title: Image-based computational quantification and visualization of genetic alterations and tumour heterogeneity.
abstract: Recent large-scale genome analyses of human tissue samples have uncovered a high degree of genetic alterations and tumour heterogeneity in most tumour entities, independent of morphological phenotypes and histopathological characteristics. Assessment of genetic copy-number variation (CNV) and tumour heterogeneity by fluorescence in situ hybridization (ISH) provides additional tissue morphology at single-cell resolution, but it is labour intensive with limited throughput and high inter-observer variability. We present an integrative method combining bright-field dual-colour chromogenic and silver ISH assays with an image-based computational workflow (ISHProfiler), for accurate detection of molecular signals, high-throughput evaluation of CNV, expressive visualization of multi-level heterogeneity (cellular, inter- and intra-tumour heterogeneity), and objective quantification of heterogeneous genetic deletions (PTEN) and amplifications (19q12, HER2) in diverse human tumours (prostate, endometrial, ovarian and gastric), using various tissue sizes and different scanners, with unprecedented throughput and reproducibility.
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Rüschoff
authors.affiliation: Institute of Molecular Systems Biology, ETH, Zurich, Switzerland.
authors.forename: Tiannan
authors.initials: T
authors.lastname: Guo
authors.affiliation: Zurich Labouratory, IBM Research-Zurich, Rueschlikon, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Gabrani
authors.affiliation: Department of Computer Science, ETH, Zurich, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schüffler
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Rechsteiner
authors.affiliation: Institute of Molecular Systems Biology, ETH, Zurich, Switzerland.
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Fuchs
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Niels J
authors.initials: NJ
authors.lastname: Rupp
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Fankhauser
authors.affiliation: Institute of Molecular Systems Biology, ETH, Zurich, Switzerland.
authors.forename: Joachim M
authors.initials: JM
authors.lastname: Buhmann
authors.affiliation: Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Department of Urology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Cédric
authors.initials: C
authors.lastname: Poyet
authors.affiliation: Institute for Precision Medicine and Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University and New York-Presbyterian Hospital, New York, NY, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Blattner
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Soldini
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Institute for Precision Medicine and Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University and New York-Presbyterian Hospital, New York, NY, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Noske
authors.affiliation: Targos Molecular Pathology, Pathology Nordhessen, Kassel, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Rüschoff
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Haffner
authors.affiliation: Institute of Pathology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Jochum
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
mesh_terms: D000368:Aged; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D051059:PTEN Phosphohydrolase; D018719:Erb-b2 Receptor Tyrosine Kinases