Week 1 - Cancer Genetics Flashcards
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Environmental factors that can lead to genetic changes & cause cancer to develop
Chemicals Radiation Diet and Exercise Infection – Retroviruses Physical Agents Hormones
What is Dysregulation?
Impairment of a physiological regulatory mechanism
Carcinogenesis
Process by which normal cells are transformed into cancer cells Characterized by changes at the: - cellular level - genetic level - epigenetic level - through abnormal cell division
Knudson’s Two-Hit Hypothesis
Most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change
Shows 2 things:
1. It is especially true for the recessive nature of tumour suppressor genes (needs both genes to be involved in order for the cancer to be expressed)
2. It shows that the formation of cancer is a multi-step process (involves more than one mutation
Multi-Step Nature of Carcinogenesis
- Initiation
- e.g. chemical carcinogen causes mutation (metabolism and repair processes altered) - Promotion
- cell proliferation - Tumour Progression
- promoters contribute by mechanisms which leads to cells acquiring more mutations
- forms benign or precancerous lesions
- selection/growth advantage leading to proliferation of cancerous cells
- epigenetic changes -> local invasion/metastases
Somatic Mutation Theory (SMT) vs Tissue Organisation Field Theory (TOFT)
SMT: carcinogenic agents -> increase in new mutations or already mutated genes leading to affected cell growth, differentiation or function
TOFT: carcinogenic agents disrupt interactions between cells that maintain the tissue architecture; it’s organisation, repair and regulation
What are Epigenetic Modifications?
Genetic changes other than mutations that involve:
- proteins/molecules e.g. growth factors
- adjacent stromal cells e.g. endothelial cells
- extracellular matrix (ECM) framework surrounding tumour cells
Proto-oncogenes and Oncogenes
Proto-oncogene: regulates cell growth & differentiation
- involved in signal transduction & execution of mitogenic signals
- e.g. myc involved in cell regulation - codes for transcription factor, e.g. ras, wnt
Oncogene (or cellular oncogene c-onc): potential to increase the malignancy of a cell, once it becomes activated, constitutively expressed
- e.g. c-myc, k-ras
Classification of Oncogenes: Growth Factor Receptors (Receptor Tyrosine Kinases)
Mechanism of action: overexpression or amplification - receptor kinases add phosphate groups to the amino acid tyrosine in target proteins that can cause cancer by switching the receptor permanently on without signals from outside the cell
E.g. Platelet-derived growth factor receptor (PDGFR)
Classification of Oncogenes: Regulatory GTPases
Mechanism of action: Point mutations leading to deregulated overactivity
E.g. Ras in many common cancers, lung, colon, pancreas
Classification of Oncogenes: Transcription Factors
Mechanism of action: Point mutations, amplifications or translocations
E.g. c-myc amplification in dmins in AML
Mechanisms of Oncogene Activation - Mutations
Alter structure of proto-oncogene/oncogene
Dominant gain-of-function
Involve protein regulatory regions leading to uncontrolled continuous activity of the mutated protein
Types of mutations:
- point mutations
- deletions
- insertions
- integration of pro-viral DNA from a retrovirus
Mechanisms of Oncogene Activation - Gene Amplification
Repeated copying in DNA replication process -> expansion in copy number -> increase in gene expression -(onc present)> deregulated cell growth
Amplification can result in:
- double minutes (d-mins)
- homogenously staining regions (hsrs)
- e.g. c-myc is amplified in small-cell lung ca, breast/ovarian ca and leukemias
Mechanisms of Oncogene Activation - Chromosomal Arrangements
Types of recurrent rearrangements:
- chromosomal translocation: reciprocal exchange
- inversions: segment reversed end to end
When these rearrangements happen, oncogenes can be activated by:
1. De-regulated expression of oncogenes via regulatory control of an immunoglobulin gene IGH@
- proto-onco/onc is moved close to an immunoglobulin gene and falls under its control -> deregulated expression -> neoplastic transformation
OR
2. Formation of novel hybrid fusion genes with transforming activity
- juxtaposition of 2 different genes to form a novel fusion gene -> codes for chimeric protein -> transforming activity
Types of Abnormalities Detected in Haematological Malignancies
Numerical: gains/losses (egs trisomies, monosomies)
- e.g. trisomy 8 (clone = at least 2 cells)
- e.g. monosomy 7 (clone = at least 3 cells)
Structural: any structural aberration (clone = at least 2 cells)
- e.g. intrachromosomal: inversions: segments within a chromosome, reversed end to end duplications/deletions/insertions
- e.g. interchromosomal: translocations, insertions
Tumour Suppressor Genes
Suppress cellular growth/survival when needed to prevent tumours forming
Outcomes triggered by tumour suppressor activation:
- arrest cell cycle to inhibit cell division
- induce cell cycle to DNA damage repair mechanisms
- promote apoptosis if damage cannot be repaired
- induce senescence
Two most important tumour suppressor genes; TP53 and RB
- other e.g. APC, BRCA1, BRCA2
Differences Between Oncogenes and Tumour Suppressor Genes
Oncogenes: - dominant gain of function - increase cell proliferation - inhibit apoptosis Tumour Suppressor Genes: - usually recessive nature (TP53 is exception; can be recessive or dominant) - inhibits cell proliferation - promotes apoptosis
DNA Mismatch Repair Genes
The DNA mismatch repair system normally recognises and repairs errors that arise during replication and recombination e.g. insertions of nucleotides.
But what happens if the repair is faulty?
- results in ineffective repair unstable genome
Can cause:
- mutations
- hypermethylation of promoter regions of some of the genes
What are the 6 Biological Capabilities Acquired by Cancer Cells?
- Sustaining growth signalling
- Evading growth suppressors
- Resisting cell death
- Enabling replicative immortality
- Inducing angiogenesis
- Activating invasion and metastasis
Hallmarks of Cancer: Sustaining Growth Signalling
Cancer cells can sustain growth by:
1. Producing their own growth factor molecules e.g. glioblastomas - PDGF
2. Send their own growth signals
- send their own signals to normal cells in ECM around tumour -> react and supply tumour with GF e.g. E-cadherin/catenin complex
- increase in receptor proteins at the cancer cell surface -> hyper responsive to usually limited supply ->
increase in growth signalling e.g. increased HER2/neu receptors in some breast cancers
Outcome: circumvent limited pathway & keep growth signalling switched on
Hallmarks of Cancer: Evading Growth Suppressors
Function of a growth suppressor is to control growth (regulatory pathways/factors)
Many of these are dependent on tumour suppressor genes e.g. RB and TP53
Defects in pathways/genes -> cancer cells able to resist inhibitory signals that would usually stop their growth
Hallmarks of Cancer: Resisting Cell Death
Different pathways regulating/effecting apoptosis (e.g. TP53 mediated/BCL2 regulated)
Opportunities for cancer cells to resist apoptosis through defects in these pathways
BCL2 can:
- anti cell death function (BCL2 hyperphos’d) -> cell lives
- promotes cell death -> cell dies
TP53 can:
- promote cell death
- promote DNA repair
Apotosis acts to control cancer cells but it can be overcome if:
1. Over expression of BCL2 (translocation, controlled by IGH)
2. Mutation/loss of TP53
Hallmarks of Cancer: Enabling Replicative Immortality
Multiply forever!
Normally cells have limited # growth/division cycles
Telomeres involved immortalisation:
- telomeres protect ends of chromosomes
- as cells reach end of lifespan, telomeres shorten -> genome instability/apoptosis
- telomerase, maintains telomere length is almost absent in normal cells but -> increase in 90% immortalised cells, including cancer cells
E.g. Loss of TP53 and RB pathway function and activation of RAS or myc -> increased telomerase -> genomic stability -> multiply forever
Hallmarks of Cancer: Inducing Angiogenesis
Formation of new blood vessels
Balanced by inducers and inhibitors
- e.g. inducers VEGF-A which bind to receptors on endothelial cells and inhibitor TSP-1 regulated by TP53
For cancer cells to grow they need a blood supply
During carcinogenesis an “angiogenic switch” is tripped and remains on, inducers & inhibitors control this switch
- e.g. TP53 loss or mutation can dysregulate TSP-1 and induce angiogenesis as seen in growth of breast and melanoma cancers
Hallmarks of Cancer: Activating Invasion and Metastasis
Activated by changes in molecules needed for cell adhesion:
- cadherins & integrins
E-cadherin assembles epithelial cells sheets & maintain integrity
- mutation or decrease in E-cadherin by some cancer cells -> cells to detach which activates invasion and metastasis
Integrins - mediate cell attachment/integrity & send signals to regulate this
- involved in the motility of cells
- increased expression of integrins have been correlated with metastatic progression in breast, prostate and lung ca.
Genetic alteration in cadherins/integrins or factors that regulate/effect their pathways -> activation of invasion/metastasis
