectal cancer. Gastroenterology (in press).
    Grady WM, Rajput A, Myeroff L et al. (1998) Mutation of the type II transforming growth factor-beta receptor is coincident with the transformation of human colon adenomas to malignant carcinomas. Cancer Research 58(14): 3101–3104.
    Greenman C, Stephens P, Smith R et al. (2007) Patterns of somatic mutations in human cancer genomes. Nature 446: 153–158.
    He L and Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nature Reviews Genetics 5: 522–531.
    Ionov Y, Peinado MA, Malkhosyan S, Shibata D and Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363: 558–561.
    Issa JP and Kantarjian HM (2009) Targeting DNA methylation. Clinical Cancer Research 15: 3938–3946.
    Jones S, Chen W, Parmigiani G et al. (2008) Comparative lesion sequencing provides insights into tumor evolution. Proceedings of the National Academy of Sciences of the USA 105(11): 4283–4288.
    Kern SE, Fearon ER, Tersmette KW et al. (1989) Clinical and pathological associations with allelic loss in colorectal carcinoma. Journal of the American Medical Association 261(21): 3099–3103.
    Lengauer C, Kinzler KW and Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386: 623–627.
    Markowitz S, Wang J, Myeroff L et al. (1995) Inactivation of the type II TGR-beta receptor in colon cancer cells with microsatellite instability. Science 268(5215): 1336–1338.
    Souza RF, Appel R, Yin J et al. (1996) Microsatellite instability in the insulin-like growth factor II gene in gastrointestinal tumors. Nature Genetics 14(3): 255–257.
    Suzuki MM and Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nature Reviews Genetics 9: 465–476.
    Thibodeau SN, Bren G and Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260(5109): 816–981.
    Vogelstein B, Fearon ER, Hamilton SR et al. (1988) Genetic alterations during colorectal-tumor development. New England Journal of Medicine 319: 525–532.
    Wood LD, Parsons DW, Jones S et al. (2007) The genomic landscapes of human breast and colorectal cancers. Science 318: 1108–1113.
 Further Reading
    Bell DW (2010) Our changing view of the genomic landscape of cancer. Journal of Pathology 220: 231–243.
    Brait M and Sidransky D (2011) Cancer epigenetics: aboveand beyond. Toxicology Mechanisms and Methods 21(4): 275–288.
    Friedberg EC (2001) How nucleotide excision repair protects against cancer. Nature Reviews Cancer 1: 22–33.
    Hanahan D and Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144: 646–674.
    Kan K, Jaiswal BS, Stinson J et al. (2010) Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466: 869–873.
    Preston BD, Albertson TM and Herr AJ (2010) DNA replication fidelity and cancer. Seminars in Cancer Biology 20: 281–293.
    Sharma S, Kelly TK and Jones PA (2010) Epigenetics in cancer. Carcinogen 31(1): 27–36.
    Stratton MR (2011) Exploring the genomes of cancer cells: progress and promise. Science 331: 1553–1558.
    Stratton MR, Campbell PJ and Futreal A (2009) The cancer genome. Nature Reviews 458: 719–724.

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Article Title: Tumour Formation: Number of Mutations Required
 
How to Cite close
Butcher, Lindsay D, and Boland, C Richard(Oct 2012) Tumour Formation: Number of Mutations Required. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006050.pub2]