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NY Prostate Cancer Conference - C.L. Sawyers - Session 1:  Gene copy number analysis as a prognostic tool
 

NY Prostate Cancer Conference - C.L. Sawyers - Session 1: Gene copy number analysis as a prognostic tool

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    NY Prostate Cancer Conference - C.L. Sawyers - Session 1:  Gene copy number analysis as a prognostic tool NY Prostate Cancer Conference - C.L. Sawyers - Session 1: Gene copy number analysis as a prognostic tool Presentation Transcript

    • Integrated Prostate Cancer Oncogenome Dataset
      218 tumors (181 primaries, 37 metastases)
      13 prostate cancer cell lines and xenografts
      Data collection:
      arrayCGH
      mRNA transcriptome (exon array)
      microRNAtranscriptome
      exonresequencing/mutation detection (157 genes)
      linked to clinical outcome (5 year median follow-up)
      William Gerald
    • Copy Number Alterations in Prostate Cancer Genomes
      8-21% of primaries
      NCOA2
      MYC
      8q
      n = 194 tumors
      Barry Taylor, Chris Sander
    • NCOA2 amplifies AR pathway output in prostate cancer
      LNCaP cells
      Human tumors
      Vivek Arora, Haley Hieronymus
    • Overview of AR pathway alterations
      (expression outliers)
      Niki Schultz, Chris Sander
    • Cooperativity betweeenTMPRSS2-ERG and other genetic alterations
      • ERG overexpression alone does not cause prostate cancer in transgenic mouse models
      • ERG may cooperate with other common alterations to drive prostate oncogenesis
      • Can we identify genetic events that cooperate with TMPRSS2-ERG to promote prostate oncogenesis?
      • aCGH analysis of prostate tumor set (n=121) to find copy number alterations associated with TMPRSS2-ERG fusion
    • TMPRSS2-ERG positive tumors enriched for three regions of copy number loss
      Amplification: No association of TMPRSS2-ERG and regions of copy number amplifications
      Deletions associated with TMPRSS2-ERG:
      • PTEN loss: Chr10 copy number deletion spanning PTEN (p= 5e-4)
      • p53 loss: Chr17 deletion spanning TP53 (q= 6e-3)
      • Multigenic 3p14 deletion containing several genes of interest (p = 5e-5)
      Barry Taylor
    • Multigenic 3p14 deletion enriched in TMPRSS2-ERG positive prostate cancer
    • Correlation between copy number loss and expression decreases for ERG-associated genes
    • Sequencing revealed SHQ1 point mutation,in addition to copy number truncation
    • Do genomes define different subtypes
      of prostate cancer?
      -breast cancer is now divided into three major subgroups based on mRNA analysis and these women are treated differently
      • can we do the same thing with prostate cancer?
      • mRNA doesn’t work as well in prostate cancer. What about DNA changes?
    • Do genomes define different subtypes
      of prostate cancer?
      -breast cancer is now divided into three major subgroups, defined in part by their transcriptomes
      • similarly robust subgroups have not emerged from prostate cancer transcriptomes
      • TMPRSS2-ERG fusion is present in 50% of prostate cancers but these tumors are not obviously distinct clinically
    • Unsupervised Clustering of Tumors by Copy Number Alterations
      Defines Robust Subgroups
    • Copy Number Alteration at Diagnosis
      and Time to Biochemical Relapse
      Barry Taylor, Brett Carver
    • This finding raises the possibility of knowing who need aggressive therapy right away (surgery, radiation, etc) and who can be followed with active surveillance.
      Next steps
      evaluate the gene copy number hypothesis on 1000 tumors with 10 year follow-up
      miniaturize the gene copy number test to work on needle biopsies and on circulating tumor cells
      To determine whether CNAs predict disease-specific death in prostate cancer patients managed conservatively
    • Acknowledgements
      AnuGopolan
      Nicholas Mitsiades
      Victor Reuter
      James Eastham
      Howard Scher
      Peter Scardino
      Yonghong Xiao
      William Gerald
      Barry Taylor
      Niki Schultz
      PoorviKaushik
      Chris Sander
      John E. Major
      Manda Wilson
      Nicholas D. Socci
      Alex Lash
      Haley Hieronymus
      Brett Carver
      VivekArora
      Charles Sawyers
      Thomas Landers
      Igor Dolgalev
      Adriana Heguy