Tumour heterogeneity Flashcards
What are the three types of tumour heterogeneity
Intertumour, intratumour and intracellular
How are somatic mutations identified?
Tumour regions whole exome sequences are compared with matched individuals germline samples which are derived from whole blood.
Somatic mutations and copy number alterations (CNAs) are clonal and subclonal events. True or false?
True
subclonal CNAs have no significant impact on relapse free survival whereas there is a significant association between subclonal somatic mutation number and relapse free survival? True or false?q
False - It is the other way round. Increased subclonal CNAs increases the likelihood of relapse.
How was chromosomal instability measured in TRACERx
Gains and losses of chromosomes by observing SNP heterozygosity.
Look at SNPs which differ between maternal and paternal alleles i.e. normal tissue will be heterozygous for these markers. Then look in tumour regions and see if there is any deviation from this 50%, i.e has the ratio gone from 50:50 to 66:33 due to a single gain of a chromosomal region.
How is it deciphered whether the paternal or maternal allele has undergone a CNA? and what is this known as?
Label the SNPs in a tumour region which has undergone a CNA (e.g label the SNPs under 50% blue and those over 50% in red). Then apply this to another tumour region to see if the CNA is an independent event or not, i.e. does it mimic the previous event or is it the exact opposite. If it is the exact opposite this is known as mirrored subclonal allelic imbalance.
How does selection and parallel evolution present in NSCLC
Mimics species evolution. The same mutational event occurs in independent subclones. Different regions experience CNA in the same gene in either allele (MSAI). This suggests that this is a focal event converging on specific oncogenes. Suggests that the tumour has experienced certain stresses that this mutational evolution has allowed it to overcome.
How does multi region analysis help to show parallel evolution. How can this be used therapeutically
Detected through MSAI profiles. If MSAI is seen in different regions of the same tumour, at a specific chromosomal location. It suggests that a gene found at this location has a strong selection pressure. So it could be a good target for therapy.
How was it checked whether genome doubling is permissive or the result of chromosomal instability.
Compared tetraploid cells in a cancer cell line Vs sister subclones that were diploid.
Non-doubled clone chromosomes appear to be very stable (no gains or losses of chromosomes)
Tetraploid cells gained and lost many chromosomes with events occurring independently in different subclones (suggests selection for these events). This showed that tetraploid cells become more unstable and then begin to come down in ploidy. Which translates to genome doubling being permissive for the tolerance of chromosomal instability i.e when the genome is doubled, chromosomal instability goes up.
What is the mutational signature of tobacco
Linked with C>A transversions.
What transversions are dominant in late tumours
C>G, C>T
What is important about the mutational signature of the late C>G and C>T mutations?
Looking at the sequence that the mutations occur in, there is a high density of these transversions in C when it is immediately following a T.
What are TCA and TCT C>G/C>T mutational signatures related to
APOBEC enzyme mutations. The more APOBEC branch mutations in late tumours causes an increase in heterogeneity found in the tumour.
What is the difference between clonal and subclonal driver mutational events in LUAD?
Clonal drivers occur at a high frequency, early on during tumour development. Contrast to subconal drivers which explore a more vast evolutionary space (more genes able to be mutated). Essentially, early - certain genes must be mutated whereas later on its not quite as specific.
