Padovan-Merhar Olivia M, Raman Pichai, Ostrovnaya Irina, Kalletla Karthik, Rubnitz Kaitlyn R, Sanford Eric M, Ali Siraj M, Miller Vincent A, Mossé Yael P, Granger Meaghan P, Weiss Brian, Maris John M, Modak Shakeel
Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, PA, United States of America.
Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.
PLoS Genet. 2016 Dec 20;12(12):e1006501. doi: 10.1371/journal.pgen.1006501. eCollection 2016 Dec.
Neuroblastoma is characterized by a relative paucity of recurrent somatic mutations at diagnosis. However, recent studies have shown that the mutational burden increases at relapse, likely as a result of clonal evolution of mutation-carrying cells during primary treatment. To inform the development of personalized therapies, we sought to further define the frequency of potentially actionable mutations in neuroblastoma, both at diagnosis and after chemotherapy. We performed a retrospective study to determine mutation frequency, the only inclusion criterion being availability of cancer gene panel sequencing data from Foundation Medicine. We analyzed 151 neuroblastoma tumor samples: 44 obtained at diagnosis, 42 at second look surgery or biopsy for stable disease after chemotherapy, and 59 at relapse (6 were obtained at unknown time points). Nine patients had multiple tumor biopsies. ALK was the most commonly mutated gene in this cohort, and we observed a higher frequency of suspected oncogenic ALK mutations in relapsed disease than at diagnosis. Patients with relapsed disease had, on average, a greater number of mutations reported to be recurrent in cancer, and a greater number of mutations in genes that are potentially targetable with available therapeutics. We also observed an enrichment of reported recurrent RAS/MAPK pathway mutations in tumors obtained after chemotherapy. Our data support recent evidence suggesting that neuroblastomas undergo substantial mutational evolution during therapy, and that relapsed disease is more likely to be driven by a targetable oncogenic pathway, highlighting that it is critical to base treatment decisions on the molecular profile of the tumor at the time of treatment. However, it will be necessary to conduct prospective clinical trials that match sequencing results to targeted therapeutic intervention to determine if cancer genomic profiling improves patient outcomes.
神经母细胞瘤的特点是在诊断时复发性体细胞突变相对较少。然而，最近的研究表明，复发时突变负担会增加，这可能是由于携带突变的细胞在初次治疗期间发生克隆进化所致。为了为个性化治疗的发展提供信息，我们试图进一步确定神经母细胞瘤在诊断时和化疗后的潜在可操作突变频率。我们进行了一项回顾性研究以确定突变频率，唯一的纳入标准是可获得来自Foundation Medicine的癌症基因检测测序数据。我们分析了151份神经母细胞瘤肿瘤样本：44份在诊断时获得，42份在化疗后对稳定疾病进行二次手术或活检时获得，59份在复发时获得（6份在未知时间点获得）。9名患者有多个肿瘤活检样本。ALK是该队列中最常发生突变的基因，我们观察到复发性疾病中疑似致癌性ALK突变的频率高于诊断时。复发患者平均有更多报告在癌症中复发的突变，以及更多在现有治疗方法可能靶向的基因中的突变。我们还观察到化疗后获得的肿瘤中报告的复发性RAS/MAPK通路突变有所富集。我们的数据支持最近的证据，表明神经母细胞瘤在治疗期间经历了大量的突变进化，并且复发性疾病更可能由可靶向的致癌途径驱动，这突出了根据治疗时肿瘤的分子特征做出治疗决策的重要性。然而，有必要进行前瞻性临床试验，将测序结果与靶向治疗干预相匹配，以确定癌症基因组分析是否能改善患者预后。
