title: Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.
abstract: Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.
authors.affiliation: Department of Medical Genetics, University of Lausanne (UNIL), 1011 Lausanne, Switzerland; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ciriello
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Gatza
authors.affiliation: Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wilkerson
authors.affiliation: Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA.
authors.forename: Suhn K
authors.initials: SK
authors.lastname: Rhie
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pastore
authors.affiliation: The Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Hailei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: The Genome Institute, Washington University School of Medicine, MO, 63108, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: McLellan
authors.affiliation: Buck Institute For Research on Aging, Novato, CA, 94945, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Yau
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Cyriac
authors.initials: C
authors.lastname: Kandoth
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z4S6, Canada.
authors.forename: Reanne
authors.initials: R
authors.lastname: Bowlby
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Sikander
authors.initials: S
authors.lastname: Hayat
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Fieldhouse
authors.affiliation: Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Lester
authors.affiliation: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Gary M K
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, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Collins
authors.affiliation: Department of Pathology, School of Medicine, Stanford University Medical Center, Stanford University, Stanford, CA, USA.
authors.forename: Kimberly H
authors.initials: KH
authors.lastname: Allison
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, 94143, USA.
authors.forename: Yunn-Yi
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Pathology, School of Medicine, Stanford University Medical Center, Stanford University, Stanford, CA, USA; VA Palo Alto Healthcare System, Palo Alto, 94304, CA, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
authors.forename: Nicole B
authors.initials: NB
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15232, USA.
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.affiliation: MD Anderson Cancer Center, The University of Texas, Houston, TX, 77230, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: The Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cherniack
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z4S6, Canada.
authors.forename: Gordon
authors.initials: G
authors.lastname: Robertson
authors.affiliation: Buck Institute For Research on Aging, Novato, CA, 94945, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Benz
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Tari A
authors.initials: TA
authors.lastname: King
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address: cperou@med.unc.edu.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
mesh_terms: D015703:Antigens, CD; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D051058:Oncogene Protein v-akt / Q000378:metabolism; D059467:Transcriptome
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D051058:Oncogene Protein v-akt