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SUMMARY:Analysis of a large cancer gene screen in myelodysplastic syndrome
 s - Moritz Gerstung (Sanger)
DTSTART:20131021T150000Z
DTEND:20131021T160000Z
UID:TALK46649@talks.cam.ac.uk
CONTACT:Florian Markowetz
DESCRIPTION:Myelodysplastic syndromes (MDS) are a heterogeneous group of b
 lood cancers leading to an ineffective production of blood cells. I will p
 resent computational methods and results from a large screen of 111 cancer
  genes sequenced at 250x coverage in 738 MDS patients. To analyse such dat
 a we have developed a new variant caller which analyses all samples jointl
 y to estimate the local distributions of sequencing artefacts\, for an inc
 reased specificity. At the same time this method gains power from  incorpo
 rating prior knowledge about mutational hotspots.\nThe resulting mutationa
 l landscape of MDS displays complex patterns of pairwise association betwe
 en genes\, indicative of epistatic interactions involving components of th
 e spliceosome machinery and epigenetic modifiers. Coupled with inferences 
 on subclonal mutations\, these data suggest a hypothesis of genetic 'prede
 stination'\, in which early driver mutations\, typically affecting genes i
 nvolved in RNA splicing\, dictate future trajectories of disease evolution
  with distinct clinical phenotypes. Driver mutations had equivalent progno
 stic significance whether clonal or subclonal\, and leukemia-free survival
  deteriorated steadily as numbers of driver mutations increased. Thus\, an
 alysis of oncogenic mutations in large\, well-characterized cohorts of pat
 ients illustrates the interconnections between the cancer genome and disea
 se biology\, with considerable potential for clinical application.
LOCATION:Cancer Research UK Cambridge Institute\, Lecture Theatre
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