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SUMMARY:Genetic Architecture of Leukaemia - Mel Greaves\, Institute of Can
 cer Research
DTSTART:20110519T151500Z
DTEND:20110519T170000Z
UID:TALK30731@talks.cam.ac.uk
CONTACT:Scientific Meetings Co-ordinator
DESCRIPTION:Contemporary cancer research has two prominent paradigms:\n\n-
 	That whole genome sequencing will identify the mutational spectrum of eac
 h patient’s cancer cells and facilitate a new era of targeted or ‘pers
 onalised’ therapy\;\n\n-	That a subset of cells in each cancer – the c
 ancer ‘stem’ cells drive and sustain the disease and it is these cells
  (and their specific mutations) that provide the ‘bull’s eye’ for th
 erapy.\n\nUntil recently these two strands of research – genetics and st
 em cells\, have not been combined and\, when they now are\, a striking and
  disconcerting result emerges.\n\nWe have interrogated the evolution of ca
 ncer clones in childhood lymphoblastic leukaemia (ALL) and identified the 
 dynamic architecture of disease\, i.e. the timing and sequence of acquisit
 ion of mutations and the distribution of mutations in sub-clones and stem 
 cells.  To achieve this\, we exploited the unusual situation of leukaemia 
 in identical twins and analysed the genetic make-up of individual leukaemi
 c cells.  This enabled us to designate certain mutations as initiating or 
 primary events\, usually occurring pre-natally\, in utero\, and a ‘set
 ’ of additional secondary mutations arising post-natally closer to the c
 linical diagnosis.  Strikingly\, the full set of mutations does not accumu
 late in a linear fashion in sequentially dominant sub-clones (as widely an
 ticipated) but rather via a complex\, branching architecture of clonal evo
 lution.  Moreover\, separate branches of the clonal\, evolutionary tree ar
 e sustained by genetically distinct stem cells.\n\nThese data are entirely
  consistent with the concept of cancer clone development as a Darwinian ev
 olutionary process.  They highlight that the so-called ‘bull’s eye’ 
 in cancer is\, in fact\, a dynamically diverse and moving target which may
  provide an explanation of why advanced disease is so difficult to eradica
 te.\n\n1.	Anderson K\, Lutz C\, van Delft FW\, Bateman CM\, Guo Y\, Colman
  SM\, Kempski H\, Moorman AV\, Titley I\, Swansbury J\, Kearney L\, Enver 
 T\, Greaves M (2011)  Genetic variegation of clonal architecture and propa
 gating cells in leukaemia.  Nature\, 469: 356-361.\n\n2.	Greaves M (2010) 
  Cancer stem cells: back to Darwin?  Seminars in Cancer Biology\, 20: 65-7
 0.\n
LOCATION:Max Perutz Lecture Theatre\, Medical Research Council (MRC) (MRC 
 Laboratory of Molecular Biol
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