Lecture 28- Genes and Cancer Flashcards
Cancer
Uncontrolled proliferation of cells/
Cancers are caused by mutations in cancer causing genes (genes which function is around cell growth and death). Environmental factors (UV, smoking) can cause damage to DNA > mutation.
These mutations may be acquired/somatic
or inherited (less common)
or both (2 hit concept).
Genes involved in cancer
Oncogenes: promote cell growth/proliferation (activated)
Tumor Suppressor genes: Recessively acting, involved blocking cell growth and proliferation
Apoptosis: normal cell death (blocks) so there’s a slow accumulation of apoptotitc cells.
Oncogenes
Dominant acting genes- transform cells. Give them a proliferative growth advantage (gain of function).
Normal state= proto-oncogene
which is activated to an oncogene via mutation.
Activated oncogenes will cause normal cells to become neoplastic cells. It does this by increased cell proliferation and blocking normal cell differentiation
Proto-oncogenes.
Critical in normal cell growth. Activation (to oncogene) may result in uncontrolled cell proliferation.
- Growth Factors
- Growth factor receptors
- Signal Transmission pathway
- Transcription factors
Activation of oncogenes
1) Gene amplification (increased copy numbers of the gene)
2) Over-expression of the gene at an inappropriate time (somy amount copies but over-expressed)
3) Point mutations of the gene (RAS point mutation > constant activation)
4) gene rearrangment or translocation
5) epigenetic mechanisms
Gene Amplification
Increased # leading to increased expression and over activity of the gene
HER-2 gene: encodes Epidermal growth factor in mammary cells
red= HER-2 many dots
green= ch 12 centromere, 2 dots (control)
HER-2 is over-expressed in 30% of breast cancer patients.
Target of herceptin (AB)
( also N-myc oncogene amplification in neuroblastoma)
Gene-rearrangment and translocation
structural changes in chromosomes
1) bring two genes together (5prime to 3 prime)
Fusion gene > fusion mRNA > fusion protein with increased activity
eg) CML
2) move a oncogene adjacent to an actively trancribed gene or promotor region, leading to increased expression.
eg) the immunoglobulin gene in B cell cancers
eg) Burkitts Lymphoma: Myc translocation where myc gene on Ch8 is taken next to Ch 14s immunoglobulin genes promotor > Myc oncogene
Tumor Suppresor Genes
Reccesive acting or ‘anti-oncogenes’
Loss of both alleles required for los of activity.
“brakes” for normal cell growth. A loss of activity leads to increased cell proliferation
Somatic Cancer:
Wild Type TSGs > 1st Hit: muation in one copy > 2nd Hit: deletion in other copies
Familial Cancer:
1st hit: germline mutation > 2nd Hit: A deletion in the other copy
This is shown in retinoblasatoma
Somatic (late-onset, only one)
Familial (early-onset, two tumors)
Apoptotic activation
Doesn’t give proliferative advantage, accumulation of abnormal cells, leading to a slow growth of malignant cells > tumor
- loss of expression of genes that mediate apoptosis
- upregulation of genes that block apoptosis
REMEMBER
Cancer is a MULTISTEP process. Often involves a series of mutations and a variety of genes before the full cancer phenotype develops.
Clinical Relevance
PERSONALISED medicine based on cancer genomics.
- molecular diagnosis and classification of tumors
- prognostic markers
- targets for therapy
- Markers to monitor response to therapy
- biomarkers eg) free cell DNA
Chronic Myloid Leukaemia (CML)
Due to a proliferation of myeloid cells in the bone marrow.
- High WBC count
- Splenomegaly
- Spresence of Philadelphia chromosome in the bone marrow (1st to be noted with cancer!!)
Philadelphia Chromosome is a acquired t(9;22) Translocation to form a fusion gene BCR-ABL > fusion mRNA > Fusion protein which is a potent tyrosine kinase. TK activates signalling pathways
Allows for Diagnostic criteria
- Target for therapy
- montering/biomarker to look at therapy response
Survival rate went from 4-5yr to a chronic condition with the introduction of ‘Imatinab’
