TissueCypher™: A systems biology approach to anatomic pathology
Jeffrey W Prichard1, Jon M Davison2, Bruce B Campbell3, Kathleen A Repa3, Lia M Reese3, Xuan M Nguyen3, Jinhong Li1, Tyler Foxwell2, Lansing D Taylor4, Rebecca J Critchley-Thorne3
1 Department of Pathology and Laboratory Medicine, Geisinger Medical Center, Danville, PA 17822, USA
2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
3 Cernostics, Inc., 235 William Pitt Way, Pittsburgh, PA 15238, USA
4 Department of Computational and Systems Biology, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA
Rebecca J Critchley-Thorne
Cernostics, Inc., 235 William Pitt Way, Pittsburgh, PA 15238
Source of Support: This work was supported by a grant from the Pennsylvania Department of Health CURE Program Grant, Research on Cancer Diagnostics or Therapeutics with Commercialization Potential RFA#10-07-03 (J.W.P., J.D., R.J.C-T), a Qualifying Therapeutic Discovery Project Grant, Internal Revenue Service/Affordable Care Act 2010, (R.J.C-T) and by Cernostics, Inc., Conflict of Interest: Lia Reese, D. Lansing Taylor and Rebecca Critchley-Thorne hold equity ownership or stock options in Cernostics and Bruce Campbell, Kathleen Repa, Lia Reese, Xuan Mai Nguyen and Rebecca Critchley-Thorne are or were employed by Cernostics, Inc, the commercial entity that developed the proprietary TissueCypher™ technology. Bruce Campbell and Rebecca Critchley-Thorne report being inventors on a patent application for the TissueCypher™ technology used in this study. Rebecca Critchley-Thorne and D. Lansing Taylor are founders of Cernostics, Inc.
Background: Current histologic methods for diagnosis are limited by intra- and inter-observer variability. Immunohistochemistry (IHC) methods are frequently used to assess biomarkers to aid diagnoses, however, IHC staining is variable and nonlinear and the manual interpretation is subjective. Furthermore, the biomarkers assessed clinically are typically biomarkers of epithelial cell processes. Tumors and premalignant tissues are not composed only of epithelial cells but are interacting systems of multiple cell types, including various stromal cell types that are involved in cancer development. The complex network of the tissue system highlights the need for a systems biology approach to anatomic pathology, in which quantification of system processes is combined with informatics tools to produce actionable scores to aid clinical decision-making. Aims: Here, we describe a quantitative, multiplexed biomarker imaging approach termed TissueCypher™ that applies systems biology to anatomic pathology. Applications of TissueCypher™ in understanding the tissue system of Barrett's esophagus (BE) and the potential use as an adjunctive tool in the diagnosis of BE are described. Patients and Methods: The TissueCypher™ Image Analysis Platform was used to assess 14 epithelial and stromal biomarkers with known diagnostic significance in BE in a set of BE biopsies with nondysplastic BE with reactive atypia (RA, n = 22) and Barrett's with high-grade dysplasia (HGD, n = 17). Biomarker and morphology features were extracted and evaluated in the confirmed BE HGD cases versus the nondysplastic BE cases with RA. Results: Multiple image analysis features derived from epithelial and stromal biomarkers, including immune biomarkers and morphology, showed significant differences between HGD and RA. Conclusions: The assessment of epithelial cell abnormalities combined with an assessment of cellular changes in the lamina propria may serve as an adjunct to conventional pathology in the assessment of BE.