Chromosomes, Cancer and the Cancer Genome Flashcards
What is cancer?
A disease of the genome
What is the first stage of cancer?
- Genetic and/or genomic alterations
- Can be a complete gain/loss of chromosomes
- Can be a mutation of a chromosome (insertion, deletion etc)
What is the second stage of cancer?
- The change in the genome results in altered protein expression
- Can increase/decrease the expression of the protein
- Can produce an entirely different mutant protein
What is the third stage of cancer?
- The change in protein expression results in altered pathways
- Can be overactivated cell survival
- Can be loss of apoptotic signals
What is the fourth stage of cancer?
- The change in pathway results in altered biology
- Can induce limitless replication, tissue invasion, evade immune system etc
- Expressed as the hallmarks of cancer
Where did cancer genomics come from?
Discovered by Theodore Boveri who proposed the origin of a cancerous tumour was a cell which contained scrambled chromosomes
What can be used to analyse cancer genomes?
Next-generation sequencing can analysis large quantities
What are different features of cancer genomes?
- Aneuploidy (change in chromosome no.)
- Copy number changes (within chromosomes)
- Double minutes (extrachromosomal fragments of DNA)
- Chromothripsis (shattering of chromosomes)
- Translocation (movement of part of a chromosome to another)
- Telomeres (protect chromosomes at ends)
- Point mutations (small nucleotide changes)
- Epigenetics (regulators of gene expression)
Why study cancer genomes?
- Increase knowledge of biology of cancer through understanding eg how DNA damage and repair occurs/how cancers metastasise in the body
- Clinical application using the information learnt in order to predict patient patterns/produce more therapies
What is chromosomal instability (CIN)?
- Loss, gain or rearrangement of chromosomes
- Prognostic hallmark of solid/haematological cancers
- May cause/effect carcinogenesis
- May arise through errors in chromosome duplication and/or segregation
What are the 2 types of CIN?
- Numerical -> complete loss/gain of chromosomes
- Structural -> loss/gain of individual parts of chromosomes
What is aneuploidy?
- Change in the normal number of chromosomes (46, 23 pairs)
- Common in cancer to see these changes
- Defects in chromosome segregation in cell division
What is copy number alterations?
- Sections of the genome are repeated
- The number of repeats in the genome varies between individuals
- It is a type of structural variation (duplication or deletion) that affects a considerable number of base pairs.
What are double minutes?
- Extrachromosomal circular fragments
- Replicate in the nucleus
- Lack centromeres and telomeres
What is chromothripsis?
- Chromosomes shatter and then reassemble in a random order
What is translocation?
- Balanced -> parts of two different chromosomes detach from their own chromosome and attach to the other, eg Philadelphia chromosome
- Unbalanced -> a part of a chromosome detaches from its own chromosome and attaches to another but its own chromosome remains missing a part
What are telomeres?
- Repetitive sequences at chromosome ends
- Protect against chromosome fusion
- Causes the end replication problem where after each cell division, the telomeres shorten because of the incomplete replication of the linear DNA molecules by the conventional DNA polymerases
What does telomerase do?
- A ribonucleoprotein
- Maintains telomeres in order to enable cell survival
- Active in stem cells but inactive in somatic cells
- Active in approx 90% of cancer
What is the ALT pathway?
- Alternative lengthening of telomeres
- Found in approx 10% of cancers
- Preponderance in certain cancer types eg bone
- Poor prognosis through chromosome instability
- Mediated by homologous recombination
What are point mutations in cancer?
- Insertions/deletions (frame shift) or substitutions
- There are many agents that can cause this
- Cancer cells have a high mutation burden compared to normal cells
- Somatic vs germline mutations
Is cancer a multi stage process?
Yes, no single mutation is sufficient enough to cause cancer, the cells accumulate mutations over time until the cancer phenotype (hallmarks) have been achieved
What does the cancer genome atlas show?
- 127 genes were significantly mutated across 12 tumour types
- p53 was the most commonly mutated gene
Are all mutations equal?
- Driver mutations -> implicated in carcinogenesis
- Passenger mutations -> do not contribute to cancer development
How can you identify driver mutations?
Most mutations are seen in only a few tumours, a small proportion are seen in many tumours - these are driver mutations
Which pathways can be affected by mutated genes in order to allow carcinogenesis?
- Cell cycle
- Genome integrity
- DNA methylation
- Splicing
- RTK/MAPK signalling
What are some breast cancer driver genes?
- AKT1
- CDH1
- TP53
What are 3 types of epigenetic mechanisms?
- DNA methylation
- Histone modifications
- ncRNA expression (miRNA, lncRNAs)
What do epigenetic mechanisms do?
Regulate gene expression through chemical modifications of DNA bases and changes to the chromosomal structure in which DNA is packaged.
What is DNA methylation?
- A biological process by which methyl groups are added to the DNA molecule
- Methylation can change the activity of a DNA segment without changing the sequence
- When located in a gene promoter, DNA methylation typically acts to block gene transcription.
What happens with DNA methylation in cancer?
- Local hypermethylation which results in loss of function of TSGs allowing carcinogenesis
- Global hypomethylation which leads to chromosomal instability
What are histone modifications?
- Control chromatin structure and gene transcription, thereby impacting on various important cellular phenotypes
- Do this via chromatin compaction
What happens with histone modifications in cancer?
- Global changes across the genome
- Genes which encode the enzymes can mutate to allow carcinogenesis
