title: Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors.
abstract: Phyllodes tumors are rare fibroepithelial tumors with variable clinical behavior accounting for a small subset of all breast neoplasms, yet little is known about the genetic alterations that drive tumor initiation and/or progression. Here, targeted next-generation sequencing (NGS) was used to identify somatic alterations in formalin-fixed paraffin-embedded (FFPE) patient specimens from malignant, borderline, and benign cases. NGS revealed mutations in mediator complex subunit 12 (MED12) affecting the G44 hotspot residue in the majority (67%) of cases spanning all three histologic grades. In addition, loss-of-function mutations in p53 (TP53) as well as deleterious mutations in the tumor suppressors retinoblastoma (RB1) and neurofibromin 1 (NF1) were identified exclusively in malignant tumors. High-level copy-number alterations (CNA) were nearly exclusively confined to malignant tumors, including potentially clinically actionable gene amplifications in IGF1R and EGFR. Taken together, this study defines the genomic landscape underlying phyllodes tumor development, suggests potential molecular correlates to histologic grade, expands the spectrum of human tumors with frequent recurrent MED12 mutations, and identifies IGF1R and EGFR as potential therapeutic targets in malignant cases.
  
  
  CONCLUSIONS
  Integrated genomic sequencing and mutational profiling provides insight into the molecular origin of phyllodes tumors and indicates potential druggable targets in malignant disease. Visual Overview: http://mcr.aacrjournals.org/content/early/2015/04/02/1541-7786.MCR-14-0578/F1.large.jpg.
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, Michigan.
authors.forename: Andi K
authors.initials: AK
authors.lastname: Cani
authors.affiliation: Department of Computational Medicine and Bioinformatics University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hovelson
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, Michigan.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McDaniel
authors.affiliation: Life Sciences Solutions, ThermoFisher Scientific, Ann Arbor, Michigan.
authors.forename: Seth
authors.initials: S
authors.lastname: Sadis
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, Michigan.
authors.forename: Michaela J
authors.initials: MJ
authors.lastname: Haller
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, Michigan.
authors.forename: Venkata
authors.initials: V
authors.lastname: Yadati
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, Michigan.
authors.forename: Anmol M
authors.initials: AM
authors.lastname: Amin
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, Michigan.
authors.forename: Jarred
authors.initials: J
authors.lastname: Bratley
authors.affiliation: Life Sciences Solutions, ThermoFisher Scientific, Ann Arbor, Michigan.
authors.forename: Santhoshi
authors.initials: S
authors.lastname: Bandla
authors.affiliation: Life Sciences Solutions, ThermoFisher Scientific, Ann Arbor, Michigan.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Williams
authors.affiliation: Life Sciences Solutions, ThermoFisher Scientific, Carlsbad, California.
authors.forename: Kate
authors.initials: K
authors.lastname: Rhodes
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, Michigan.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, Michigan. Department of Pathology, Oregon Health and Sciences University, Portland, Oregon.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quist
authors.affiliation: Life Sciences Solutions, ThermoFisher Scientific, Ann Arbor, Michigan.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Rhodes
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, Michigan. Department of Pathology, Oregon Health and Sciences University, Portland, Oregon.
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Grasso
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, Michigan.
authors.forename: Celina G
authors.initials: CG
authors.lastname: Kleer
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, Michigan. Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan. Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan. tomlinss@umich.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D056892:Mediator Complex / Q000235:genetics*; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics; D003557:Phyllodes Tumor / Q000235:genetics* / Q000473:pathology; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C000597236:IGF1R protein, human; C460107:MED12 protein, human; D056892:Mediator Complex; D025542:Neurofibromin 1; D017451:Receptors, Somatomedin; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1