title: Aberrant CDK4 amplification in refractory rhabdomyosarcoma as identified by genomic profiling.
abstract: Rhabdomyosarcoma (RMS) is the most commonly occurring type of soft tissue tumor in children. However, it is rare in adults, and therefore, very little is known about the most appropriate treatment strategy for adult RMS patients. We performed genomic analysis of RMS cells derived from a 27-year-old male patient whose disease was refractory to treatment. A peritoneal seeding nodule from the primary tumor, pleural metastases, malignant pleural effusion, and ascites obtained during disease progression, were analyzed. Whole exome sequencing revealed 23 candidate variants, and 10 of 23 mutations were validated by Sanger sequencing. Three of 10 mutations were present in both primary and metastatic tumors, and 3 mutations were detected only in metastatic specimens. Comparative genomic hybridization array analysis revealed prominent amplification in the 12q13-14 region, and more specifically, the CDK4 proto-oncogene was highly amplified. ALK overexpression was observed at both protein and RNA levels. However, an ALK fusion assay using NanoString technology failed to show any ALK rearrangements. Little genetic heterogeneity was observed between primary and metastatic RMS cells. We propose that CDK4, located at 12q14, is a potential target for drug development for RMS treatment.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Silvia
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: In-Gu
authors.initials: IG
authors.lastname: Do
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jiryeon
authors.initials: J
authors.lastname: Jang
authors.affiliation: Korean Bioinformation Center (KOBIC), KRIBB, Daejeon 305-806, Korea.
authors.forename: Kyoohyoung
authors.initials: K
authors.lastname: Rho
authors.affiliation: Korean Bioinformation Center (KOBIC), KRIBB, Daejeon 305-806, Korea.
authors.forename: Seonjoo
authors.initials: S
authors.lastname: Ahn
authors.affiliation: Pfizer Oncology, 10724 Science Center Dr, San Diego, CA 92121, USA.
authors.forename: Lira
authors.initials: L
authors.lastname: Maruja
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sung Joo
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Kyoung-Mee
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Pfizer Oncology, 10724 Science Center Dr, San Diego, CA 92121, USA.
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.affiliation: Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Ensel
authors.initials: E
authors.lastname: Oh
authors.affiliation: Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jhingook
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Yoon-La
authors.initials: YL
authors.lastname: Choi
mesh_terms: D000328:Adult; D002881:Chromosomes, Human, Pair 12; D055028:Comparative Genomic Hybridization; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D018450:Disease Progression; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D000090063:Proto-Oncogene Mas; D012208:Rhabdomyosarcoma / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D014057:Tomography, X-Ray Computed
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4