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Biology of Cancer > Chromosomes, Cancer and the Cancer Genome > Flashcards

Chromosomes, Cancer and the Cancer Genome Flashcards

1
Q

What is cancer?

A

A disease of the genome

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2
Q

What is the first stage of cancer?

A
  • Genetic and/or genomic alterations
  • Can be a complete gain/loss of chromosomes
  • Can be a mutation of a chromosome (insertion, deletion etc)
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3
Q

What is the second stage of cancer?

A
  • 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
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4
Q

What is the third stage of cancer?

A
  • The change in protein expression results in altered pathways
  • Can be overactivated cell survival
  • Can be loss of apoptotic signals
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5
Q

What is the fourth stage of cancer?

A
  • The change in pathway results in altered biology
  • Can induce limitless replication, tissue invasion, evade immune system etc
  • Expressed as the hallmarks of cancer
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6
Q

Where did cancer genomics come from?

A

Discovered by Theodore Boveri who proposed the origin of a cancerous tumour was a cell which contained scrambled chromosomes

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7
Q

What can be used to analyse cancer genomes?

A

Next-generation sequencing can analysis large quantities

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8
Q

What are different features of cancer genomes?

A
  1. Aneuploidy (change in chromosome no.)
  2. Copy number changes (within chromosomes)
  3. Double minutes (extrachromosomal fragments of DNA)
  4. Chromothripsis (shattering of chromosomes)
  5. Translocation (movement of part of a chromosome to another)
  6. Telomeres (protect chromosomes at ends)
  7. Point mutations (small nucleotide changes)
  8. Epigenetics (regulators of gene expression)
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9
Q

Why study cancer genomes?

A
  1. Increase knowledge of biology of cancer through understanding eg how DNA damage and repair occurs/how cancers metastasise in the body
  2. Clinical application using the information learnt in order to predict patient patterns/produce more therapies
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10
Q

What is chromosomal instability (CIN)?

A
  • 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
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11
Q

What are the 2 types of CIN?

A
  1. Numerical -> complete loss/gain of chromosomes
  2. Structural -> loss/gain of individual parts of chromosomes
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12
Q

What is aneuploidy?

A
  • Change in the normal number of chromosomes (46, 23 pairs)
  • Common in cancer to see these changes
  • Defects in chromosome segregation in cell division
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13
Q

What is copy number alterations?

A
  • 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.
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14
Q

What are double minutes?

A
  • Extrachromosomal circular fragments
  • Replicate in the nucleus
  • Lack centromeres and telomeres
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15
Q

What is chromothripsis?

A
  • Chromosomes shatter and then reassemble in a random order
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16
Q

What is translocation?

A
  • 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
17
Q

What are telomeres?

A
  • 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
18
Q

What does telomerase do?

A
  • 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
19
Q

What is the ALT pathway?

A
  • 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
20
Q

What are point mutations in cancer?

A
  • 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
21
Q

Is cancer a multi stage process?

A

Yes, no single mutation is sufficient enough to cause cancer, the cells accumulate mutations over time until the cancer phenotype (hallmarks) have been achieved

22
Q

What does the cancer genome atlas show?

A
  • 127 genes were significantly mutated across 12 tumour types
  • p53 was the most commonly mutated gene
23
Q

Are all mutations equal?

A
  • Driver mutations -> implicated in carcinogenesis
  • Passenger mutations -> do not contribute to cancer development
24
Q

How can you identify driver mutations?

A

Most mutations are seen in only a few tumours, a small proportion are seen in many tumours - these are driver mutations

25
Q

Which pathways can be affected by mutated genes in order to allow carcinogenesis?

A
  • Cell cycle
  • Genome integrity
  • DNA methylation
  • Splicing
  • RTK/MAPK signalling
26
Q

What are some breast cancer driver genes?

A
  • AKT1
  • CDH1
  • TP53
27
Q

What are 3 types of epigenetic mechanisms?

A
  1. DNA methylation
  2. Histone modifications
  3. ncRNA expression (miRNA, lncRNAs)
28
Q

What do epigenetic mechanisms do?

A

Regulate gene expression through chemical modifications of DNA bases and changes to the chromosomal structure in which DNA is packaged.

29
Q

What is DNA methylation?

A
  • 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.
30
Q

What happens with DNA methylation in cancer?

A
  • Local hypermethylation which results in loss of function of TSGs allowing carcinogenesis
  • Global hypomethylation which leads to chromosomal instability
31
Q

What are histone modifications?

A
  • Control chromatin structure and gene transcription, thereby impacting on various important cellular phenotypes
  • Do this via chromatin compaction
32
Q

What happens with histone modifications in cancer?

A
  • Global changes across the genome
  • Genes which encode the enzymes can mutate to allow carcinogenesis

Biology of Cancer (19 decks)

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