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SUMMARY:Profiling the Subclonal Copy Number Architecture from Whole Genome
  Sequencing of Heterogeneous Tumours - Gavin Ha\, BC Cancer Research Centr
 e
DTSTART:20140127T160000Z
DTEND:20140127T170000Z
UID:TALK49311@talks.cam.ac.uk
CONTACT:Florian Markowetz
DESCRIPTION:Hosted by Nitzan Rosenfeld\n\nGenomic aberrations and chromoso
 mal instability are hallmarks of malignant human cancers. These mutational
  abnormalities\, which encompass copy number alterations (CNA) and loss of
  heterozygosity (LOH)\, can have a measurable effect on the structure and 
 dosage of chromosomal regions. Tumour suppressors and oncogenes altered by
  CNAs can contribute to a phenotype of increased proliferation. Branched e
 volution throughout tumour progression results in genomic heterogeneity in
  which divergent clones with distinct aberrations are often present at dia
 gnosis. Measuring and modeling subclonal CNA/LOH events can elucidate the 
 abundance of specific clones in cell populations. This will enable the stu
 dy of clonal evolution dynamics\, which have far-reaching implications for
  understanding modes of selection\, and the genetic basis of metastatic po
 tential and therapeutic resistance. Whole genome sequencing (WGS) provides
  a high-resolution genome-wide assay for profiling the genomes of cancer c
 ell populations. However\, accurate and statistically robust computational
  methods for inferring CNA and LOH in these data remain under-developed. \
 n\nI will present two probabilistic approaches that employ hidden Markov m
 odels (HMM) to analyze CNA and LOH in tumour WGS data. The first approach\
 , APOLLOH\, was developed to profile LOH in heterogeneous tumour-normal ad
 mixture data. We applied APOLLOH to analyze 23 triple negative breast canc
 ers (TNBC)\, and investigated the contribution to allelic expression in ma
 tching transcriptome (RNAseq) data. The second approach\, TITAN\, simultan
 eously infers CNA/LOH and estimates their cellular prevalence in the tumou
 r sample by accounting for multiple tumour populations. We evaluated TITAN
  on simulated tumour subclones using real intra-patient samples from an ov
 arian carcinoma. Finally\, I will report preliminary results from the appl
 ication of TITAN to analyze the clonal selection patterns in breast cancer
  patient xenograft tumours.
LOCATION:Cancer Research UK Cambridge Institute\, Lecture Theatre
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