title: The molecular basis of breast cancer pathological phenotypes.
abstract: The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or reverse-phase protein assay subtype. Marked nuclear pleomorphism, necrosis, inflammation and a high mitotic count were associated with the basal-like subtype, and had a similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed by use of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of poorly differentiated epithelial tubules was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative breast cancer. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has the potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology, and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.|Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Yujing J
authors.initials: YJ
authors.lastname: Heng
authors.affiliation: Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Lester
authors.affiliation: Department of Anatomical & Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong.
authors.forename: Gary Mk
authors.initials: GM
authors.lastname: Tse
authors.affiliation: Department of Pathology, School of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Factor
authors.affiliation: Department of Pathology, School of Medicine, Stanford Medical Center, Stanford University, Stanford, CA, USA.
authors.forename: Kimberly H
authors.initials: KH
authors.lastname: Allison
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.|Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Collins
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Yunn-Yi
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Pathology, School of Medicine, Stanford Medical Center, Stanford University, Stanford, CA, USA.|VA Palo Alto Healthcare System, Palo Alto, CA, USA.
authors.forename: Kristin C
authors.initials: KC
authors.lastname: Jensen
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.|Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Nicole B
authors.initials: NB
authors.lastname: Johnson
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.|Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Jong Cheol
authors.initials: JC
authors.lastname: Jeong
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.|Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Rahi
authors.initials: R
authors.lastname: Punjabi
authors.affiliation: Department of Pathology & Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Shin
authors.affiliation: Department of Pathology & Laboratory Medicine, Brown University, Providence, RI, USA.
authors.forename: Kamaljeet
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Krings
authors.affiliation: Department of Pathology & Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Eberhard
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Puay Hoon
authors.initials: PH
authors.lastname: Tan
authors.affiliation: Department of Pathology, Greater Poland Cancer Centre, Poznan, Poland.
authors.forename: Konstanty
authors.initials: K
authors.lastname: Korski
authors.affiliation: Department of Laboratory Medicine, School of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Frederic M
authors.initials: FM
authors.lastname: Waldman
authors.affiliation: Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Gutman
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Melinda
authors.initials: M
authors.lastname: Sanders
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.|Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Sydney R
authors.initials: SR
authors.lastname: Flanagan
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Deena Ma
authors.initials: DM
authors.lastname: Gendoo
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Chen
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ciriello
authors.affiliation: Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.affiliation: Department of Pathology & Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.|Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.|Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen
keywords: PAM50; TCGA; bioinformatics; epithelial tubule formation; genomics; histological grade; mRNA