Cancer Flashcards
Inherited forms of cancer
- 5-10% of all cancers have germ line mutations- predisposition only
- Genetic testing for certain types, eg familial adenomatous polyposis, and BRCA-1/2
- Most inherited forms of cancer involve a defect in tumor-suppressor genes (the brakes)
- Predisposition results from heterozygosity in suppressor gene, where cancer occurs as a result of the loss of heterozygosity- eg point mutation, loss of good chromosome
- Several molecular tests can be employed in order to determine if supressor gene is involved- directly genome, RNA sequencing, protein truncation assay, microarrays
Molecular profiling to classify tumours
- Tumours are classified by where they arise
- Sometimes the tumour present is a secondary tumour- i.e. it metastasized- Unknown Primary Cancer- how does the clinician decide what treatment might be appropriate. For example, bowel-like cancer on ovary
- Molecular profiling has revolutionized the way we understand ovarian cancer
`Classes of normal regulatory genes that are the principle targets of genetic damage relevant in carcinogenesis
-Genes involved in DNA repair
-Growth-promoting proto-oncogenes
-Growth-inhibiting tumour suppressor genes
-Genes that regulate programmed cell death (apoptosis)
In almost all cases of oncogenesis, all classes of genes are involved and the pathways they are part of cooperate/interact
Proto-oncogenes
Normal cellular genes whose products almost always promote proliferation and/or suppress differentiation and cell death
Oncogenes
Mutant versions of proto-oncogenes that are biochemically active without a requirement for normal (preceding) growth-promoting signals
Oncoproteins
Proteins encoded by oncogenes
Oncogenic factors
- Growth factorsd- over expression
- Growth factor receptors- over expression or always active/on
- Signal transduction proteins- intermediates in cascade, especially G-proteins, phosphorylases, kinases
- Transcription factors
- Cyclins and CDKs- uncontrolled cell cycle progression
Worst case scenario of DNA repair
Damage in DNA repair genes- eg BRCA1/2, which kleads to accumulation of errors- some genomic regions are more prone to this- mutation hot spots in oncogenes. tumour suppressor genes, regulatory regions of oncogenes or TSGs, controlling levels of expression
-Hot spots potentially caused by an area where chromatin is more active.
Cell cycle and cancer
- Loss of proliferative control via oncogenic activation and TSG inactivation leads to loss of cell cycle control
- Cell division is controolled by the cell cycles
- Mutations in certain types of genes may lead to cancer because they ddirectly/indirectly affect the cell cycle
- Cancer is a disease of the cell cycle
Tumour suppressor genes
- Tumour suppressor genes encode proteins that inhibit cellular proliferation by regulating the cell cycle directly (eg Rb, p53) or inhibit oncogenic pathways (eg P-TEN)
- Unlike oncogenes, both copies of the gene must be lost for tumour development, leading to loss of heterozygosity (LOH) at the gene locus
- In cases with familial predisposition to develop tumours, the affected individuals inherit one defective (non-functional) copy of a tumour suppressor gene and lose the second one through somatic mutation. In sporadic cases, both copies are lost through somatic mutations.
Evasion of apoptosis
- Loss of p53 (TSG) leading to reduced function of pro-apoptotic factors
- Reduced egress of cytochrome-c from mitochondria as a result of upregulation of anti-apoptotic factors
- Loss of apoptotic peptidase activating factor
- Upregulation of inhibitors of apoptosis (IAP)
- Reduced CD95 level
- Inactivation of death-induced signalling complex. FADD, Fas-associated via death domain
Lymphoid neoplasms
- Diverse group of tumours of B- T- and NK- cell origin.
- In many instances, phenotype of the neoplastic cell closely resembles that of a particular stage of normal lymphocyte differentiation
- This feature is used in the diagnosis and classification of these disorders
Myeloid neoplasms (MNs)
- Originate from haematopoietic progenitor cells
- Primarily involve bone marrow, to a lesser degree the secondary haematopoietic organs (spleen, liver, lymph nodes)
- Usually present with symptoms related to altered haematopoiesis
- 3 categories
MN: Acute myeloid leukaemia (AML)
Immature progenitor cells accumulate in the bone marroe which suppresses normal haematopoiesis
- Most common adult leukaemia
- Rare- 0.8% of all cancers diagnosed
MN: Myelodysplastic syndromes
Associated with ineffective haemapoiesis and resultant peripheral cytopaenias- defective maturation
MN: Chronic myeloproliferative Leukaemias (CML)
Increased production of one or more terminally differentiated myeloid elements (eg granulocytes) usually leads to elevated peripheral blood counts
Disease triggers for AML
Mutations on one or more of the genes that normally control blood cell development caused by:
- High doses of radiation, either accidentally or therapeutically
- Chemicals (long-term exposure)- benzenes, certain types of chemo, carcinogens in cigarettes
- Some people with pre-existing genetic disorders- eg Down Syndrome- higher chance of AML
Treatment for AML
- Chemiotherapy
- Peripheral blood stem cell and bone marrow transplantation (either culture their normal blood and reinfuse post treatment, or use a healthy person’s blood)
- Radiotherapy to the head (prevent metastasis)
