title: Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma.
abstract: BACKGROUND
  Alveolar rhabdomyosarcoma (aRMS) is a myogenic childhood sarcoma frequently associated with a translocation-mediated fusion gene, Pax3:Foxo1a.
  
  
  METHODS
  We investigated the complementary role of Rb1 loss in aRMS tumor initiation and progression using conditional mouse models.
  
  
  RESULTS
  Rb1 loss was not a necessary and sufficient mutational event for rhabdomyosarcomagenesis, nor a strong cooperative initiating mutation. Instead, Rb1 loss was a modifier of progression and increased anaplasia and pleomorphism. Whereas Pax3:Foxo1a expression was unaltered, biomarkers of aRMS versus embryonal rhabdomyosarcoma were both increased, questioning whether these diagnostic markers are reliable in the context of Rb1 loss. Genome-wide gene expression in Pax3:Foxo1a,Rb1 tumors more closely approximated aRMS than embryonal rhabdomyosarcoma. Intrinsic loss of pRb function in aRMS was evidenced by insensitivity to a Cdk4/6 inhibitor regardless of whether Rb1 was intact or null. This loss of function could be attributed to low baseline Rb1, pRb and phospho-pRb expression in aRMS tumors for which the Rb1 locus was intact. Pax3:Foxo1a RNA interference did not increase pRb or improve Cdk inhibitor sensitivity. Human aRMS shared the feature of low and/or heterogeneous tumor cell pRb expression.
  
  
  CONCLUSIONS
  Rb1 loss from an already low pRb baseline is a significant disease modifier, raising the possibility that some cases of pleomorphic rhabdomyosarcoma may in fact be Pax3:Foxo1a-expressing aRMS with Rb1 or pRb loss of function.
authors.affiliation: Department of Pediatrics, Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Portland, OR 97239, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Kikuchi
authors.affiliation: Departments of Epidemiology & Biostatistics, Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Eri
authors.initials: E
authors.lastname: Taniguchi
authors.affiliation: Departments of Epidemiology & Biostatistics, Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Hung-I Harry
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Portland, OR 97239, USA.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Svalina
authors.affiliation: Department of Pediatrics, Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Portland, OR 97239, USA.
authors.forename: Jinu
authors.initials: J
authors.lastname: Abraham
authors.affiliation: Department of Pediatrics, Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Portland, OR 97239, USA.
authors.forename: Elaine T
authors.initials: ET
authors.lastname: Huang
authors.affiliation: Departments of Epidemiology & Biostatistics, Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Nishijo
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD 20877, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Davis
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD 20877, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Louden
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD 20877, USA.
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Zarzabal
authors.affiliation: Department of Pediatrics, Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Portland, OR 97239, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Recht
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Ayeza
authors.initials: A
authors.lastname: Bajwa
authors.affiliation: Department of Pediatrics, Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Portland, OR 97239, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Berlow
authors.affiliation: Institut de Medicina Predictiva i Personalitzada del Càncer, Ctra. de Can Ruti, Barcelona 08916, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Suelves
authors.affiliation: ARUP Laboratories and Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Sherrie L
authors.initials: SL
authors.lastname: Perkins
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD 20877, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Atiya
authors.initials: A
authors.lastname: Mansoor
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD 20877, USA.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Michalek
authors.affiliation: Departments of Epidemiology & Biostatistics, Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA.|Oncogenomics Section, Pediatric Oncology Branch, Advanced Technology Center, National Cancer Institute, Gaithersburg, MD 20877, USA.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Departments of Anatomic Pathology and Molecular Genetics, Taussig Cancer Center and Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: Department of Pediatrics, Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Portland, OR 97239, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Keller