title: Genes associated with histopathologic features of triple negative breast tumors predict molecular subtypes.
abstract: Distinct subtypes of triple negative (TN) breast cancer have been identified by tumor expression profiling. However, little is known about the relationship between histopathologic features of TN tumors, which reflect aspects of both tumor behavior and tumor microenvironment, and molecular TN subtypes. The histopathologic features of TN tumors were assessed by central review and 593 TN tumors were subjected to whole genome expression profiling using the Illumina Whole Genome DASL array. TN molecular subtypes were defined based on gene expression data associated with histopathologic features of TN tumors. Gene expression analysis yielded signatures for four TN subtypes (basal-like, androgen receptor positive, immune, and stromal) consistent with previous studies. Expression analysis also identified genes significantly associated with the 12 histological features of TN tumors. Development of signatures using these markers of histopathological features resulted in six distinct TN subtype signatures, including an additional basal-like and stromal signature. The additional basal-like subtype was distinguished by elevated expression of cell motility and glucose metabolism genes and reduced expression of immune signaling genes, whereas the additional stromal subtype was distinguished by elevated expression of immunomodulatory pathway genes. Histopathologic features that reflect heterogeneity in tumor architecture, cell structure, and tumor microenvironment are related to TN subtype. Accounting for histopathologic features in the development of gene expression signatures, six major subtypes of TN breast cancer were identified.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, USA.|Department of Health Sciences Research, Mayo Clinic, Stabile 2-42, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Kristen S
authors.initials: KS
authors.lastname: Purrington
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Visscher
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Stabile 2-42, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Molecular Diagnostics Laboratory INRASTES, National Centre for Scientific Research "Demokritos", Athens, Greece.
authors.forename: Drakoulis
authors.initials: D
authors.lastname: Yannoukakos
authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.affiliation: Department of Oncology, University of Sheffield, Sheffield, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Cox
authors.affiliation: Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Stabile 2-42, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Eckel-Passow
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Sotiris
authors.initials: S
authors.lastname: Lakis
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
authors.affiliation: Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Kabisch
authors.affiliation: Institute of Pathology, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rüdiger
authors.affiliation: Department of Pathology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.affiliation: Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.affiliation: Department of Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Stabile 2-42, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Olson
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Gilbert
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Deming-Halverson
authors.affiliation: Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.|School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.affiliation: Centre for Cancer Research, University of Sydney at the Westmead Millennium Institute, Westmead, Australia.
authors.forename: Christine
authors.initials: C
authors.lastname: Clarke
authors.affiliation: Division of Genetics, Hunter Area Pathology Service and University of Newcastle, Newcastle, Australia.
authors.forename: Rodney
authors.initials: R
authors.lastname: Scott
authors.affiliation: Barts Cancer Research Institute, Queen Mary University of London, London, UK.
authors.forename: J Louise
authors.initials: JL
authors.lastname: Jones
authors.affiliation: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.|School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.affiliation: Faculty of Medicine and NIHR/CRUK Clinical Trials Unit, University of Southampton, Southampton, UK.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Eccles
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Stabile 2-42, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
authors.forename: Celine M
authors.initials: CM
authors.lastname: Vachon
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Stabile 2-42, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. couch.fergus@mayo.edu.|Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA. couch.fergus@mayo.edu.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D017423:Sequence Analysis, RNA / Q000379:methods*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology*
keywords: Breast cancer; Gene expression; Germline mutation; Pathology; Tumor biology