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Summary Pecorino Molecular Biology of Cancer Ch. 6
This is an extensive, English summary of Pecorino's 'Molecular Biology of Cancer' book, Ch. 9– about growth inhibition and tumor suppressor genes.
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Oncology 6HC 4
6.1
Tumor suppressor genes are important in maintaining the balance between cell
proliferation, differentiation and apoptosis, as they function as stop signs for uncontrolled
cell growth. So, they stop the cell cycle and initiate apoptosis. Historically, they were termed
anti-oncogenes, as they undo pathways of oncogenic activation. For example,
phosphorylation which evokes oncogenic activity is counteracted by anti-oncogenes that are
phosphatases. If this phosphatase is mutated, this would add to dysregulation and cancer
cell growth. PTEN is such an example, is dephosphorylated PIP3 into PIP2, antagonizing the
PI3 kinase pathway initiated by EGFR. Loss of inhibitory dephosphorylation with a PTEN
mutation constitutively activates PI3, with inhibition of apoptosis and induction of
proliferation – favoring oncogenesis.
However, only if both copies of a gene are lost or inactivated, unregulated cell growth may
arise, a common hallmark of cancer. It has been found, actually, through investigations of
hereditary syndromes that predisposes individuals to a certain cancer, that both alleles must
be dysfunctional. By inheriting germline mutations in one tumor suppressor allele, you only
need one more somatic mutation or other inactivating alteration to have lost both alleles.
The phenomenon is known as Knudson’s two-hit hypothesis: in the case of a tumor
suppressor gene, this is a gene in which a germline mutation predisposes an individual to
cancer. This also indicates why the inherited form has an earlier onset than a random
sporadical tumor which requires two mutations of the same allele in the same cell. This is a
small chance but more likely at old age when mutations accumulate. Sporadic cases may
also very well be due to epigenetic mechanisms. For inherited cases, the second hit is always
in the cell which already misses the first; it’s a germline mutation after all. Tumor suppressor
genes, to this extent, are recessive and require an inactivation of both alleles to contribute
to carcinogenesis. Oncogenes are dominant, one mutation suffices.
Common tumor suppressor genes include RB1, p53, APC and BRCA. Loss of BRCA1/2 is a
common causative agent that predisposes offspring to breast cancer. This gene follows the
two-hit hypothesis. It is part of the homologous repair mechanism and thus helps to
maintain genome integrity. They recruit recombinase enzymes, whereby defects in BRCA
destabilize the genome and lead to chromosomal rearrangements.
6.2
The retinoblastoma gene (Rb) is an important tumor suppressor gene and has been
implicated to have a sporadic and hereditary form of disease. In the latter, one allele is
already mutated and passed on, meaning that a second mutation due to say faulty
recombination is likely. Where this mutation occurs does not matter, as every cell in the
body has one dysfunctional allele already. Hence, a blastoma of the retina in familial Rb is
bilateral, affecting both eyes. In sporadic cases, it’s almost always unilateral, as two new
mutations in one cell causing cancer, does not happen twice in the lifetime of one
individual. This is a clear example of the two-hit hypothesis: two separate mutations are
needed to inactivate Rb and prevent expression of the RB protein. RB functions as a tumor
suppressor, as it binds E2F and prevents it from transcribing genes needed for cell cycle
progression.
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