Joshua J Waterfall

Publications (2)30.18 Total impact

• Article: Targeting epigenetic misregulation in synovial sarcoma.

  Joshua J Waterfall, Paul S Meltzer
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  ABSTRACT: Like many sarcomas, synovial sarcoma is driven by a characteristic oncogenic transcription factor fusion, SS18-SSX. In this issue of Cancer Cell, Su et al. elucidate the protein partners necessary for target gene misregulation and demonstrate a direct effect of histone deacetylase inhibitors on the SS18-SSX complex composition, expression misregulation, and apoptosis.
  Cancer cell 03/2012; 21(3):323-4. · 25.29 Impact Factor
• Article: A methyl-deviator epigenotype of estrogen receptor-positive breast carcinoma is associated with malignant biology.

  J Keith Killian, Sven Bilke, Sean Davis, Robert L Walker, Erich Jaeger, M Scott Killian, Joshua J Waterfall, Marina Bibikova, Jian-Bing Fan, William I Smith, Paul S Meltzer
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  ABSTRACT: We broadly profiled DNA methylation in breast cancers (n = 351) and benign parenchyma (n = 47) for correspondence with disease phenotype, using FFPE diagnostic surgical pathology specimens. Exploratory analysis revealed a distinctive primary invasive carcinoma subclass featuring extreme global methylation deviation. Subsequently, we tested the correlation between methylation remodeling pervasiveness and malignant biological features. A methyl deviation index (MDI) was calculated for each lesion relative to terminal ductal-lobular unit baseline, and group comparisons revealed that high-grade and short-survival estrogen receptor-positive (ER(+)) cancers manifest a significantly higher MDI than low-grade and long-survival ER(+) cancers. In contrast, ER(-) cancers display a significantly lower MDI, revealing a striking epigenomic distinction between cancer hormone receptor subtypes. Kaplan-Meier survival curves of MDI-based risk classes showed significant divergence between low- and high-risk groups. MDI showed superior prognostic performance to crude methylation levels, and MDI retained prognostic significance (P < 0.01) in Cox multivariate analysis, including clinical stage and pathological grade. Most MDI targets individually are significant markers of ER(+) cancer survival. Lymphoid and mesenchymal indexes were not substantially different between ER(+) and ER(-) groups and do not explain MDI dichotomy. However, the mesenchymal index was associated with ER(+) cancer survival, and a high lymphoid index was associated with medullary carcinoma. Finally, a comparison between metastases and primary tumors suggests methylation patterns are established early and maintained through disease progression for both ER(+) and ER(-) tumors.
  American Journal Of Pathology 07/2011; 179(1):55-65. · 4.89 Impact Factor