Park Silvia, Lee Jeeyun, Do In-Gu, Jang Jiryeon, Rho Kyoohyoung, Ahn Seonjoo, Maruja Lira, Kim Sung Joo, Kim Kyoung-Mee, Mao Mao, Oh Ensel, Kim Yu Jin, Kim Jhingook, Choi Yoon-La
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Sci Rep. 2014 Jan 10;4:3623. doi: 10.1038/srep03623.
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.
横纹肌肉瘤（RMS）是儿童中最常见的软组织肿瘤类型。然而，它在成人中很少见，因此，对于成人RMS患者最合适的治疗策略知之甚少。我们对一名27岁男性患者来源的RMS细胞进行了基因组分析，该患者的疾病对治疗难治。分析了疾病进展期间获得的来自原发性肿瘤的腹膜种植结节、胸膜转移灶、恶性胸腔积液和腹水。全外显子测序揭示了23个候选变异，23个突变中的10个通过桑格测序得到验证。10个突变中的3个在原发性和转移性肿瘤中均存在，3个突变仅在转移标本中检测到。比较基因组杂交阵列分析显示12q13 - 14区域有显著扩增，更具体地说，细胞周期蛋白依赖性激酶4（CDK4）原癌基因高度扩增。在蛋白质和RNA水平均观察到间变性淋巴瘤激酶（ALK）过表达。然而，使用NanoString技术的ALK融合检测未显示任何ALK重排。在原发性和转移性RMS细胞之间观察到很少的基因异质性。我们提出位于12q14的CDK4是RMS治疗药物开发的潜在靶点。
