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Case 12: Human Genetics (Genomics, Genetics and Cancer) - Coggle Diagram
Case 12: Human Genetics (Genomics, Genetics and Cancer)
Cancer as a Genetic DisorderDefine Cancer as a Genetic Disorder
- Cancer is a genetic disorder arising from the progressive accumulation of mutations that promote the clonal selection of cells with increasingly deregulated growth
- Most of these alterations are somatically acquired, but some cases are inherited
- Cancer cannot be inherited, only the predisposing factors of cancer can be inherited
Cancer PhenotypeDefine the Cancer Phenotype
- Phenotype refers to the observable physical properties of an organism
- Phenotype is the effect of a genotype
- Genotype is the genetic make-up of an organism
- Cancer Phenotype is a result of complex interactions involving not only the cancer gene products but also other proteins and environmental factors
Somatic Cells and Germ CellsDefine the terms Somatic Cells and Germ Cells
- Somatic cell is any cell in the body except the sperm and egg cell. Somatic cells occur after fertilisation, in the early embryological development
- Somatic Cells are diploid cells which means they contain two sets of chromosomes, one inherited from each parent.
- Mutations in the Somatic Cells can affect the individual but they are not passed down to the offspring.
- Germ Cell is any biological cell that gives rise to gametes of an organism that reproduces sexually
Somatic Mutations and Germline MutationsDifferentiate between Somatic Mutations and Germline Mutations
- Somatic Mutations occur only in a single cell of the body (except for the sperm and egg cell) and cannot be inherited.
- In the case of Somatic Mutation, ONLY tissues derived from the mutated cell are affected.
- Germline Mutations occur in the Gametes and can be passed on to the offspring.
- In the case of Germline Mutation, every cell in the entire organism will be affected
The Cell CycleDefine the Cell Cycle
- Cell Cycle is a series of events that result in cell division.
- G0: Resting
- G1: Growth
- S: DNA Synthesis
- G2: Growth
- M: Mitosis
- The Cell Cycle is divided into 2 Major Phases:
- Interphase (G0, G1, S and G2)
- The cell growth and makes another copy of DNA through DNA Replication
- Mitotic Phase (M)
- The cells separates its DNA into 2 sets and divides its Cytoplasm.
Describe the regulation of cell cycle processes by CDK-cyclin Complexes
- Cyclin and Cyclin-dependent Kinases (CDK) drive the cell cycle
- If an individual has a low amount of CDK/CDK-cyclin complexes the cell will not progress through the cell cycle
- G2 is regulated by the Cyclin A2
- Mitosis is regulated by the Cyclin B1 and B2
- G0, and G1 is regulated by the Cyclin D2
- S is regulated by the Cyclin A2, Cyclin E1 and E2
10 Molecular Hallmarks of CancerList the 10 Molecular Hallmarks of Cancer
- Sustaining proliferative programming
- Evading Growth Suppressors
- Resisting Cell Death
- Enabling replicative immortality
- Inducing angiogenesis
- Activating invasion and metastasis
- Genome instability and Mutation
- Tumour-Promoting Inflammation
- Reprogramming Energy Metabolism
- Evading Immune Destruction
Proto-Oncogenes and Tumour Suppressor GenesOutline the Proto-Oncogenes and Tumour Suppressor Genes
- Proto-Oncogenes are genes that encode for proteins that promote cells division and normal cell growth
- Through mutations, Proto-Oncogenes can be altered and activated to form Oncogenes
- Tumour Suppressor Genes are genes that encode for proteins that halt cell division to prevent cancerous growth
- NOTE: A balance between Proto-Oncogenes and Tumour Suppressor Genes needs to be established to maintain normal physiology and appropriate growth
- A disturbance in balance can allow for an Altered Phenotype
- If Proto-oncogenes are activated
- Tumour Suppressor Genes are inactivated
- Proto-Oncogenes will act dominantly and Gain Function
- Tumour Suppressor Genes will act recessively and Loss Function
- This results in Neoplasia, Uncontrolled Cell Division and Growth leading to Cancer
Tumour Suppressor GeneOutline the process of Inactivation of the Tumour Suppressor Genes
- Tumour Suppressor Genes occur in each allele
- Therefore, in each alleles the inactivation of the Tumour Suppressor Gene may result from either:
- "Loss of function" mutation of the Gene
- "Epigenetic silencing" of the Gene Promoter through the Methylation of Gene Promoter
- Methylation of the Gene Promoter prevents the binding of the Transcription Factor and thus prevents switching on of the Gene Transcription
EpigeneticsDefine Epigenetics
- Epigenetics is when the function or the ability of a DNA to transcribe is altered by other Factors such as Methylation
- Methylation blocks the transcription factor from reading the DNA sequence
Relative Risk of Cancer per affected First Degree Relative (FDR)Describe the concept of the Relative Risk of Cancer per affected First Degree Relative (FDR)
- Family History is an important starting point for understanding how the Genetic Background can influence Cancer
- Family History should involve: Parents, Siblings, Children, and Grandparents
- Relative Risk of Cancer means that if a First Degree Relative has a certain type of cancer the chances of you getting the same cancer increases, due to the Inherited Predisposition of that Cancer
- Therefore, the greater the presence of a certain subtype of Cancer in a family, the greater the likelihood of the patient developing the Cancer
- For example: Breast, Colorectal, Prostate Cancer and much less for Cervical Cancer
- This is because Cervical cancer is driven by an Environmental Factors such as HPV 16 and 18
- Therefore, the risk of developing Cervical Cancer are not higher if your sister has it.
Genetic Basis of Inherited Forms of CancersOutline the Genetic Basis of Inherited Forms of Cancers
- Cancer is not inherited ONY the Genetic Variants which increase the likelihood of cancer are inherited
- We have two copies of Genes, one from each parent
- Therefore, it is important to understand if the Gene influencing the predisposition to a Cancer has a Variant in one or both copies
- This is because the effect induced by the number of Genetic Variants present is different between the Proto-Oncogenes and Tumour Suppressor Genes
- Germline activation of Proto-Oncogenes has a stronger signal for deregulated growth compared to the Inactivation of One Copy of a Tumour Suppressor Gene
Examples of the Genetic Basis of Inherited Forms of CancerOutline the examples of the Genetic Basis of Inherited Forms of Cancer
- Germline Activation of the Proto-Oncogenes has a High Penetrance
- This means that all the cells in the body have a mutation in the Proto-Oncogenes which activates cell division and cell growth
- As a result, there is an increased chance of the Genetic variant penetrating and developing the cancer
- Individuals with germline activation of proto-oncogenes are most likely to develop a cancer at a younger
- Germline Inactivation of One Copy of a Tumour Suppressor Gene has Incomplete Penetrance
- This is because according to Knudson's 2 Hit Hypothesis in order for a cell to be cancerous, both of the cell's Tumour Suppressor Genes need to be mutated
- Therefore, there needs to be a Somatic Mutation or Epigenetic Change in the Second Copy of the Tumour Suppressor Gene
- This will result in Complete Penetrance and development of the Cancer
- Individuals with germline inactivation of one copy of tumour suppressor gene and need a Somatic mutation most likely develop cancer at a later stage or do not develop cancer
- Bi-allelic Germline Inactivation of Tumour Suppressor Genes has Complete Penetrance
- An individual with Bi-allelic Germline Inactivation of Tumour Suppressor Genes is most likely to develop cancer at a younger age
- This is compared to an individual with Germline Inactivation of one copy of the Tumour Suppressor Gene
Effects of Complete PenetranceList the Effects of Complete Penetrance
- Alteration of the Cell Cycle, Apoptosis, DNA Repair and Chromosome Segregation
- This results in Genomic instability and Tumour development
- Multiple Endocrine Neoplasia Type 2
- Family has generation to generation transmission
- Transmission is not gender dependent, indicating Autosomal Dominance
- There is early onset of cancer
- Therefore, this typical of the Germline Activation of a Proto-oncogene
- Multiple Endocrine Neoplasia Type 2 is due to a mutation in the Ret proto-oncogene
- Mutation of "gain of function" proto-oncogene accelerate cell division
- Retinoblastoma
- Dominant transmission from generation to generation
- Transmission is not gender dependent indicating Autosomal Inheritance
- Part of the Gene is deleted indicating "loss of function" Tumour Suppressor Gene
- Retinoblastoma is due to RB1 Tumour Suppressor
Autosomal Dominance and Tumour Suppressor GenesOutline Autosomal Dominance(AD) Inheritance and Tumour Suppressor Genes
- Tumour Suppressor Genetic Disorders are inherited in an Autosomal Dominant way
- Autosomal Dominant (AD) Inheritance is the Inheritance of a mutation in one allele
- In the case of AD Inheritance there is a 50% risk of passing on the 'Predisposing' Variant
- For example, an offspring will inherit a normal Allele from one parent and Allele with a mutated Tumour Suppressor Gene from the other Parent
- Tumour Suppressor Genes are recessive genes
- Therefore, according to Knudson's 2 Hit Hypothesis the mutation of both copies is required for cancerous growth
- 2nd Hit is a somatic change in the normal allele, resulting in two alleles with mutated Tumour Suppressor Genes
- NOTE: In Tumour Suppressor Genes only at cell level where the 2nd mutation is required to produce a malignancy
BRCA 1/2 GenesOutline the relationship between the BRCA1/2 Genes
- BRCA1/2 Genes are Breast Cancer and Ovarian Cancer related genes
- Mutations in the Breast Cancer (BRCA) 1/2 Genes are an example of Autosomal Dominant Tumour Suppressor Inheritance
- BRCA1/2 are involved in the Fanconi Protein complex/pathway to promote homologous recombination repair of double stranded DNA breaks
Multifactorial (Sporadic) Cancer vs Inherited CancersDifferentiate between Sporadic (Multifactorial) Cancers and Inherited Cancers
- Sporadic Cancers imply a steady series of acquired changes on a lower background genetic risk
- As the cause is multifactorial, environmental risk factors are more important
- In Sporadic Cancers there is typically no strong family history and the cancer has a more usual age of onset (often in older people)
- For example: ALL Cervical Cancers, and MOST Breast, Ovarian, Colon, & Lung Cancers
- Inherited Cancers means that a strong predisposition, a gene associated with an increased risk of cancer, has been inherited
- Typically, Inherited Cancers are transmitted in Autosomal Dominant manner and show up in multiple generations
- For example: SOME BRCA Gene related Breast Cancers, Ovarian Cancer & Colon Cancers such as Hereditary Non-Polyposis Colon Cancer and Familial Adenomatous Polyposis
- It is NB to identify "inherited" cancers as the implications affect both the individual and other family members
Epigenetics and CancerOutline the relationship between Epigenetics and Cancer
- Major contributors of cancer are epigenetic changes
- Activation of Oncogenes
- Inactivation of Tumour Suppressor genes
- DNA methylation
- Epigenetic changes are changes that influence the expression of the DNA, that in turn encodes for proteins important in cell cycle control and regulation
- List the 10 Hallmarks of Cancer
Aberrations in Epigenetics Control seen in CancerList the Aberrations in Epigenetics Control seen in Cancer
- DNA Methylation
- Histone modifications and Histone variants
- Nuclear architecture
- Non-coding RNAs
- DNA methylation
Outline the characteristics of DNA Methylation as an abnormality of Epigenetic Control of Cancer
- DNA Methylation involves preventing the binding of the Transcription factor which in turns prevents the switching on of Gene Transcription
- DNA Methylation is mitotically inheritable
- Epimutations are rapidly selected and are reversible
- DNA Methylation can also be used as a Biomarker:
- To inform prognosis
- To inform treatment
- Histone Modifications and Histone variants
Outline the characteristics of Histone Modifications and Histone variants as an abnormality of Epigenetic Control of Cancer
- Histone Modifications and Histone variants results in:
- Global alterations
- Increased Genomic instability involved in chromosome structure
- Increased mutations rate in regions of Heterochromatin
- Nuclear Architecture
Outline the characteristics of Nuclear Architecture as an abnormality of Epigenetic Control of Cancer
- Long-range Epigenetic Silencing (LRES) or Long-range Epigenetic Activation (LREA)
- Non-coding RNAs
Outline the characteristics of Non-coding RNAs as an abnormality of Epigenetic Control of Cancer
- ALL types of Non-Coding RNAs can show dysregulation
Clinical Implications of Aberrant (Abnormal) Epigenetic ControlDescribe the Clinical Implications of Aberrant (Abnormal) Epigenetic Control
- Environment may alter the Epigenotype and promote Tumorigenesis
- And Tumorigenesis may alter the Epigenotype
- Therefore, Epigenotype can used in various ways:
- Diagnosis
- Epigenetic alterations can be used as Biomarkers
- Prognosis
- Specific Epigenetic alterations are associated with Outcome
- Therapy
- Small molecule inhibitors of the Epigenetic Machinery can be used in Epigenetic Therapy
Somatic Nature of CancerOutline the use of the Somatic Nature of Cancer
- Somatic Nature of Cancer refers to the interpretation of cancer at a molecular level, the DNA/RNA of the Cancer
- RNA represents the first step of expression
- Somatic Nature of Cancer is used for:
- Diagnosis
- Prognosis and Treatment stratification
- Biomarkers for monitoring
- Biomarkers for early detection
- Understanding the mechanisms and pathways in which different proteins interact
Ethical ConcernsList the Ethical Concerns of Genetic Predisposition DNA Testing
- Informed Consent
- Patient autonomy
- Confidentiality
- Emotional distress
- Misinformation
- Discrimination