ECON 546 Lecture Notes - Lecture 18: Apoptosis, Neurofibromatosis, Metastasis
27 Jun 2018
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BIOL 568 – Gottlieb L18: 20/3/18
L18: Genetics of Cancer Ontogeny – Traditional Genetic Theories & Hypotheses
o2000 years ago – saw growths. Removal greater survival
oDescription of cancer cells = neoplasia
oPresent day theories of cancer ontology – most genetically based
oWhy has all the cancer ‘success’ not led to the big ‘breakthrough’?
oWhy does our understanding of cancer genetics not seem to explain the ontology of many
forms of cancer?
oHow can non-mutagenic agents have such a profound effect on cancer occurrence if it is
based on gene variance? E.g. diet, lifestyle – exercise, weight
oNGS and its effect on our understanding of cancer ontology and genetics in general – the so-
called “New Genetics”.
Ontogeny – what causes a cell to be cancerous? Noone knows! Risk factors etc. but not the
physiological processes
Cancer Ontogeny – Carcinogenesis
oNeoplasia = physical cellular structures; growths
oHypotheses of the Origin of Neoplasia
oAgents causing neoplasia: chemical, radiation, viral, nutritional, hormonal, genetic
oncogenesis.
Origin of Neoplasia
Neoplasia: an abnormality of cell growth and multiplication characterised by:
1. At cellular level
a. Excessive cellular proliferation
b. Uncoordinated growth – don’t look like the tissue that they are part of
c. ‘Tissue infiltration’ – caution, could just be a cell with a new property
2. At molecular level
a. Disorder of growth regulatory genes
b. Develops in a multistep fashion – start with small cancer growth, then spreads
oNeoplasia – Latin ‘new growth’
oCancer – ‘crab’
Cancer Ontogeny
Popular genetic hypotheses for the origin of cancer (decreasing):
1. Oncogenes and Tumor Suppressor Genes – mutations can be loss and gain of function.
1
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BIOL 568 – Gottlieb L18: 20/3/18
2. Viral Oncogene Hypothesis – genes that cause cell to be cancerous. Viruses may be stimuli?
3. Epigenetic Hypothesis – post-genomic events, must be acting with other factors
4. Failure of Immune Surveillance – body does not recognise the cancer cell
5. Telomere and Telomerase Hypothesis
6. Failure of DNA Repair Mechanisms Hypothesis
Hypotheses of the Origin of Neoplasia
Two types of origin:
1. Monoclonal – initial neoplastic change affects a single cell
Definitely not.
2. Field origin (polyclonal, multiple discrete, or multifocal) – carcinogen acts on large number of
cells producing field of potentially neoplastic cells
Came back into favour
Hypothesis of the Genetic Origin of Neoplasia
Classic Theory – multiple genetic ‘hits’ (mutations) and multiple environmental factors:
oKnudson (1970) proposed that carcinogenesis requires two hits:
1st event – initiation. Carcinogen = initiator
2nd event – promotion. Agent = promoter
oMultiple hits occur – 5 or more
Each hit produces a change in the genome which is transmitted to its progeny (i.e. clone)
oLag period
Time between exposure (first hit) and development of clinically apparent cancer
Altered cell shows no abnormality during lag period
1. Oncogenes and Tumour Suppressor Genes
oTwo categories of cell regulatory genes:
a) Proto-oncogenes
b) Tumour suppressor gene
oProto-onocogenes code for:
Growth factors
Receptors
Signal-relay of transduction factors
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BIOL 568 – Gottlieb L18: 20/3/18
oTumour suppressor genes code for factors that down-regulate the cell cycle:
P53
Rb
Gene Activation and Inactivation:
oProto-oncogene is activated OR tumour suppressor gene is inactivated
oNormal growth regulation is diverted into oncogenesis
oActivated proto-oncogene = activated oncogene, mutant oncogene, cellular oncogene
oProblem: different mutations in the same gene (i.e. p53) can change its properties from
tumour suppressor to proto-oncogene
oSignificant factor is that cancerous cell gains properties – characteristics that are completely
different from the original cell. As opposed to losing properties of the original cell.
How to Proto-Oncogenes get activated:
oPoint mutations
oTranslocations
oGene Amplification
Production of Neoplastic cells:
1. Increased in growth factor
2. Increased in growth factor receptors
3. Increased in signal transduction
4. Increased in activation of transcription
Relationship between Gene products of proto-oncogenes and oncogenesis:
oGrowth factors, growth factor receptors
oSignal transducing factors
oCell cycle proteins
oDNA binding proteins concerned w transcription
These qualities do not necessarily make the cell cancerous.
2. Viral Oncogene Hypothesis – viral infection promotes cancer
RNA Retrovirus – produces DNA provirus:
oDNA provirus containing viral oncogene (v-onc) is introduced OR
oDNA provirus without v-onc is inserted adjacent to v-onc in host cell DNA
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