Chromosomes, Cancer and the Cancer Genome Flashcards
What are the features in cancer genome
- aneuploidy
- copy number changes
- double minutes
- chromothripsis
- translocation
- telomeres
- point mutations
- epigenetics
CIN
- loss, gain or rearrangements of chromosomes
- prognostic hallmark of solid and haematological cancers
- cause or effect of carcinogenesis
- thought to arise through errors in chromosome duplication and or segregation
What are the two types of CIN
- Numerical - gain or loss of whole chromosomes
- structural - gain or loss of individual chromosomal regions
What is aneuploidy
- deviation from normal number of chromosomes
- common in cancer
- defects in chromosome segregation in cell division
What are copy number alterations
- regions within chromosomes which are lost
What does double minutes mean?
- extrachromosomal circular fragments
- replicate in the nucleus
- lack centromere and telomeres
- not rare - found in 50%
What is chromothripsis?
- mechanism which gives rise to double minutes
- chromosome shattering and random reassembly
- loss of key regions
Describe translocations
- one chromosomal region is moved from one region to another chromosome
- two forms : balanced or imbalanced
What are fusion genes?
- hybrid genes, formed from two separate genes
- sometimes lead to functional proteins with oncogenic properties
- eg. BCR-ABL and the philadelphia chromosome
Describe Gleevec/Imatinib
- introduced in the 1990s
- 5 year CML survival before gleevec = 30%
- 5 year survival with gleevec = 89%
- can only be used in Ph+ cancers
Describe inversions with an example
- EML4-ALK fusion gene
- EML4 and ALK inverted
- can give rise to solid tumour
What drug targets ALK?
- crizotinib
- approved after phase 1 trial
- 82 patients, ALK rearranged lung cancer
response rate : 57% (expt. 10%)
Describe telomeres
- repetitive sequences at chromosome ends
- protect chromosome against fusion
What is the end replication problem?
- telomeres role to fix
- during each cell division, small part of chromosome at the ends are lost
- when telomere becomes too short, (critical point) cell recognises and induced apoptosis
What is telomerase?
- ribonucleoprotein : protein - reverse transcriptase (TERT), RNA template (TERC)
- maintain telomeres, enables cell survival
- active in stem cells, inactive in somatic cells
- active in 90% of cancers
- cancer cells escape the apoptotic signal which usually kicks in after certain number of cell divisions
What is the ALT pathway?
- alternative lengthening of telomeres
- found in 10% cancers
- preponderance in certain cancer types eg. bone
- poor prognosis through CIN
- mediated by homologous recombination
What are point mutations?
- mutations which impact single nucleotides
- insertions and deletions (frame shift), substitutions (silent, missense, nonsense)
Are all mutations equal?
- no
- driver mutations : causally implicated in cancer
passenger : does not contribute to cancer
How are different mutations identified?
- sequence the genome
What are the 3 forms of epigenetic mechanisms?
- DNA methylation
- Histone modification
non-coding RNAs (ncRNAs)
What is DNA methylation?
- addition of a methyl group to DNA
- CpG dinucleotides
- repetitive sequences
- CpG islands in promoters
- causes transcriptional repression
DNA methylation in cancer
- local hypermethylation - TSGs
- global hypomethylation
- mutations of DNA methyltransferase genes eg. DNMT3a in AML
What are histone modifications?
- acetylated
- methylated
- phosphorylated
- contribute to control of gene expression via chromatin compaction
Histone modifications in cancer
- global changes in histone modifications - levels of modifiers
- modifiers can be mutated in cancer eg. MLL2 in follicular lymphoma
- HDAC inhibitors as therapy - vorinostat and romidepsin in T cell lymphoma
