Parsons D Williams, Roy Angshumoy, Yang Yaping, Wang Tao, Scollon Sarah, Bergstrom Katie, Kerstein Robin A, Gutierrez Stephanie, Petersen Andrea K, Bavle Abhishek, Lin Frank Y, López-Terrada Dolores H, Monzon Federico A, Hicks M John, Eldin Karen W, Quintanilla Norma M, Adesina Adekunle M, Mohila Carrie A, Whitehead William, Jea Andrew, Vasudevan Sanjeev A, Nuchtern Jed G, Ramamurthy Uma, McGuire Amy L, Hilsenbeck Susan G, Reid Jeffrey G, Muzny Donna M, Wheeler David A, Berg Stacey L, Chintagumpala Murali M, Eng Christine M, Gibbs Richard A, Plon Sharon E
Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3The Human Genome Sequencing Center, Baylor College of Medicine, Houston, T.
Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston4The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas5Department of Pathology, Texas Children's Hospital, Houston6Department of Pathology a.
JAMA Oncol. 2016 May 1;2(5):616-624. doi: 10.1001/jamaoncol.2015.5699.
Whole-exome sequencing (WES) has the potential to reveal tumor and germline mutations of clinical relevance, but the diagnostic yield for pediatric patients with solid tumors is unknown.
To characterize the diagnostic yield of combined tumor and germline WES for children with solid tumors.
Unselected children with newly diagnosed and previously untreated central nervous system (CNS) and non-CNS solid tumors were prospectively enrolled in the BASIC3 study at a large academic children's hospital during a 23-month period from August 2012 through June 2014. Blood and tumor samples underwent WES in a certified clinical laboratory with genetic results categorized on the basis of perceived clinical relevance and entered in the electronic health record.
Clinical categorization of somatic mutations; frequencies of deleterious germline mutations related to patient phenotype and incidental medically-actionable mutations.
Of the first 150 participants (80 boys and 70 girls, mean age, 7.4 years), tumor samples adequate for WES were available from 121 patients (81%). Somatic mutations of established clinical utility (category I) were reported in 4 (3%) of 121 patients, with mutations of potential utility (category II) detected in an additional 29 (24%) of 121 patients. CTNNB1 was the gene most frequently mutated, with recurrent mutations in KIT, TSC2, and MAPK pathway genes (BRAF, KRAS, and NRAS) also identified. Mutations in consensus cancer genes (category III) were found in an additional 24 (20%) of 121 tumors. Fewer than half of somatic mutations identified were in genes known to be recurrently mutated in the tumor type tested. Diagnostic germline findings related to patient phenotype were discovered in 15 (10%) of 150 cases: 13 pathogenic or likely pathogenic dominant mutations in adult and pediatric cancer susceptibility genes (including 2 each in TP53, VHL, and BRCA1), 1 recessive liver disorder with hepatocellular carcinoma (TJP2), and 1 renal diagnosis (CLCN5). Incidental findings were reported in 8 (5%) of 150 patients. Most patients harbored germline uncertain variants in cancer genes (98%), pharmacogenetic variants (89%), and recessive carrier mutations (85%).
Tumor and germline WES revealed mutations in a broad spectrum of genes previously implicated in both adult and pediatric cancers. Combined reporting of tumor and germline WES identified diagnostic and/or potentially actionable findings in nearly 40% of newly diagnosed pediatric patients with solid tumors.
全外显子组测序（WES）有潜力揭示具有临床相关性的肿瘤和种系突变，但实体瘤患儿的诊断率尚不清楚。
描述实体瘤患儿联合肿瘤和种系WES的诊断率。
2012年8月至2014年6月的23个月期间，在一家大型学术儿童医院的BASIC3研究中，前瞻性纳入了未经过选择的新诊断且未经治疗的中枢神经系统（CNS）和非CNS实体瘤患儿。血液和肿瘤样本在一家经过认证的临床实验室进行WES，基因检测结果根据感知到的临床相关性进行分类，并录入电子健康记录。
体细胞突变的临床分类；与患者表型相关的有害种系突变频率以及偶然发现的具有医学可操作性的突变。
在前150名参与者（80名男孩和70名女孩，平均年龄7.4岁）中，121名患者（81%）有足够用于WES的肿瘤样本。121名患者中有4名（3%）报告了具有既定临床效用（I类）的体细胞突变，另有29名（24%）患者检测到具有潜在效用（II类）的突变。CTNNB1是最常发生突变的基因，还发现了KIT基因、TSC2基因以及MAPK通路基因（BRAF、KRAS和NRAS）的复发性突变。在121个肿瘤中的另外24个（20%）发现了共识癌症基因（III类）的突变。所鉴定的体细胞突变中，不到一半位于已知在所检测肿瘤类型中经常发生突变的基因中。在150例病例中有15例（10%）发现了与患者表型相关的诊断性种系结果：成人和儿童癌症易感基因中有13个致病性或可能致病性显性突变（包括TP53、VHL和BRCA1各2个），1例伴有肝细胞癌的隐性肝病（TJP2），以及1例肾脏诊断（CLCN5）。150名患者中有8名（5%）报告了偶然发现。大多数患者在癌症基因（98%）、药物遗传学基因（89%）和隐性携带者突变（85%）中携带种系不确定变异。
肿瘤和种系WES揭示了一系列先前在成人和儿童癌症中涉及的基因中的突变。联合报告肿瘤和种系WES在近40%新诊断的实体瘤患儿中发现了诊断性和/或潜在可操作的结果。
