Authors' Affiliations: Department of Pediatrics; Cancer Genomics Project, Graduate School of Medicine; Laboratory of DNA Information Analysis and Sequence Data Analysis, Human Genome Center, Institute of Medical Science; Department of Cell Therapy and Transplantation Medicine, The University of Tokyo, Tokyo; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto; Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito, Ibaraki; Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Saitama; Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka; Gunma Children's Medical Center, Shibukawa, Gunma; Department of Hematology and Oncology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Hyogo; and National Center for Child Health and Development, Tokyo, Japan.
Authors' Affiliations: Department of Pediatrics; Cancer Genomics Project, Graduate School of Medicine; Laboratory of DNA Information Analysis and Sequence Data Analysis, Human Genome Center, Institute of Medical Science; Department of Cell Therapy and Transplantation Medicine, The University of Tokyo, Tokyo; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto; Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito, Ibaraki; Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Saitama; Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka; Gunma Children's Medical Center, Shibukawa, Gunma; Department of Hematology and Oncology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Hyogo; and National Center for Child Health and Development, Tokyo, JapanAuthors' Affiliations: Department of Pediatrics; Cancer Genomics Project, Graduate School of Medicine; Laboratory of DNA Information Analysis and Sequence Data Analysis, Human Genome Center, Institute of Medical Science; Department of Cell Therapy and Transplantation Medicine, The University of Tokyo, Tokyo; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto; Division of Pediatric Hematology and Oncology, Ibaraki Children's Hospital, Mito, Ibaraki; Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Saitama; Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka; Gunma Children's Medical Center, Shibukawa, Gunma; Department of Hematology and Oncology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Hyogo; and National Center for Child Health and Development, Tokyo, Japan.
Cancer Res. 2014 May 15;74(10):2742-9. doi: 10.1158/0008-5472.CAN-13-2470. Epub 2014 Mar 27.
Pleuropulmonary blastoma (PPB) is a rare pediatric malignancy whose pathogens are poorly understood. Recent reports suggest that germline mutations in the microRNA-processing enzyme DICER1 may contribute to PPB development. To investigate the genetic basis of this cancer, we performed whole-exome sequencing or targeted deep sequencing of multiple cases of PPB. We found biallelic DICER1 mutations to be very common, more common than TP53 mutations also found in many tumors. Somatic ribonuclease III (RNase IIIb) domain mutations were identified in all evaluable cases, either in the presence or absence of nonsense/frameshift mutations. Most cases had mutated DICER1 alleles in the germline with or without an additional somatic mutation in the remaining allele, whereas other cases displayed somatic mutations exclusively where the RNase IIIb domain was invariably affected. Our results highlight the role of RNase IIIb domain mutations in DICER1 along with TP53 inactivation in PPB pathogenesis.
肺胸膜胚细胞瘤 (PPB) 是一种罕见的儿科恶性肿瘤，其病原体尚未完全了解。最近的报告表明，miRNA 加工酶 DICER1 的种系突变可能有助于 PPB 的发展。为了研究这种癌症的遗传基础，我们对多个 PPB 病例进行了全外显子组测序或靶向深度测序。我们发现 DICER1 的双等位基因突变非常常见，比在许多肿瘤中也发现的 TP53 突变更为常见。在所有可评估的病例中均发现了体细胞核糖核酸酶 III (RNase IIIb) 结构域突变，无论是否存在无义/移码突变。大多数病例的 DICER1 等位基因在种系中发生突变，而在另一个等位基因中存在或不存在额外的体细胞突变，而其他病例则仅显示体细胞突变，且 RNase IIIb 结构域始终受到影响。我们的研究结果强调了在 PPB 发病机制中，RNase IIIb 结构域突变与 DICER1 以及 TP53 失活共同发挥作用。
