Lecture 12 - Cancer Flashcards
Cancer
Neoplasia, either malignant (invading adjacent tissue - 2nd tumour generation) or benign (restricted to anatomical site)
Tumours
Monoclonal in origin
Takes years to develop as it progressively increases
Normal epithelium -> hyperplastic epithelium -> dysplastic epithelium -> benign neoplasm > malignant neoplasm -> metastasis
Dysplasia
Abnormal cell growth in tissue to a precancerous degree - may not always become cancerous but has the potential to be
Hyperplasia
Abnormal cell growth in tissue - often used with regard to cancer
Epithelial cancer
Carcinoma - 80% of cancers
Glandular/mucular cancer - adenocarcinoma
Connective tissue/muscle/fat/bone cancers
Sarcoma:
Myosarcoma/liposarcoma/osteosarcoma
Brain/nervous system cancer
Blastoma
Neuroblastoma, glioblastoma, Schwannoma
Blood/bone marrow/lymphoid cancer
Leukaemia, lymphoma
Neural crest/neuroendocrine
Diverse - melanoma is one
Carcinogens and aetiological factors
Agents strongly associated with cancer
Factors that have an extremely strong association with cancer:
watch leccy
Cancer risk factors: what do they do and what are some examples?
Risk factors increase our exposure to aetiological agents and/or otherwise exacerbate disease progression
- Occupation - e.g. asbestos mining and mesothelioma
- Reproductive history - e.g. age of first pregnancy, number of pregnancies and breast cancer
- Diet - e.g. high-fat, red meat, processed food
- Lifestyle - e.g. smoking, drinking, sexual promiscuity, sunbathing
- Family history - cancer susceptibility can show Mendelian inheritance or polygenic inheritance
Ames test
Used to test carcinogenic properties
Used in testing products to determine their mutagenic properties for safety
Mutagenicity and carcinogens are directly correlated
Tumour promoters
Not all agents that induce tumours are mutagens/genotoxic (e.g. asbestos), these substances are called tumour promoters
They stimulate the growth of mutated cells
Promoters can be endogenous or exogenous growth factors, but also toxic compounds that induce compensatory proliferation
Potentially, it is ‘environmental’ exposure to promoters rather than carcinogens (which are often only present at low doses in the environment) which constitutes the commonest avoidable cancer risk
Oncogenes
Act dominantly - one allele enough
Protooncogene
- Amplification
- Translocation
- Missense mutation (gain of function)
- Incorporation into acutely transforming retroviruses
- Insertion of retrovirus/transposon
- ?
Transcriptional activation
SRC, RAS, MYC
Tumour suppressor genes
Act recessively - need both copies mutated for an effect
- Deletion
- Nonsense mutation
- Missense mutation - loss of function (LOF)
- Inactivated by proteins encoded by DNA tumour viruses (?)
- Insertion of retrovirus or transposon
Transcriptional repression, promoter silencing by methylation
p53, RB, APC, PTEN
Abl in leukaemia: what two genes are formed by translocation, what chromosomes are involved in the translocation, what is the end result, what does the protein normally do, what does the carcinogenic form do, and what cancers are produced?
The translocation in CML results in the rearrangement of two genes: Breakpoint Cluster Region (BCR) and the Abelson Leukaemia Virus proto-oncogene (ABL)
Expression of a fusion protein
ABL encodes a non-receptor tyrosine kinase involved in growth and survival signalling
Somehow the fused product is deregulated (signals constitutively) stimulating the proliferation of leukaemia cells
ALL, acute lymphoblastic leukaemia; CML, chronic myeloid leukaemia; CNL, chronic neutrophilic leukaemia
Retinoblastoma: what is it, what are the forms, how is the second hit formed, how is the first hit formed, and what is encompassed in both forms?
Hereditary - passed down from the parents
Sporadic retinoblastoma - random form involving one eye, passed down spontaneously
Familial retinoblastoma - familial form involving both eyes, passed down from parents
Second hits occur through independent mutational events and non-disjunction events - mitotic recombination is perhaps the commonest mechanism for generating a second hit
The former had one hit in a tumour suppressor gene in the germline that was passed down
The latter required that the first and second mutations occur in a somatic cell
It is accompanied by a loss of heterozygosity (LOH) in the affected area - so can be used to visualise LOH and pinpoint TSG location as LOH is frequently detected the closer the physical distance between the marker and affected gene
Driving tumour progression: normal -> hyperplastic epithelia -> early adenomas -> intermediate adenomas -> late adenomas -> carcinoma -> invasion and metastasis
Loss of adenomatous polyposis coli (APC) - tumour suppressor gene
DNA hypomethylation - decrease in the content of 5-methylcytosine in the genome (decrease in tissue-specific transcription control)
Activation of k-Ras - Ras is involved in the regulation of cell growth, division, and differentiation transducing signals from the extracellular environment to the cell nucleus
Loss of 18q TGS - loss of a TSG
Loss of p53 - p53 gene makes a tumour suppressor protein (TP53)
How many mutations from carcinogens are needed to cause cancer?
6-7 mutagenic events roughly
How is genome instability caused?
DNA damage, defective chromosome maintenance and segregation
DNA damage: what causes it, what specific molecules cause it, and what does it cause?
Carcinogens/mutagens
Reactive oxygen species O₂*⁻, H₂O₂, NO, OCl⁻ (oxidative phosphorylation, intracellular metabolism, ionizing radiation, phagocytes)
- Errors during DNA replication
- Defective repair mechanisms
Defective chromosome maintenance and segregation
Defective mitosis
Erosion of telomeres
DNA damage repair pathways
Direct reversal pathway
Mismatch repair pathway
Nucleotide excision repair pathway
Base excision repair pathway
Homologous pathway
Non-homologous end-joining pathway
Direct reversal pathway: what is it, name one big strength, and what mechanisms are there behind it?
Direct repair of the DNA
No DNA synthesis is required to correct the error - error-free
Photolyases, alkyltransferases, and dioxygenase-mediated mechanisms used along with the main two mechanisms - O6-methylguanine-DNA methyltransferase (MGMT) and the alkylated DNA repair protein B (AlkB) homologs
Mismatch repair pathway: the four main steps
Recognition of a mismatch by the MutS homologs (MSHs)
Recruitment of the MutL homologs (MLHs) by ATP-bound MSHs that then connect the mismatch recognition signal to the distant DNA strand scission where excision begins
Excision of the DNA strand containing the wrong nucleotide
Resynthesis of the excision gap by the replicative DNA polymerase using the remaining DNA strand as a template
Nucleotide excision repair pathway
Removal of a damaged nucleotide by dual incisions bracketing the lesion, accomplished by a multisubunit enzyme – excision nuclease or exonuclease
Base excision repair pathway
Corrects small DNA lesions (e.g., those caused by oxidation) - a DNA glycosylase removes the damaged base; short-patch or long-patch repair then fills the gap
Small base lesions are corrected in a way that does not significantly distort the DNA helix structure
Homologous pathway: what is it and when does it occur?
Mechanism in cells to repair double-strand DNA lesions
Occur in DNA before the cell enters mitosis during the S and G2 phases of the cell cycle
Non-homologous end-joining pathway
Highly versatile pathway that utilizes an array of processing enzymes to modify damaged DNA ends and enable their ligation
Aneuploidy
The condition of having an abnormal number of chromosomes in a haploid set
Darwinian evolution theory in cancer progression
Each mutation could potentially help a cancer cell adapt to its environment better to survive, more and more mutations occur until the cancerous cell is dominant in the neoplasm
