how do we know whether 1 gene is involved in cell death pathway or cell proliferation pathway?

Question:

which key cells in cell death pathway and in cell proliferation pathway?

Answers:
The Genetics of Cancer

•Several types of genes play roles in cell growth and are particularly important in the development of cancer:
•Oncogenes (mutated forms of proto-oncogenes) promote cancer.
•Tumour suppressor genes/antioncogenes prevent cancer.
•Mismatch repair genes function to repair mutated DNA.
•For colon cancer to progress to its full malignancy, three tumour suppressor genes and one oncogene must be mutated in sequence.
•Many cancers are now diagnosed by oligonucleotide probe hybridisation for identified mutations.

Oncogenes

•Oncogenes are altered forms of proto-oncogenes, which are normal genes which promote cell growth and differentiation. The mutation may be acquired or inherited.
•Proto-oncogenes are normally “switched off” in differentiated, non-dividing cells.
•Some proto-oncogenes control apoptosis. Mutations in these genes may prevent apoptosis, causing a predisposition to cancer.

•Oncogenes and proto-oncogenes are responsible for:
•Growth factors
•Growth factor receptors
•Transducers (intracellular signalling proteins)
•Transcription factors
•Cell cycle control proteins

•Mutant forms of the products of proto-oncogenes may signal cells to divide inappropriately and promote cell growth in inappropriate circumstances.
•Only one oncogene is required for predisposition to cancer (as the mutation leads to an increase in function).
•Signalling proteins are often mutated in human cancers. An important group of signalling proteins which are often mutated to become more active are tyrosine kinases. These are most commonly mutated in brain and breast cancers. – is it the growth factor or the receptor which changes?
•Cellular signals can initiate cell proliferation or differentiation.

•Proto-oncogenes may become oncogenes by translocation activating mutations or gene amplification.
•Gene amplification means the gene is over-represented in the genome (up to 100 copies) and thus creates excess product. This is a common cause of breast and brain cancer.
•Activating mutations result in increased activity of the gene product. eg.: epidermal growth factor receptor in breast cancer.
•Translocation is seen in >90% (or 95%?) of leukaemias and many lymphomas. It is limited to somatic cells.
•Oncogenes result in increased gene product activity or the production of more gene product of the same activity.
•Tyrosine kinase (a growth factor) receptors are produced by proto-oncogenes, which often mutate to oncogenes causing increased tyrosine kinase activity.

Tumour Suppressor Genes/ Anti-Oncogenes

•Tumour suppressor genes are found in all cells.
•Tumour suppressor genes control critical checkpoints in the cell cycle, induce the transcription of inhibitory/regulatory genes, control for proteins that regulate signal delay mechanisms and generally negatively control cell growth.
•Tumour suppressor genes code for cell cycle proteins, transcription factors, cell surface proteins, DNA repair proteins and apoptosis related proteins. They may code for cell adhesion and stop the cell cycle in G1 for DNA repair or other reasons (known as the G1-S checkpoint).
•The loss of function of tumour suppressor genes can lead to cancer. This loss of function may be acquired or inherited.
•The loss of function of one tumour suppressor gene may provide a slight cell progression advantage. The loss of both leads to a significant growth advantage and predisposition to cancer.
•The “two hit hypothesis” states that both copies of the gene must be “lost” for cancer to develop.
•Tumour suppressor genes prevent rapid cell cycling/growth.
•An individual may be born with only one functioning copy of a tumour suppressor gene and may lose the second copy, becoming predisposed to cancer.

Acquired Cancer

•Acquired DNA damage can be induced by environmental factors such as chemical carcinogens, bacteria, viruses, radiation (ionising such as X-rays or non-ionising such as UV light), age, diet and chronic infection. This is notable as cancers have different frequencies for the same people in different countries/areas.
•Spontaneous mutations arise because of chemical changes in nucleotide sequences.
•Carcinogens include UV light, tobacco smoke, meat preservatives and ionising radiation.
•Thousands of chemicals are found in food. “Natural carcinogens” may account for up to 80% of carcinogens in our diet.
•High fat, low fibre, obesity and chronic inflammation predisposes people to cancer.

•Rapidly dividing cells have less time for DNA repair and accumulate genetic errors over time. Often the G1-S checkpoint is lost in cancer cells.

•There is some evidence that chronic or latent (present, but not always clinically apparent) infection may account for up to 15% of cancers.
•Viral genes persist in host DNA of a subset of infected cells.
•Periodically, the viral genes will produce new virons.
•Papillomavirus is associated with anogenital cancers (eg.: carcinoma of the cervix), HIV with lymphomas and human T-cell leukemia with HTLV-1.
•Some population groups clear the virus better than others and are thus less at risk of associated cancers.
•Retroviruses (eg.: HIV) may alter genes critical for regulating cell growth by inserting their own genes upstream or within the coding sequences of genes, leading to over expression of the gene or over active (sometimes constitutively active) proteins.
•DNA tumour viruses associate with the replication machinery of the host cell.

Inherited Cancer

•About 10% of cancers result from the inheritance of a mutated gene which predisposes the individual to cancers. This is relevant to virtually every type of human cancer.
•Some familial aggregation of cancer is due to shared exposure to carcinogens, others to genetic predisposition and others still to both.
•Features which suggest inherited susceptibility include:
•Several 1st degree family members with a common cancer.
•Several 1st degree relatives with related cancers. eg.: ovarian and breast
•Two members of the same family with a rare cancer.
•Early age of onset of cancer.
•Bilateral cancers in paired organs. eg.: kidneys and eyes.
•Tumors in two or more organs of one individual.
•NOT one close relative with a common cancer.
•A person with a parent or sibling who develops a cancer at an age less than 40 has twice the risk of developing the same cancer.
•Knowledge of cancer due to genetic predisposition allows:
•Regular screening (eg.; colonoscopies) which generally begins five years before the age of onset in the patient.
•Genetic counseling.
•Treatment/prognosis changes.
•Prophylactic treatment.
•Identification of the molecular basis of cancers, leading to the design of novel therapies.
•Generally, for cancer to occur due to a genetic predisposition, an accompanying environmental stimuli must be present.
•A defined dose of carcinogen may have different effects on individuals, depending on their genetic makeup. eg.: UV light vs. skin colour.

•Familial susceptibility to cancer can be to a specific type of cancer (eg.: colon cancer), or a number of cancers due to a familial predisposing syndrome (eg.: multiple endocrine neoplasms).
•Genes implicated in familial cancer can be also implicated in sporadic cancer. eg.: colon cancer, but not BRCA1 or BRCA2 in breast cancer.
•Cancer has both genetic and environmental influences for phenotypic expression (ie.: the clinical expression, type of disease, etc.).
•Penetrance varies depending on the gene. eg.: familial polyposis will lead to 100% penetrance of cancer, whereas inherited breast cancers show a 40-70% penetrance.
•Penetrance varies with age of death.
•BRCA1, BRCA2 and Rb genes help to demonstrate the genetic nature of cancer.
•For women with the BRCA1 mutation, the chance developing breast cancer by the age of 50 is 60% and 82% by the age of 70, as opposed to women without who have the chances of 2% and 7% respectively.

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how do we know whether 1 gene is involved in cell death pathway or cell proliferation pathway?

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