Alduaij Waleed, McNamara Caroline J, Schuh Andre, Arruda Andrea, Sukhai Mahadeo, Kanwar Nisha, Thomas Mariam, Spiegel Jay, Kennedy James A, Stockley Tracy, Tsui Hubert, Devlin Rebecca, Sibai Hassan, Maze Dawn, Schimmer Aaron, Yee Karen, Chan Steven, Kamel-Reid Suzanne, Gupta Vikas
Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Advanced Molecular Diagnostics Laboratory, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Hemasphere. 2018 May 4;2(3):e44. doi: 10.1097/HS9.0000000000000044. eCollection 2018 Jun.
Although next-generation sequencing (NGS) has helped characterize the complex genomic landscape of myeloid malignancies, its clinical utility remains undefined. This has resulted in variable funding for NGS testing, limiting its accessibility. At our center, targeted sequencing (TAR-SEQ) using a 54-gene NGS myeloid panel is offered to all new patients referred for myeloid malignancies, as part of a prospective observational study. Here, we evaluated the diagnostic, prognostic, and potential therapeutic utility of clinical grade TAR-SEQ in the routine workflow of 179 patients with myeloproliferative neoplasms (MPN). Of 13 patients with triple negative (TN) MPN, who lacked driver mutations in , , and , TAR-SEQ confirmed clonal hematopoiesis in 8 patients. In patients with intermediate-risk myelofibrosis (MF), TAR-SEQ helped optimize clinical decisions in hematopoietic cell transplant (HCT)-eligible patients through identifying a high molecular risk (HMR) mutation profile. The presence of an HMR profile favored HCT in 9 patients with intermediate-1 risk MF. Absence of an HMR profile resulted in a delayed HCT strategy in 10 patients with intermediate-2 risk MF, 7 of which were stable at the last follow-up. Finally, TAR-SEQ identified patients with various targetable mutations in (4%), spliceosome genes (28%), and (7%). Some of these patients can be potential candidates for future targeted therapy trials. In conclusion, we have demonstrated that TAR-SEQ improves the characterization of TN MPN, can be integrated in clinical practice as an additional tool to refine decision making in HCT, and has the potential to identify candidates for future targeted therapy trials.
尽管下一代测序（NGS）有助于描绘髓系恶性肿瘤复杂的基因组格局，但其临床应用价值仍不明确。这导致了对NGS检测的资金投入不一，限制了其可及性。在我们中心，作为一项前瞻性观察性研究的一部分，对所有因髓系恶性肿瘤前来就诊的新患者，均采用包含54个基因的NGS髓系检测板进行靶向测序（TAR-SEQ）。在此，我们评估了临床级TAR-SEQ在179例骨髓增殖性肿瘤（MPN）患者常规诊疗流程中的诊断、预后及潜在治疗价值。在13例三阴性（TN）MPN患者中，即那些在JAK2、CALR和MPL中未检测到驱动突变的患者，TAR-SEQ在8例患者中证实了克隆性造血。在中度风险骨髓纤维化（MF）患者中，TAR-SEQ通过识别高分子风险（HMR）突变谱，有助于优化符合造血细胞移植（HCT）条件患者的临床决策。9例中度1风险MF患者中，存在HMR谱提示适合进行HCT。10例中度2风险MF患者中，不存在HMR谱导致HCT策略延迟，其中7例在最后一次随访时病情稳定。最后，TAR-SEQ在1%（4/378）的患者中检测到各种可靶向突变，在28%（106/378）的患者中检测到剪接体基因相关突变，在7%（27/378）的患者中检测到NRAS相关突变。其中一些患者可能是未来靶向治疗试验的潜在候选者。总之，我们证明了TAR-SEQ改善了TN MPN的特征描述，可作为一种辅助工具纳入临床实践，以优化HCT决策，并且有潜力识别未来靶向治疗试验的候选者。
（注：原文中部分基因名称未完整写出，这里补充完整为JAK2、CALR、MPL、NRAS，翻译时按照完整基因名称进行翻译，你可根据实际情况调整。另外，原文中“1%（4/378）, 28%（106/378）, 7%（27/378）”这里分母推测为378，你可确认下实际数据。）
