Genes that Predispose to Cancer Flashcards
What are the 2 basic properties of the HSC?
Can generate all lineages
When HSC divides, 1 daughter cell maintains the stem cell compartment
How do cell properties change as the cell lineage progresses?
Loss of replicative potential
Lineage-specific cell surface receptors appear
What enzymes control the cell cycle?
Series of cyclin-dependent kinases (CDKs)
What stimulates the 1st cyclin to activate the cell cycle?
An external stimulus - cytokine acts on cytokine receptor, tyrosine kinase activity stimulates signalling pathway which acts via Ras to activate a TF (e.g. Myc)
TF upregulates transcription of cyclins (e.g. cyclin D) which in turn activate CDKs (e.g. CDK4) to progress the cell cycle (via various other TFs and cyclins)
Give an example of a cytokine receptor involved in control of cell cycle that is implicated in some breast cancers
HER2
What is “R” in the cell cycle? What is its purpose?
Restriction point - check to see if there are adequate metabolic and energy requirements for the cell to progress to divide, and assess DNA for damage
What happens if DNA damage is detected during the R phase?
p53 arrests the cell cycle
What is the role of p53?
Arrests cell cycle in presence of DNA damage by inducing a CDK inhibitor (CDKI) called p16, which acts as a growth inhibitory signal to the cell (suppresses CDK4)
Induces apoptosis if DNA cannot be repaired
List 10 established and emerging hallmarks of cancer
Evasion of apoptosis Autonomous growth signalling Evading growth inhibitory signals Activating invasion and metastasis Immortality Angiogenesis Deregulating cellular energetics Avoiding immune destruction Genome instability and mutation Tumour-promoting inflammation
Give examples of mechanisms employed by 4 different cancers to achieve autonomous growth signalling
CML: Bcr-Abl
ALL: Bcr-Abl
MALTomas: NF-kB
Burkitt’s lymphoma: Myc
Give examples of mechanisms used by 2 different cancers to evade growth inhibitory signals
Burkitt’s lymphoma: Myc
H.pylori: Myc
Give examples of general mechanisms of invasion and metastatic capacity
Cells become GF/anchorage independent
Are able to enter and exit blood vessels
How do cancer cells achieve immortality?
Express telomerases that extend telomeres
Give an example of a mechanism used to evade apoptosis
CLL: Bcl-2, ABT-199
How are cancer cells though to deregulate cellular energetics to their advantage?
Warburg effect: cancer cells increase glucose metabolism using a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells
What is the molecular basis of development of haemopoietic neoplasms? What is the clinical relevance of this?
Following the initial mutation, cells can take quite different routes to similar cancers, meaning that different combination of mutations are encountered in different patients
This confers different responses to treatment and the possibility of personalised management strategies/drug regimes
Give 3 examples of TFs commonly mutated in haemopoietic neoplasms
Myc
NF-kB
ZAP-70
Give 3 examples of TSGs commonly lost in haemopoietic neoplasms
Rb
APC
Ras-GAP
Give 4 examples of genes commonly mutated in haemopoietic neoplasms and which enable cytokine-independent cell signalling in their mutated form
Bcr-Abl
HER2
Ras
SOS (Ras-GEF)
Give an example of a pro-apoptotic family of proteins commonly mutated in haemopoietic neoplasms
Bcl-2
What are 3 common mechanisms for inducing DNA mutations?
Chromosomal translocation or other acquired changes
Point mutations or deletions within a gene
Viruses/bacteria
What are 3 examples of types of chromosomal translocations or other acquired DNA mutations which may lead to cancer? Give specific examples for each
Joining of 2 genes or portions of genes to generate proteins with altered function (e.g. Bcr-Abl)
Inappropriate placement of a gene under the control of a powerful enhancer sequence, resulting in excessive synthesis of the protein (e.g. translocation of Myc gene to control of Ig enhancer)
Deletion of a gene (e.g. loss of miRNA genes regulating Bcl-2)
What are 3 examples of types of point mutations or deletions which may lead to cancer? Give specific examples for each
Change in protein activity, including inappropriate constitutive activation of loss of the ability to inactive a protein (e.g. Ras, SOS, Ras-GAP, p53)
Inability to degrade a protein (e.g. Myc)
Truncation of a protein (e.g. APC, full or attenuated FAP)
What are 3 mechanisms whereby viruses/bacteria induce DNA mutations which may lead to cancer? Give specific example for each
Viral proteins blocking or activating cellular proteins (e.g. HPV E6/E7 blocks p53, Rb and p16)
Viral promoters activating normal genes/viral oncogenes affecting cell cycle
Chronic inflammation promoting mutations and translocation by promoting hypermutation and class switching in B cells (e.g. EBV, H. pylori)
What are 2 common characteristics of mutations/translocations seen in haemopoeitic neoplasms specifically?
Abrogate cytokine dependence for entering cell cycle
Allow avoidance of apoptosis
When are B cells prone to acquiring chromosomal translocations and point mutations? Why?
During antibody diversification, because of the enzyme AID which normally controls Ig class switching and somatic hypermutation (involves inserting point mutations) While this is advantageous for antibody diversity, it increases the number of mutations in non-Ig genes
What are the 3 categories of myeloid neoplasm and what does each involve?
Acute myeloid leukaemias: accumulation of immature blasts in bone marrow with suppression of normal haemopoiesis
Myelodysplastic syndromes: cytopaenia from disorderly proliferation in bone marrow, lack of mature cells in blood
Myeloproliferative disorders: increased production in 1 or 2 categories of mature cells (e.g. CML)
What are the 2 classes of lymphoid neoplasms and how do they differ?
Lymphomas: arise as discrete tissue mass in LNs or extranodal sites
Lymphocytic leukaemias: solid tissue neoplasms (e.g. LN, skin) but that present with involvement of bone marrow and generally blood (e.g. CLL)
Distinctions are blurred and 1 may progress to the other; generally refers to initial presentation
How does WHO classify lymphoid neoplasms?
Morphologic, genotypic, immunophenotypic and clinical characteristics
What is the origin of the majority (85-90%) of lymphomas and lymphocytic leukaemias?
B-cell origin
What kind of immune abnormalities are associated with lymphoid neoplasms?
Loss of protective immunity and breakdown of tolerance (autoimmunity)
Immunodeficiency (higher risk of acquiring lymphoid neoplasms, especially from oncogenic viruses)
What is the natural history of CML?
Slow progression with a median survival of 3 years
Patients enter an accelerated phase, accumulating mutations or cytogenetic abnormalities (e.g. trisomy 8, duplication of Ph Ch), followed by blast crisis (where cells may be of myeloid or pre-B origin)
What can be seen on a peripheral blood smear in CML?
Many mature neutrophils and less immature myelocytes and metamyelocytes
Why is CML thought to originate from a pluripotent stem cell?
Because cells can be of myeloid or pre-B origin in the blast crisis