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
DNA viruses that can cause cancer
- HPV
- EBV
- HHV8
- HBV
- Merkel cell polyoma virus
HPV
- low risk types that cause warts do not integrate into the host genome, while high risk ones doe
- E7 binds RB and displaces it from E2F, and also inactivates p21 and p27; promotes proliferation
- E6 binds and degrades p53 and BAX, reducing apoptosis, and activates telomerase
Tumors associated with EBV
-Burkitt, BCL in immunocompromised/AIDS patients, some Hodgkin’s lymphoma, nasopharyngeal and gastric carcinomas and some NK/T cell lymphomaes
How do HCV and HBV cause cancer
- immunologically mediated chronic inflammation with hepatocyte death leading to regeneration and genomic damage
- i.e. the immune response to the virus induces the damage
Immune surveillance
- the immune system when functioning normally is responsible for surveilling the body for emerging malignant cells and destroying them
- products of mutated proto-oncogenes, etc are produced in the cell and can be expressed on MHC 1 and recognized by CD8 cells
- some tumors overexpress normal antigens (e.g. tyrosinase in melanoma) and T cells may mount a response to these
- CTLs recognize proteins produced by oncogenic viruses
- cell-mediated immunity is the dominant antitumor mechanism in vivo
Molecular diagnostics related to cancer
- diagnosis (e.g. clonality, specific translocations, etc) by PCR
- prognosis (e.g. m-myc amplification in neuroblastoma, Her2)
- detection of minimal residual disease (e.g. amplification of BCR-ABL in CML
- diagnosis of hereditary predisposition (e.g. BRCA)
How do tumor cells evade the immune system?
- selective outgrowth of antigen negative variants by eliminating highly immunogenic subclones
- reduced expression of Mhc molecules
- lack of costimulation (may both prevent the response but also induce anergy)
- release of immunosuppressive products
- antigen masking by glycocalyx molecules such as silicon acid
- apoptosis of cytotoxic t cells
