Cancer and Genes Flashcards
Carcinogenesis stages
INITIATION- interaction of carcinogen and DNA
PROMOTION- selective growth advantage (free radicals) + early pre-cancer (adenoma) reversible
PROGRESSION- enhanced cell division (additional mutations) + later pre-cancer (late adenoma) reversible
MALIGNANT CONVERSION- cancer, not reversible
What is the first gene lost in colorectal cancer?
APC- adenomatous polyposis coli tumour suppressor gene
What is progression?
Unlimited growth (not self-limited as in benign tumours) - as long as an adequate blood supply is available to prevent hypoxia.
Invasiveness
Migration of tumour cells into the surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs.
Metastasis
Spread of tumour cells from the primary site to form secondary tumours at other sites in the body.
Mechanisms of cell invasion
Increased mechanical pressure caused by rapid cellular proliferation.
Hypoxia and blood supply.
Increased motility of the malignant cells (epithelial to mesenchymal transition- EMT).
Increased production of degradative enzymes by both tumour cells and stromal cells.
What happens to malignant cells to increase their motility?
New transcriptional programme is activated to promote the mesenchymal fate.
Cells become:
Fibroblast like shape and motility
N-cadherin
Invasiveness
Vimentin intermediate filament expression
Mesenchymal gene expression (fibronectin, PDGF receptor, avB6 integrin)
Protease secretion (MMP2, MMP9)
Cells lose:
Epithelial shape and cell polarity
Cytokeratin intermediate filament expression
Epithelial adherent junction protein (E-cadherin)
Hereditary cancer predisposition syndromes
Li-Fraumeni syndrome
Down syndrome
Examples of chemical, physical and viral carcinogens?
Chemical- benzene, alkylating agents (chemotherapy)
Physical- X rays, UV light, alpha particles
Viral- hepatitis B, Human papilloma
Ionising radiation vs non ionising radiation carcinogens and the damage they cause?
Ionising: gamma, X rays, particulate radiaiton
Non ionising: UV light
Cause: DNA breaks, pyrimidine dimers -> failed repair -> translocations and mutations
Tumour suppressors and oncogenes in cell cycle
p53 in charge of maintaining cell checkpoints
Proto oncogenes like Myc, ras involved in cell proliferation
Proto oncogene
normal cellular genes which regulate cell growth and/or division and differentiation.
Oncogene
a proto-oncogene that has been activated by mutation or overexpression. (malignant)
What are the 2 types of conversion from proto-oncogene to oncogene?
- Mutation in the gene results in a different oncoprotein to the normal protein within the cell.
- Oncoproteins are the same as the normal protein but expressed at higher levels. So LOADS of em
Different ways to convert proto-oncogenes to oncogenes
Point Mutation: variant in proto-oncogene (KRAS in lung cancer) or in promoter/regulatory element
Gene Amplification (c-myc in breast cancer)
Chromosomal Translocation: creation of fusion protein (BCR-ABL in CML) or disruption of regulatory elements
What is the bare minimum needed to promote an oncogene?
One pathogenic alteration on one copy of a proto oncogene is enough to cause an oncogene, ie a single copy of oncogene is sufficient to promote tumorigenesis
Why are proto oncogene mutations rarely inherited?
Somatic mutations occurring in non-germline cell types
Features of oncogene HER2
Growth factor receptor
- HER2/neu/ERBB2 gene encodes for part of the human epidermal growth factor receptor 2
Receptor dimerization is required for HER2 function
- Growth factors bind EGFR or HER3 and alter conformation of receptors that become active.
- HER2 protein has intracellular tyrosine kinase activity- can phosphorylate other proteins in signalling cascade
What gene is amplified in 20% invasive breast cancers?
HER2
Associated w aggressive disease and poor prognosis
What monoclonal antibodies therapeutically target HER2?
Trastuzumab and pertuzumab
- Only effective in HER2+ cancers
prevents dimerization of HER2 and 3
What are Ras proteins?
Cellular signal transducers
activated by phosphorylation signal of growth factor receptor like HER2 -> Activation of receptor tyrosine kinases activate the Ras proteins.
How is KRas switched on and off?
GDP (turned off) to GTP bound (on)
Ras gene products are involved in kinase signalling pathways that control the transcription of genes, which then regulate cell growth and differentiation
Point mutations in what gene are observed in 30% of cancers?
Kras
codons 12, 13 (and 18,61,117,146)
Permanent “on” position → permanent cell growth and proliferation
BCR-ABL1 oncogene
ABL resides on ch9
BCR on ch22
Involved in balanced translocation between small fragment of long arm of ch9 and long arm ch22 = Philadelphia chromosome
in 95% cases of chronic myeloid leukaemia
BCR function
ABL function
and joined BCR-ABL oncoprotein function
BCR: encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins
ABL encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition)
=
BCR-ABL protein has constitutive (unregulated) protein tyrosine kinase activity
BCR promoter starts controlling ABL gene = constant activation = lots of TK activity
Unregulated BCR-ABL leads to what?
Unregulated BCR-Abl= tyrosine kinase activity that causes:
- Proliferation of progenitor cells in the absence of growth factors
- Decreased apoptosis
- Decreased adhesion to bone marrow stroma
Abl is the oncogene
What drug specifically inhibits BCR-ABL1?
Imatinib
c-Myc oncogene
Encodes for transcription factors
Pathogenic alterations in c-myc involve gene retrovirus activation, amplifications and translocations.
Translocation between chromosome 8 (c-Myc proto-oncogene) and chromosome 14 (immunoglobulin heavy chain gene) are commonly observed in Burkitt’s lymphoma.
What do drugs for c-Myc oncoproteins do?
Can’t directly target
Inhibitors of its translation and Myc protein destabilizing drugs show great promise
Tumour suppressor genes
TSG encode proteins that maintain the checkpoints and control genome stability. Inhibit replication and proliferation of damaged cells by:
- Repair of DNA damage (e.g. MLH1, BRCA1/2)
- Apoptosis (TP53)
Knudson’s two-hit hypothesis
Most of loss-of-function mutations that occur in tumour suppressor genes are recessive in nature- Generally, one normal allele is sufficient for the cellular control.
A “second hit” affecting the normal allele is needed to disrupt gene’s function.
When do heritable cancers develop?
Heritable cancers develop after additional loss of the normal functional allele (loss of heterozygosity).
Functions of tumour suppressor genes
Oncogenes antagonists
DNA repair (eg BRCA1, 2)
Induce apoptosis (eg p53)
Block proliferation- cell cycle inhibitors, activate TFs, repress TFs
DNA repair genes: BRCA1/2
Knockout of the DNA repair function of one or more DNA repair genes leads to sequential acquisition of more mutations.
Defects in DNA repair genes cause genomic instability and accelerate the activation of oncogenes and the loss of tumour suppressors.
Tumours arising in patients as a result of inherited defects in DNA repair genes tend to have a very high mutational load.
Synthetic lethality
When combination of deficiencies in 2 or more genes leads to cell death
Single strand breaks can be repaired by…
PARP
Double strand breaks can be repaired by…
BRCA1/2
PARP inhibitors
Olaparib
Rucaparib
Niraparib
Talazoparib
for breast cancers BRCA1/2
TP53
TP53 is the gene, p53 is the protein
active when phosphorylated
Detects cellular stress, especially DNA damage
Induces G2 cell cycle arrest
If failure to repair damage induces apoptosis
- Over 50% of cancers contain mutations in the TP53 gene.
- Most commonly affected tumour suppressor gene in human cancer.
- Missense mutations in hotspots (DNA binding domain).
Li-Fraumeni syndrome and TP53
Approximately 70% of families with LFS will have a mutation (alteration) in the TP53
How to restore p53 functions?
Current advances suggest the use of small molecules (MIRA-1, PRIMA-1) that can restore wild-type p53 functions.
RB1 oncogene
‘gatekeeper’ girlboss. encodes Rb protein
Prevents cell growth by inhibiting cell cycle until cell is ready to divide
Phosphorylation = inactivation
Retinoblastoma:
- 90% present before 5 years of age
- Treatment: surgery & radiotherapy
- 98% of cases are cured
2 forms of retinoblastoma
Mendelian/monogenic disease
Disease caused by a single gene, with little or no impact from the environment (e.g. PKD)
Oligogenic/polygenic disease
Diseases or traits caused by the combined effect of:
- a few genes (oligogenic) each having a large effect, or
- many different genes (polygenic) each having only a small individual impact on the final condition (e.g. psoriasis)
Multifactorial disease
(= polygenic + environmental factors)
Diseases or traits resulting from an interaction between multiple genes and often multiple environmental factors (e.g. heart disease)
What chance do two parent carriers have of having a baby inheriting 1) the recessive allele and 2) the actual condition?
50% chance of inheriting a recessive allele from either of the parent.
Two carrier parents have 25% chance of having a child affected by the disorder.
Normal allele is denoted capital R. The mutant allele is denoted small r.
And as I said, in a recessive disease you need to inherit two copies of the mutant allele to be affected.
Imagine two parents who carry one normal allele capital R and one mutant allele small r which is the one that carries the mutation.
These two parents have the genotype of a carrier because they carry a copy of the mutated allele.
But their phenotype is unaffected because they’d need 2 copies for that
Key points of an autosomal recessive pedigree
The condition is always expressed in homozygotes (individuals with two altered copies);
and carried by heterozygotes (individuals who carry one copy).
Males and females are equally affected.
Typically often no family history.
Consanguinity is frequent in autosomal recessive disorders.
Autosomal dominant
one faulty gene copy is enough to cause disease in an autosomal dominant inherited condition
eg achondroplasia- (heterozygous) genetic defect in the FGFR3 gene.
Key points of an autosomal dominant pedigree
An autosomal dominant trait is expressed in heterozygotes.
Usually the homozygotes are lethal.
So an alteration in only one gene is sufficient to cause the disorder.
Males=females
Vertical pedigree
Often adult onset disorders
An affected heterozygote has a 1 in 2 chance of passing the trait on to his or her offspring.
X linked recessive
• In X-linked conditions the faulty gene copy is located on
Chromosome X.
• X-linked recessive traits are expressed in male hemizygotes
and carried by a female heterozygote.
• The son of a female heterozygote has a 1 in 2 chance of being
affected.
• The daughter of a female heterozygote has a 1 in 2 chance of
being a carrier.
• When an affected male has children all his daughters will be
carriers and none of his sons will be affected.
• It is important to remember that X-linked conditions cannot
be passed on from father to son- ffected fathers cannot pass on
the disease to a son, because any
son would get a Y-chromosome
from their father.
Common situation with X linked recessive
- Only males are affected
- The females are carriers
- There is no male to male transmission
Reduced penetrance in an autosomal dominant condition
Family with familial Parkinson’s disease.
And we know this is a autosomal dominantly inherited condition. This affected male here would have received the mutated genecopy from his dad, but the dad is clinically normal, and doesn’t show any symptoms at all.
So this is an example of a pedigree showing a trait with incomplete penetrance.
And that of course can cause confusion when drawing out pedigrees.
How is variable expression shown here?
Using different shadings you can indicate in a pedigree who in the family is affected and how severe. So the lighter shade indicates those in the family that have only minor clinical abnormalities, whereas the black shading indicates the most severe cases.
If you get a genogram that do not have a clear inheritance pattern – think…
Mitochondrial disease
How does inheritance of a germline mutation act as a risk factor for cancer?
Inheritance of a germline mutation acts as a risk factor for cancer by reducing the number of somatic mutations required to cause cancer.
The probability of the a 2nd mutation happening in an already mutated cell is much higher in a person with a germline mutation as all cells carry a mutation, than in a person with a sporadic mutation, because the 2nd mutation needs to happen in exactly that same cell to have an effect on disease risk
Benign vs malignant microscopic features
Colour appearance of tumour cells
Renal cell adenocarcinoma (clear cell carcinoma) : tumour cells
appear clear due to their high glycogen content
Connective tissue types
Mature vs immature teratoma
When is TNM not applicable?
If primary tumour originates in a lymph node
then use another system eg ANN ARBOR STAGING FOR HODGKINS
