inimum E vent D istance for I ntratumour C opynumber C omparisons Intra tumour heterogeneity Population Intratumor Spatial temporal Intrasample Tissue Intrasample ID: 779847
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Slide1
MEDICC
Roland F Schwarz
M
inimum
E
vent
D
istance for
I
ntra-tumour
C
opy-number
C
omparisons
Slide2Intra-
tumour heterogeneity
Population
Intra-tumor
Spatial
, temporal
Intra-sample
Tissue
Intra-sample
Genetic
Single nucleotide variants
Genomic rearrangements / CN changes
Polyploidies
Chromothripsis
Slide3ITH enables resistance development
Merlo
et al.
Nature Reviews Cancer
; published online 16 November 2006
Main goals:
Reconstruct evolutionary history of cancer in the patient
Quantify ITH and tumour adaptability
Evaluate potential application for routine diagnostics
Slide4CN profiling
Challenges:
Phasing of allele-specific CNs
Deal with horizontal dependencies and overlapping events
Find meaningful distance measure
Find a measure that quantifies ITH
Slide5MEDICC’s 3 steps of tree inference
Slide6Minimum Event Distance
Minimum Event DistanceThe distance is the shortest path over all possible ancestorsCascading events and horizontal dependencies
Slide7Allele-specific CN assignment
Possible phasing choices are modelled as CFGEvery parse tree realises one possible phasing scenarioEvolutionary shortest distance gives us the optimal phasing
Slide8MEDICC’s 3 steps of tree inference
Slide9Quantifying ITH
k(
x,z
) = -
exp
(d(
x,z
))
Schwarz et al. 2011, Evolutionary distances in the twilight zone: a rational kernel approach
From distances to relative positions and angles
Allows computation of centers of mass
Allows measuring the distribution of genomes in the mutational landscape
Slide10Quantifying ITH
A) Neutral evolution with no selection pressure
Slide11Quantifying ITH
Neutral evolution with no selection pressure
Certain mutations confer fitness advantage
Slide12Quantifying ITH
Neutral evolution with no selection pressure
Certain mutations confer fittness advantageClonal expansions (Ripley’s K)Distances between subgroups (Robust
center
of mass)
Slide13ITH and clonal expansion determines survival
OV03-01
OV03-08
OV03-13
OV03-22
OV03-20
sensitive
resistant
A high degree of clonal expansion and temporal heterogeneity indicates poor outcome.
OV03-17
Slide14Acknowledgements
EBI:
Nick Goldman
Boton
Sipos
CI:
Florian
Markowetz
Anne Trinh
CUED:Adria de Gispert Gonzalo IglesiasUBC:
Sohrab Shah
Slide15Ancestral reconstruction allows
timing of events4q: EGFR ligand epiregulin
(EREG) Toll-like receptor 3 (TLR3) NPY5R, VEGFC
8p: DEFA/DAFB, ANGPT2
17: P53, BRCA1
5q: GNB2L1/RACK1
Slide16Simulation results