Gay Laurie M, Kim Sungeun, Fedorchak Kyle, Kundranda Madappa, Odia Yazmin, Nangia Chaitali, Battiste James, Colon-Otero Gerardo, Powell Steven, Russell Jeffery, Elvin Julia A, Vergilio Jo-Anne, Suh James, Ali Siraj M, Stephens Philip J, Miller Vincent A, Ross Jeffrey S
Foundation Medicine, Inc., Cambridge, Massachusetts, USA
Department of Pathology, Albany Medical College, Albany, New York, USA.
Oncologist. 2017 Jul;22(7):834-842. doi: 10.1634/theoncologist.2016-0287. Epub 2017 May 11.
Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit.
We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions).
Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was (17%), with GA in , , , and occurring in 7% of samples.
We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB.
Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was (17%), and alterations in , , , or were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics.
嗅神经母细胞瘤（ENB），也称为嗅觉神经母细胞瘤，是一种罕见的嗅黏膜恶性肿瘤。尽管采用手术切除联合放疗及辅助化疗，但ENB常复发且进展迅速。目前针对复发ENB的多模式非靶向治疗临床获益有限。
我们探究复发或难治性ENB的综合基因组分析（CGP）能否揭示可用于识别这些患者潜在靶向治疗方法的基因组改变（GA）。使用基于杂交捕获、衔接子连接的二代测序分析，对41例连续临床病例的福尔马林固定、石蜡包埋切片进行CGP，平均覆盖深度达593倍。对结果分析碱基替换、插入和缺失、特定重排及拷贝数变化（扩增和纯合缺失）。
临床相关GA（CRGA）定义为与市场上已有的或正在临床试验中评估的药物相关的GA。共有28例ENB存在GA，每个样本平均有1.5个GA。约一半的ENB（21例，51%）具有至少一种CRGA，每个样本平均有1个CRGA。最常发生改变的基因是 （17%）， 、 、 和 中的GA在7%的样本中出现。
我们报告了41例ENB肿瘤的综合基因组图谱。CGP揭示了潜在的新治疗靶点，包括mTOR、CDK和生长因子信号通路中的可靶向GA，突出了基因组分析在ENB中的临床价值。
对41例复发或难治性ENB的综合基因组分析揭示了复发性改变或突变类型，包括5号染色体上编码的酪氨酸激酶扩增以及影响mTOR/PI3K通路中基因的突变。约一半的ENB（21例，51%）具有至少一种临床相关基因组改变（CRGA），每个样本平均有1个CRGA。最常发生改变的基因是 （17%），7%的样本中鉴定出 、 、 或 的改变。结合肿瘤基因组学展示了激酶抑制剂舒尼替尼、依维莫司和帕唑帕尼治疗的反应。
