Lu Hsiang-Chih, Eulo Vanessa, Apicelli Anthony J, Pekmezci Melike, Tao Yu, Luo Jingqin, Hirbe Angela C, Dahiya Sonika
Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Oncotarget. 2018 May 1;9(33):23018-23028. doi: 10.18632/oncotarget.25195.
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive soft tissue sarcomas that can occur sporadically or in the setting of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. These tumors carry a dismal overall survival. Previous work in our lab had identified ATRX chromatin remodeler (), previously termed, Alpha Thalassemia/Mental Retardation Syndrome X Linked as a gene mutated in a subset of MPNSTs. Given the great need for novel biomarkers and therapeutic targets for MPNSTs, we sought to determine the expression of ATRX in a larger subset of sporadic and NF1 associated MPNSTs (NF1-MPNSTs). We performed immunohistochemistry (IHC) on 74 MPNSTs (43 NF1-associated and 31 sporadic), 21 plexiform neurofibromas, and 9 atypical neurofibromas. Using this approach, we have demonstrated that 58% (43/74) of MPNSTs have aberrant ATRX expression (<80% nuclear expression) compared to only 7% (2/30) of benign (plexiform and atypical) neurofibromas. Second, we demonstrated that 65% (28/43) of NF1-MPNSTs displayed aberrant ATRX expression as did 48% (15/31) of sporadic MPNSTs. Finally, we show that aberrant ATRX expression was associated with a significantly decreased overall survival for patients with NF1-MPNST (median OS of 17.9 months for aberrant expression and median OS not met (>120 months) for intact expression, = 0.0276). In summary, we demonstrate that ATRX is aberrantly expressed in the majority of NF1-MPNSTs, but not plexiform or atypical neurofibromas. Additionally, aberrant ATRX expression is associated with decreased overall survival in NF1-MPNST, but not sporadic MPNST and may serve as a prognostic marker for patients with NF1-MPNST.
恶性外周神经鞘瘤（MPNSTs）是侵袭性软组织肉瘤，可散发性发生或在1型神经纤维瘤病（NF1）癌症易感综合征背景下发生。这些肿瘤的总体生存率很低。我们实验室之前的研究已确定ATRX染色质重塑因子（以前称为X连锁α地中海贫血/智力迟钝综合征）是在一部分MPNSTs中发生突变的基因。鉴于对MPNSTs新型生物标志物和治疗靶点的迫切需求，我们试图确定ATRX在更大的散发性和NF1相关MPNSTs（NF1-MPNSTs）亚组中的表达情况。我们对74例MPNSTs（43例NF1相关和31例散发性）、21例丛状神经纤维瘤和9例非典型神经纤维瘤进行了免疫组织化学（IHC）检测。通过这种方法，我们证明58%（43/74）的MPNSTs存在异常ATRX表达（核表达<80%），而良性（丛状和非典型）神经纤维瘤中只有7%（2/30）存在这种情况。其次，我们证明65%（28/43）的NF1-MPNSTs显示异常ATRX表达，散发性MPNSTs中这一比例为48%（15/31）。最后，我们表明异常ATRX表达与NF1-MPNST患者的总体生存率显著降低相关（异常表达患者的中位总生存期为17.9个月，完整表达患者的中位总生存期未达到（>120个月），P = 0.0276）。总之，我们证明ATRX在大多数NF1-MPNSTs中异常表达，但在丛状或非典型神经纤维瘤中不表达。此外，异常ATRX表达与NF1-MPNST患者的总体生存率降低相关，但与散发性MPNST无关，并且可能作为NF1-MPNST患者的预后标志物。
