Cancer Genetics, Epigenetics, Trx of Genetic Diseases, Multifactorial Genetics Flashcards
Cancer can result from?
Somatic mutations: lead to increased proliferation in somatic cells (due to gene mutations, translocations/deletions, genomic imprinting, and gene amplification)
Microsatellite instability shows DNA repair mutations
Genomic imprinting
Methylation causes condensation of chromatin leading to it not being expressed. Parent of origin difference in gene expression.
Clonal expansion
Uncontrolled division of defective cells leading to tumor formation.
Three classes of cancer genes
(1) Tumor suppressor genes (2) Oncogenes (3) Mutator genes
Tumor suppressor genes
- Do?
- Dominant or recessive oncogenes? Why? Inheritance has what pedigree?
- Examples?
- Tumor suppressor genes inhibit cell proliferation, repair DNA, make sure DNA damage checkpoints are passed.
- Are considered recessive oncogenes because two copies of the gene need to be mutated in order to become tumorigenic. Autosomal dominant.
- Retinoblastoma, p53 (leads to Li-Fraumeni syndrome), BRCA1/BRCA2
Two-Hit Hypothesis
In relation to tumor suppressor genes.
First hit mutation is inherited making individual more susceptible to cancer because now only one copy of the gene needs to be knocked out for cancer to result. Leads to loss of heterozygosity.
Oncogenes
- Do?
- Dominant or recessive oncogenes? Why? Originate from? Inheritance is?
- Activate proliferation by leading to deregulation of cell cycle control.
- Dominant – only need one gain of function mutation for cell to be tumorigenic. Originate from proto-oncogenes – genes involved in basic regulation of normal cell growth. Mutation in proto-oncogene turns it into oncogene. Inheritance is autosomal dominant.
Mutator genes
- Mutations in genes involved with DNA repair and accurate replication. They are autosomal recessive inactivating mutations leading to complete loss of function of protein (no DNA repair enzymes). It is mutation to its ability to repair DNA that leads to cancer.
Tumorigenic cell growth
Normally, proto-oncogenes signal cell to grow and tumor suppressor inhibit cell growth and proliferation. In cancer, mutated/gain of fn oncogenes cause cell overproliferation and tumor suppressors are mutated/lose function, leading to nothing preventing cells from overproliferating.
Loss of heterozygosity (LOH)
Cancers from mutation to tumor suppressors often result from LOH, in which one mutation is inherited (initial genotype Aa) and other mutation undergoes somatic lesioning of other allele mutates other allele (final genotype aa)
Gene amplifcation
Increase of copy number in gene often involved in oncogene-driven cancers
Fusion proteins
Fused protein product due to translocation. Can drive cancer. Often implicated in leukemia/lymphoma.
Philadelphia chromosome leads to BCR-ABL fusion protein leading to chronic myelogenous leukemia. Gleevec inhibitor of BCR-Abl.
Epigenetic changes
- Are
- Common types?
- Heritable changes in gene expression not coded in DNA itself.
- (1) Histone modifications (2) DNA methylation
Histone modifications
Regulate the degree to which DNA is bound to histones
(1) Acetylation: histone acetyl transferases increase DNA expression. Histone deacetylase complexes deactivate DNA
(2) Methylation: increases expression at Lys 4 and decreases at Lys 9
(3) Phosphorylation and ubiquitylation
DNA methylation
Methylation of C5 of cytosine/guanine pairs (CpG) in DNA silences it.
CpG islands
Located in the promoter. Targets for proteins that bind to unmethylated CpGs and initiate gene trx. Methylation of DNA normally used to diferentiate unmethylated daughter strand from methylated parent strand after DNA replication
Genomic imprinting
Occurs when one chromosome (or section of chromosome) is turned off based on parent of origin. Because parent of origin is important for expression for some genes, genomic imprinting can lead to gene not being expressed.
Uniparental disomy
Occurs when both copies of a chromosome are inherited from one parent. All genes present, but not all expressed.
Prader-Willi syndrome
Angelman syndrome
PW: can be due to deletions in paternal chromosome or uniparental disomy of maternal chromosome.
Angelman: can be due to deletions in maternal or uniparental disomy of paternal. Familial inheritance is abnormal – mutations in paternal chromosome don’t matter because gene is silenced, but when mother passes gene to son, imprinting is removed leading to 50% chance of it passing to kids.
ncRNAs
Non-coding RNAs. Genome produces thousands of them - do not code for protein. Expressed in a tissue-specific manner. There are both large and small ncRNAs.
miRNAs
micro RNAs. Classic example of small ncRNA. Bind mRNA transcripts and prevent translation or faciliate their degradation.
Large ncRNAs
Trx by RNA pol II. Play a role in regulation of gene expression, X inactivation, nuclear organization, chromatin state.
Genetic traits fall on a spectrum with regards to _______.
Models of complex traits (3)
The number of loci that cause them.
(1) Major gene: single locus has major influence on risk
(2) Oligogenic: few loci account for most of risk
(3) Polygenic: many loci influence risk, each with small effects
Continuous traits
- examples
Anthropometric (height, weight etc.)
Pigmentation
Behavioral traits
