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Abstract：
BACKGROUND: Sinonasal Undifferentiated Carcinoma (SNUC) is a rare and aggressive skull base tumor with poor survival and limited treatment options. To date, targeted sequencing studies have identified IDH2 and SMARCB1 as potential driver alterations, but the molecular alterations found in SMARCB1 wild type tumors are unknown.
METHODS: We evaluated survival outcomes in a cohort of 46 SNUC patients treated at an NCI designated cancer center and identify clinical and disease variables associated with survival on Kaplan-Meier and Cox multivariate survival analysis. We performed exome sequencing to characterize a series of SNUC tumors (n = 5) and cell line (MDA8788-6) to identify high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA were utilized for validation of a novel PGAP3-SRPK1 gene fusion.
RESULTS: Overall survival analysis revealed no significant difference in outcomes between patients treated with surgery +/- CRT and CRT alone. Tobacco use was the only significant predictor of survival. We also confirmed previously published findings on IDH and SMARC family mutations and identified novel recurrent aberrations in the JAK/STAT and PI3K pathways. We also validated a novel PGAP3-SRPK1 gene fusion in the SNUC cell line, and show that knockdown of the fusion is negatively associated with EGFR, E2F and MYC signaling.
CONCLUSIONS: Collectively, these data demonstrate recurrent alterations in the SWI/SNF family as well as IDH, JAK/STAT, and PI3K pathways and discover a novel fusion gene (PGAP3-SRPK1). These data aim to improve understanding of possible driver mutations and guide future therapeutic strategies for this disease.
METHODS: We evaluated survival outcomes in a cohort of 46 SNUC patients treated at an NCI designated cancer center and identify clinical and disease variables associated with survival on Kaplan-Meier and Cox multivariate survival analysis. We performed exome sequencing to characterize a series of SNUC tumors (n = 5) and cell line (MDA8788-6) to identify high confidence mutations, copy number alterations, microsatellite instability, and fusions. Knockdown studies using siRNA were utilized for validation of a novel PGAP3-SRPK1 gene fusion.
RESULTS: Overall survival analysis revealed no significant difference in outcomes between patients treated with surgery +/- CRT and CRT alone. Tobacco use was the only significant predictor of survival. We also confirmed previously published findings on IDH and SMARC family mutations and identified novel recurrent aberrations in the JAK/STAT and PI3K pathways. We also validated a novel PGAP3-SRPK1 gene fusion in the SNUC cell line, and show that knockdown of the fusion is negatively associated with EGFR, E2F and MYC signaling.
CONCLUSIONS: Collectively, these data demonstrate recurrent alterations in the SWI/SNF family as well as IDH, JAK/STAT, and PI3K pathways and discover a novel fusion gene (PGAP3-SRPK1). These data aim to improve understanding of possible driver mutations and guide future therapeutic strategies for this disease.
摘要：
背景：鼻窦未分化癌（SNUC）是一种罕见且侵袭性的颅底肿瘤，生存率低，治疗选择有限。迄今为止,靶向测序研究已经确定IDH2和SMARCB1是潜在的驱动改变，但是在SMARCB1野生型肿瘤中发现的分子改变是未知的。
方法：我们评估了在NCI指定癌症中心接受治疗的46名SNUC患者队列的生存结果，并通过Kaplan-Meier和Cox多变量生存分析确定了与生存相关的临床和疾病变量。我们进行外显子组测序以表征一系列SNUC肿瘤（n=5）和细胞系（MDA8788-6），以鉴定高置信度突变，拷贝数更改，微卫星不稳定，和融合。使用siRNA的敲减研究用于验证新的PGAP3-SRPK1基因融合体。
结果：总生存分析显示，手术+/-CRT和单纯CRT治疗的患者在预后方面没有显著差异。烟草使用是生存的唯一重要预测因素。我们还证实了以前发表的关于IDH和SMARC家族突变的发现，并在JAK/STAT和PI3K通路中发现了新的复发性畸变。我们还在SNUC细胞系中验证了一种新型的PGAP3-SRPK1基因融合体，并显示融合的敲除与EGFR呈负相关，E2F和MYC信号。
结论：总的来说，这些数据表明SWI/SNF家族以及IDH的复发性改变，JAK/STAT,和PI3K通路，并发现了一个新的融合基因(PGAP3-SRPK1)。这些数据旨在提高对可能的驱动突变的理解，并指导该疾病的未来治疗策略。
方法：我们评估了在NCI指定癌症中心接受治疗的46名SNUC患者队列的生存结果，并通过Kaplan-Meier和Cox多变量生存分析确定了与生存相关的临床和疾病变量。我们进行外显子组测序以表征一系列SNUC肿瘤（n=5）和细胞系（MDA8788-6），以鉴定高置信度突变，拷贝数更改，微卫星不稳定，和融合。使用siRNA的敲减研究用于验证新的PGAP3-SRPK1基因融合体。
结果：总生存分析显示，手术+/-CRT和单纯CRT治疗的患者在预后方面没有显著差异。烟草使用是生存的唯一重要预测因素。我们还证实了以前发表的关于IDH和SMARC家族突变的发现，并在JAK/STAT和PI3K通路中发现了新的复发性畸变。我们还在SNUC细胞系中验证了一种新型的PGAP3-SRPK1基因融合体，并显示融合的敲除与EGFR呈负相关，E2F和MYC信号。
结论：总的来说，这些数据表明SWI/SNF家族以及IDH的复发性改变，JAK/STAT,和PI3K通路，并发现了一个新的融合基因(PGAP3-SRPK1)。这些数据旨在提高对可能的驱动突变的理解，并指导该疾病的未来治疗策略。
