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SUMMARY:Variations in genetic and phenotypic diversity during breast cance
 r progression. - Vanessa Almendro (Harvard University)
DTSTART:20140407T150000Z
DTEND:20140407T160000Z
UID:TALK51705@talks.cam.ac.uk
CONTACT:Florian Markowetz
DESCRIPTION:Cancer therapy exerts a strong selection pressure that shapes 
 tumor evolution\, yet our knowledge of how tumors change during treatment 
 is limited. To understand the effects of treatment on tumor heterogeneity 
 we devise a strategy to quantify the extent of genetic and phenotypic cell
 ular diversity in breast tumors pre- and post-neoadjuvant chemotherapy. Ce
 llular genetic diversity is distinct from clonal diversity\, as it combine
 s inputs from both clonal architecture and lower-scale differences arising
  from genomic instability that are not amplified by selection. We found th
 at intratumor genetic diversity was tumor subtype-specific and it did not 
 change during treatment in tumors with partial or no response. However\, l
 ower pre-treatment genetic diversity was significantly associated with com
 plete pathologic response. In contrast\, phenotypic diversity was differen
 t between pre- and post-treatment samples. We also observed significant ch
 anges in the spatial distribution of cells with distinct genetic and pheno
 typic features. We used these experimental data to develop a stochastic co
 mputational model to infer tumor growth patterns and evolutionary dynamics
 . We also used the same strategy to interrogate the genetic and phenotypic
  heterogeneity at the single cell level in distant metastatic lesions from
  rapid autopsy cases and in matched primary tumors and lymph node metastas
 es of breast cancer collected prior to systemic therapy. We observed that 
 genetic diversity was highest in distant metastases and was generally conc
 ordant across lesions within the same patient\, whereas treatment-naïve p
 rimary tumors and matched lymph node metastases were frequently geneticall
 y more divergent. In contrast\, cellular phenotypes were more discordant b
 etween distant metastases than primary tumors and matched lymph node metas
 tases. These results highlight the importance of integrated analysis of ge
 notypes and phenotypes of single cells in intact tissues to predict tumor 
 evolution. In addition\, quantitative measures of intratumor heterogeneity
  might aid in the clinical management of cancer patients including identif
 ying those at a high risk of progression and recurrence.
LOCATION:Cancer Research UK Cambridge Institute\, Lecture Theatre
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