Aberrant CDK4 Amplification in Refractory Rhabdomyosarcoma as Identified by Genomic Profiling

• DOI: 10.1038/srep03623
• Publication Date: 2014-01-10T10:09:10Z
• Authors: Silvia Park; Jeeyun Lee; In-Gu Do; Jiryeon Jang; Kyoohyoung Rho; Seonjoo Ahn; Lira Maruja; Sung Joo Kim; Kyoung-Mee Kim; Mao Mao; Ensel Oh; Yu Jin Kim; Jhingook Kim; Yoon-La Choi
• Keywords: Adult; Male; 0301 basic medicine; Comparative Genomic Hybridization; Chromosomes, Human, Pair 12; Genome, Human; Gene Expression Profiling; Cyclin-Dependent Kinase 4; Proto-Oncogene Mas; Article; 03 medical and health sciences; Rhabdomyosarcoma; Disease Progression; Humans; Neoplasm Metastasis; Tomography, X-Ray Computed

AbstractRhabdomyosarcoma (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.