Molecular alterations in cancer

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)

Normal cellular function and homeostasis are regulated by a series of signal transduction pathways. All cancers result from disruption of these pathways, through germ-line, epigenetic, or somatic alterations. Whereas some cancers arise from a single genetic alteration (i.e., the BCR-ABL translocation resulting in chronic myelogenous leukemia), most human cancers arise from several to many sequential genetic alterations.

Functionally, these genetic alterations result in either the aberrant activation of an oncogene, whose protein product now promotes carcinogenesis, or inactivation of a tumor suppressor gene, whose protein product is now unable to mediate its homeostatic function (i.e., inhibiting cell growth or survival). In addition, an emerging number of microRNA genes, which do not encode proteins but instead regulate the expression of other genes, have been implicated in the pathogenesis of human cancers.

Types of molecular alterations

  • Germ-line: although rare, result in hereditary (or familial) cancers
  • Somatic: most common, result in sporadic cancers
  • Genetic: result in changes in the primary DNA sequence
    • Point mutation (alteration of a base pair)
    • Deletion or insertion (loss or gain of genetic material)
    • Chromosomal rearrangements (inversions, translocations)
    • Gene amplification (increasing gene copy number) promoted by deficiency in DNA repair mechanisms
  • Epigenetic: result in changes in gene expression that are not caused by changes in the primary DNA sequence, are thus potentially reversible
  • Promoter methylation
  • Histone deacetylation


  • Derived from normal cellular genes (see Table 1.1)
  • Encode proteins that control cell growth and/or survival
  • Usually gain of function or increased function relative to the normal cellular counterpart
  • Protein products include
    • Transcription factors
    • Growth factors
    • Growth factor receptors
    • Signal transduction molecules
    • Regulators of apoptosis

Transcription factors

Often chromosomal translocations result in fusion proteins with aberrant activity.

Growth factors and growth factor receptors

Either overexpression of the growth factor or constitutive activation of the growth factor receptor occurs.

Signal transduction molecules

  • Either nonreceptor protein kinases or guanosine-triphosphate binding proteins (G proteins)
  • Nonreceptor protein kinases include both tyrosine kinases (ABL, SRC) and serine/threonine kinases (AKT, RA F)
  • Usually activating mutations (constitutive or increased activity)

Regulators of apoptosis

  • Two main pathways result in apoptosis, the death receptor or extrinsic pathway (ligands binding to death receptors) and the stress or intrinsic pathway (regulated by proteins with BCL-2 homology domains)
  • Usually increased expression of inhibitors of these pathways

Table 1.1. Examples of oncogenes

Oncogene Cancer Alteration
Transcription Factor
v-myc, N-MYC, L-MYC Breast, lung, ovarian Amplification, viral homolog
v-fos Sarcoma Viral homolog
Growth Factor
v-sis Glioma, fibrosarcoma PDGF homolog, constitutive expression
Growth Factor Receptors
EGFR Colon, lung Amplification, mutation
NEU Breast, lung Amplification, mutation
Signal Transduction Molecules
SRC Colon Viral homolog, constitutive activation
H-RAS, K-RAS, N-RAS Colon, lung, pancreas Viral homolog, mutation
Regulators of Apoptosis
BCL-2 Lymphoma Chromosomal translocation
MDM2 Sarcomas Amplification

Tumor suppressor genes

  • Encode proteins in pathways that normally control cellular homeostasis (growth, survival) (see Table 1.2)
  • Usually loss of function or decreased function relative to normal
  • Can require loss of both alleles to effect cell function
  • Loss of function can be genetic (loss of heterozygosity, mutation), epigenetic, or both
  • Can result in either familial cancer syndromes or sporadic cancers

microRNA genes

  • Encode a single strand of RNA that anneals to mRNA to either degrade the mRNA or block translation of the mRNA (see Table ..3).
  • Many microRNA genes occur in chromosomal regions involved in translocations, deletions, and amplifications in human cancer, but with no known oncogenes or tumor suppressor genes.
  • Can be upregulated (amplification, transcriptional, epigenetic) or downregulated (deletion, transcriptional, epigenetic silencing).
  • Upregulated microRNA genes function as oncogenes by downregulating tumor suppressor genes.
  • Downregulated microRNA genes function as tumor suppressor genes by downregulating oncogenes.

Table 1.2. Examples of tumor suppressor pathways and genes

Tumor suppressor pathway/genes Familial cancer syndrome Sporadic cancer
Hedgehog (PTC) Gorlin syndrome Breast, esophageal, gastric, medulloblastoma, pancreatic
HIF-1 (VHL) von Hippel–Lindau syndrome Renal cell carcinoma
PI3K/Akt (PTEN) Cowden’s disease Breast, prostate, thyroid
Rb pathway (p14ARF, p16INK4A, p21CIP1, p27KIP1) Retinoblastoma, osteosarcoma Most cancers
TP 53 pathway Li-Fraumeni syndrome Breast, colon, lung, many others
Transforming growth factor-β (TGFBR2, SMAD4) Hereditary non-polyposis colon cancer Colorectal, gastric, pancreatic
Wnt (APC) Familial adenomatous polyposis coli Colorectal, gastric, pancreatic, prostate

Table 1.3. Examples of microRNA genes

MicroRNA Target (effect) Cancer
LET7 RAS (increased) Lung
MiR15a BCL2 (increased) CLL
MiR21 PTEN (deceased) Breast, lung, prostate



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