Chapter 7 Flashcards
Three main categories of genetic predisposition to cancer
- autosomal dominant cancer syndromes (e.g. FAP)
- defective DNA repair syndromes (e.g. HNPCC)
- familial cancers without known genetic basis
Features of autosomal dominant cancer syndromes
- usually a point mutation in a gene for a tumor suppressor, with the second allele silenced in somatic cells
- usually have a “marker phenotype”, such as multiple benign tumors in the affected tissue (as in FAP)
- usually develop cancers in specific organs
- incomplete penetrance and variable expressivity can be seen
How might inflammation promote the development of cancer
- chronic inflammatory states may result in immune dysregulation
- tissue injury may result in excessive proliferation of cells
- chronic inflammation may increase the pool of stem cells
Basic principles of the molecular basis of cancer
- non-lethal genetic damage is essential (and may be triggered by environmental agents, viruses, or inherited in the germ line)
- tumors are formed by the clonal expansion of a single precursor
- the principal targets of genetic damage causing cancer are 1) proto-oncogenes; 2) tumor suppressors; 3) genes involved in apoptosis and 4)DNA repair genes
- carcinogenesis is multistep, involving several mutations
Proto-oncogenes
- may be growth factors, transcription factors, cell cycle components, signal transducers, etc
- mutation of them results in their constitutive activity, causing self-sufficiency in growth signals
Three main mechanisms for tumor suppression by p53
- temporary cell cycle arrest (quiescence)
- permanent cell cycle arrest (senescence)
- programmed cell death (apoptosis)
How does p53 cause cell cycle arrest?
-transcription of p21, which inhibits cyclin-CDK complexes and phosphorylation of RB, preventing the cell cycle from progressing
Two ways beta-catenin is involved in cancer progression
- loss of binding by APC frees it to translocate to the nucleus, interact with TCF and cause transcription of genes such as cyclinD1 and c-myc
- mutation resulting in loss of the E-cadherin/Beta-catenin contact inhibition allows beta-catenin again to travel to the nucleus to stimulate proliferation
Ways cancers can evade apoptosis
- p53 mutations preventing apoptosis
- Bcl2 upregulation preventing apoptosis (e.g. when translocated beside the IgH gene that is transcriptionally active)
How does angiogenesis get promoted in tumors?
- hypoxia induces HIF which activates transcription of angiogenic factors such as VEGF
- loss of p53 can provide a more permissive environment for angiogenesis as normally p53 stimulates expression of anti-angiogenic molecules
Possible DNA repair mechanisms contributing to cancer development
- mismatch repair genes
- nucleotide excision repair
- recombination repair
How are most carcinogens metabolised?
- p450 dependent mono-oxygenases
- therefore, susceptibility to carcinogens is dependent on inherited polymorphisms in genes encoding these enzymes
How do chemical carcinogens cause cancer?
-mutagenesis, usually of tumor suppressors and oncogenes like p53 and RAS
How is UVB carcinogenic
-forms pyrimidine dimers in DNA that should be repaired by the nucleotide excision repair pathway
HTLV-1
- the only RNA retrovirus known to cause cancer in humans
- infects T cells and is transmitted sexually and by blood products
- causes expansion of a nonmalignant polyclonal population through stimulatory effects of its Tax gene
- thse proliferating cells are at risk for mutation, eventually resulting in a monoclonal population emerging
