Marks Lianna J, Oberg Jennifer A, Pendrick Danielle, Sireci Anthony N, Glasser Chana, Coval Carrie, Zylber Rebecca J, Chung Wendy K, Pang Jiuhong, Turk Andrew T, Hsiao Susan J, Mansukhani Mahesh M, Glade Bender Julia L, Kung Andrew L, Sulis Maria Luisa
Department of Pediatric Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Division of Pediatric Hematology, Oncology and Stem Cell Transplant, Columbia University Medical Center, New York, NY, United States.
Front Pediatr. 2017 Dec 12;5:265. doi: 10.3389/fped.2017.00265. eCollection 2017.
The advent of comprehensive genomic profiling has markedly advanced the understanding of the biology of pediatric hematological malignancies, however, its application to clinical care is still unclear. We present our experience integrating genomic data into the clinical management of children with high-risk hematologic malignancies and blood disorders and describe the broad impact that genomic profiling has in multiple aspects of patient care.
The Precision in Pediatric Sequencing Program at Columbia University Medical Center instituted prospective clinical next-generation sequencing (NGS) for high-risk malignancies and blood disorders. Testing included cancer whole exome sequencing (WES) of matched tumor-normal samples or targeted sequencing of 467 cancer-associated genes, when sample adequacy was a concern, and tumor transcriptome (RNA-seq). A multidisciplinary molecular tumor board conducted interpretation of results and final tiered reports were transmitted to the electronic medical record according to patient preferences.
Sixty-nine samples from 56 patients with high-risk hematologic malignancies and blood disorders were sequenced. Patients carried diagnoses of myeloid malignancy ( = 25), lymphoid malignancy ( = 25), or histiocytic disorder ( = 6). Six patients had only constitutional WES, performed for a suspicion of an inherited predisposition for their disease. For the remaining 50 patients, tumor was sequenced with matched normal tissue when available. The mean number of somatic variants per sample was low across the different disease categories (2.85 variants/sample). Interestingly, a gene fusion was identified by RNA-seq in 58% of samples who had adequate RNA available for testing. Molecular profiling of tumor tissue led to clinically impactful findings in 90% of patients. Forty patients (80%) had at least one targetable gene variant or fusion identified in their tumor tissue; however, only seven received targeted therapy. Importantly, NGS findings contributed to the refinement of diagnosis and prognosis for 34% of patients. Known or likely pathogenic germline alterations were discovered in 24% of patients involving cancer predisposition genes in 12% of cases.
Incorporating whole exome and transcriptome profiling of tumor and normal tissue into clinical practice is feasible, and the value that comprehensive testing provides extends beyond the ability to target-specific mutations.
全面基因组分析的出现显著推进了对儿童血液系统恶性肿瘤生物学特性的理解，然而，其在临床护理中的应用仍不明确。我们介绍了将基因组数据整合到高危血液系统恶性肿瘤和血液疾病患儿临床管理中的经验，并描述了基因组分析在患者护理多个方面产生的广泛影响。
哥伦比亚大学医学中心的儿科精准测序项目对高危恶性肿瘤和血液疾病开展了前瞻性临床下一代测序（NGS）。检测包括匹配的肿瘤-正常样本的癌症全外显子组测序（WES），或在样本充足性存疑时对467个癌症相关基因进行靶向测序，以及肿瘤转录组测序（RNA-seq）。一个多学科分子肿瘤委员会对结果进行解读，并根据患者偏好将最终的分层报告传输至电子病历。
对56例高危血液系统恶性肿瘤和血液疾病患儿的69份样本进行了测序。患者的诊断包括髓系恶性肿瘤（n = 25）、淋巴系恶性肿瘤（n = 25）或组织细胞疾病（n = 6）。6例患者仅进行了全外显子组测序，因怀疑其疾病存在遗传易感性。对于其余50例患者，如有匹配的正常组织，则对肿瘤进行测序。不同疾病类别中每个样本的体细胞变异平均数较低（2.85个变异/样本）。有趣的是，在有足够RNA用于检测的样本中，58%通过RNA-seq鉴定出基因融合。肿瘤组织的分子分析在90%的患者中产生了具有临床意义的结果。40例患者（80%）在其肿瘤组织中至少鉴定出一种可靶向的基因变异或融合；然而，只有7例接受了靶向治疗。重要的是，NGS结果有助于34%的患者完善诊断和预后评估。在24%的患者中发现了已知或可能致病的种系改变，其中12%的病例涉及癌症易感基因。
将肿瘤和正常组织的全外显子组和转录组分析纳入临床实践是可行的，全面检测所提供的价值不仅限于针对特定突变的能力。
