title: Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification.
abstract: BACKGROUND
  HER2 is overexpressed and amplified in approximately 15% of invasive breast cancers, and is the molecular target and predictive marker of response to anti-HER2 agents. In a subset of these cases, heterogeneous distribution of HER2 gene amplification can be found, which creates clinically challenging scenarios. Currently, breast cancers with HER2 amplification/overexpression in just over 10% of cancer cells are considered HER2-positive for clinical purposes; however, it is unclear as to whether the HER2-negative components of such tumors would be driven by distinct genetic alterations. Here we sought to characterize the pathologic and genetic features of the HER2-positive and HER2-negative components of breast cancers with heterogeneous HER2 gene amplification and to define the repertoire of potential driver genetic alterations in the HER2-negative components of these cases.
  
  
  RESULTS
  We separately analyzed the HER2-negative and HER2-positive components of 12 HER2 heterogeneous breast cancers using gene copy number profiling and massively parallel sequencing, and identified potential driver genetic alterations restricted to the HER2-negative cells in each case. In vitro experiments provided functional evidence to suggest that BRF2 and DSN1 overexpression/amplification, and the HER2 I767M mutation may be alterations that compensate for the lack of HER2 amplification in the HER2-negative components of HER2 heterogeneous breast cancers.
  
  
  CONCLUSIONS
  Our results indicate that even driver genetic alterations, such as HER2 gene amplification, can be heterogeneously distributed within a cancer, and that the HER2-negative components are likely driven by genetic alterations not present in the HER2-positive components, including BRF2 and DSN1 amplification and HER2 somatic mutations.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. ngk1@mskcc.org.
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. martelol@mskcc.org.
authors.forename: Luciano G
authors.initials: LG
authors.lastname: Martelotto
authors.affiliation: Department of Tumor Biology, Institut Curie, 75248, Paris, France. arnaud_gauthier@yahoo.fr.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gauthier
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. wenh@mskcc.org.
authors.forename: Huei-Chi
authors.initials: HC
authors.lastname: Wen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. piscuogs@mskcc.org.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. limr@mskcc.org.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Lim
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. catherine.f.cowell@gmail.com.
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Cowell
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK. Paul.Wilkerson@icr.ac.uk.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Wilkerson
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK. Patty.wai@icr.ac.uk.
authors.forename: Patty
authors.initials: P
authors.lastname: Wai
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK. Daniel.NavaRodrigues@icr.ac.uk.
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Rodrigues
authors.affiliation: Department of Pathology and CRB Ferdinand Cabanne, Centre Georges Francois Leclerc, 21000, Dijon, France. LArnould@cgfl.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Arnould
authors.affiliation: Departments of Anatomic Pathology and Oncology, Hospital Israelita Albert Einstein, São Paulo, 05652-900, Brazil. felipecgeyer@gmail.com.
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.affiliation: Departments of Anatomic Pathology and Oncology, Hospital Israelita Albert Einstein, São Paulo, 05652-900, Brazil. sbromberg@einstein.br.
authors.forename: Silvio E
authors.initials: SE
authors.lastname: Bromberg
authors.affiliation: Department of Pathology, Institut Claudius Regaud, IUCT-Oncopole, 31059, Toulouse, France. Lacroix.Magali@iuct-oncopole.fr.
authors.forename: Magali
authors.initials: M
authors.lastname: Lacroix-Triki
authors.affiliation: Department of Pathology, Centre Jean Perrin, and University of Auvergne, 63000, Clermont Ferrand, France. Frederique.PENAULT-LLORCA@cjp.fr.
authors.forename: Frederique
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: Department of Pathology, Centre Oscar Lambret, 59000, Lille, France. S-Giard@o-lambret.fr.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Giard
authors.affiliation: Department of Tumor Biology, Institut Curie, 75248, Paris, France. xavier.sastre@curie.fr.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sastre-Garau
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK. Rachael.natrajan@icr.ac.uk.
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. nortonl@mskcc.org.
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.affiliation: Department of Medical Oncology, Institut Curie, 75248, Paris, France. paul.cottu@curie.fr.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Cottu
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. weigeltb@mskcc.org.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: Department of Tumor Biology, Institut Curie, 75248, Paris, France. anne.salomon@curie.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. reisfilj@mskcc.org.|Affiliate Member, Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. reisfilj@mskcc.org.|Affiliate Member, Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. reisfilj@mskcc.org.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D061986:MCF-7 Cells; D009154:Mutation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction; D035361:Transcription Factor TFIIIB / Q000235:genetics / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D018719:Erb-b2 Receptor Tyrosine Kinases; D035361:Transcription Factor TFIIIB; C416185:BRF2 protein, human; C532764:DSN1 protein, human; C508053:ERBB2 protein, human