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
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
|v-myc, N-MYC, L-MYC||Breast, lung, ovarian||Amplification, viral homolog|
|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|
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
- 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
|MiR21||PTEN (deceased)||Breast, lung, prostate|