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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



-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



-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

-Merkel cell polyoma virus



-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