title: A signature predicting poor prognosis in gastric and ovarian cancer represents a coordinated macrophage and stromal response.
abstract: OBJECTIVE
  Gene-expression profiling has revolutionized the way we think about cancer and confers the ability to observe the synchronous expression of thousands of genes. The use of putative genome-level expression profiles has allowed biologists to observe the complex interactions of genes that constitute recognized biologic pathways. We used gastric and ovarian datasets to identify gene-expression signatures and determine any functional significance.
  
  
  METHODS
  Microarray data of 94-tumor and 45-benign samples derived from patients with gastric cancer were interrogated using Hierarchical Ordered Partitioning and Collapsing Hybrid analysis identifying clusters of coexpressed genes. Clusters were further characterized with respect to biologic significance, gene ontology, and ability to discriminate between normal and tumor tissue. Tumor tissues were separated into epithelial and stromal compartments and immunohistochemical analysis performed to further elucidate specific cell lineages expressing genes contained in the signature.
  
  
  RESULTS
  We identified a "stromal-response" expression signature, highly enriched for inflammatory, extracellular matrix, cytokine, and growth factor proteins. The majority of genes in the signature are expressed in the tumor-associated stroma but were absent in associated premalignant conditions. In gastric cancer, this module almost perfectly differentiates tumor from nonmalignant gastric tissue and hence can be regarded as a highly tumor-specific gene-expression signature.
  
  
  CONCLUSIONS
  We show that these genes are consistently coexpressed across a range of independent gastric datasets as well as other cancer types suggesting a conserved functional role in cancer. In addition, we show that this signature can be a surrogate marker for M2 macrophage activity and has significant prognostic implications in gastric and ovarian high-grade serous cancer.
authors.affiliation: Authors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, IsraelAuthors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, IsraelAuthors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Fa
authors.forename: Rita A
authors.initials: RA
authors.lastname: Busuttil
authors.affiliation: Authors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, Israel.
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.affiliation: Authors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, Israel.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tothill
authors.affiliation: Authors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, Israel.
authors.forename: Kylie
authors.initials: K
authors.lastname: Ioculano
authors.affiliation: Authors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, Israel.
authors.forename: Adam
authors.initials: A
authors.lastname: Kowalczyk
authors.affiliation: Authors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, Israel.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mitchell
authors.affiliation: Authors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, Israel.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lade
authors.affiliation: Authors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, IsraelAuthors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, IsraelAuthors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Fa
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Authors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, IsraelAuthors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, IsraelAuthors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Fa
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.affiliation: Authors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, IsraelAuthors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Faculty of Medicine in the Galilee, Bar Ilan University, Zfat, IsraelAuthors' Affiliations: Cancer Genetics and Genomics Laboratory; Molecular Genomics Core Facility; Department of Pathology, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Medicine, Royal Melbourne Hospital; National ICT Australia (NICTA); Department of Pathology, The University of Melbourne, Parkville, Australia; Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School; Cellular and Molecular Research, National Cancer Centre; Cancer Science Institute of Singapore, National University of Singapore; Genome Institute of Singapore, Singapore; and Fa
authors.forename: Alex
authors.initials: A
authors.lastname: Boussioutas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D015331:Cohort Studies; D003937:Diagnosis, Differential; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*
chemical_list: D015676:Osteonectin; C577241:SPARC protein, human