含有Valosin的蛋白质(VCP)是一种重要的蛋白质,具有许多重要功能,主要与泛素-蛋白酶体系统有关,该系统提供蛋白质质量控制。VCP相关包涵体肌病伴骨Paget病和额颞叶痴呆,也称为VCP疾病和多系统蛋白病(MSP1),是由人类9号染色体上VCP基因的单等位基因变体引起的常染色体显性疾病。VCP也与癌症密切相关,在前列腺癌等几种癌症中发现VCP过度活跃,胰腺,子宫内膜,食道癌和骨肉瘤。由于MSP1是由VCP基因中功能变异的获得引起的,我们假设患者出现恶性肿瘤的风险增加.我们从回顾性数据集中描述了3例罕见恶性肿瘤和4例常见癌症。
在调查了106个已确认VCP变体的家族后,我们发现包括恶性外周神经鞘瘤在内的罕见肿瘤发病率较高,多形性黄色星形细胞瘤和胸腺瘤。这些受试者中的一些在显示其他经典VCP疾病表现之前发展为癌症。我们还介绍了常见癌症的病例;然而,与普通人群相比,我们没有发现发病率增加。这可能与这种疾病的早期死亡率有关,因为大多数患者死于呼吸衰竭或心肌病,比大多数癌症出现的年龄更早。
这是第一项将VCP疾病的表型扩展到可能包括罕见癌症的研究,并强调了进一步研究VCP在癌症发展中的作用的重要性。这项在VCP病患者中的研究结果表明,患者可能会增加罕见肿瘤的风险。一项更大的研究将确定患有VCP疾病的患者是否以比普通人群更高的速度发展癌症。如果是这样的话,他们应该更频繁地随访,并筛查癌症的复发和转移。
Valosin containing protein (VCP) is an important protein with many vital functions mostly related to the ubiquitin-proteasome system that provides protein quality control. VCP-associated inclusion body myopathy with Paget disease of bone and frontotemporal dementia, also termed VCP disease and multisystem proteinopathy (MSP 1), is an autosomal dominant disorder caused by monoallelic variants in the VCP gene on human chromosome 9. VCP has also been strongly involved in cancer, with over-activity of VCP found in several cancers such as prostate, pancreatic, endometrial, esophageal cancers and osteosarcoma. Since MSP1 is caused by gain of function variants in the VCP gene, we hypothesized our patients would show increased risk for developing malignancies. We describe cases of 3 rare malignancies and 4 common cancers from a retrospective dataset.
Upon surveying 106 families with confirmed VCP variants, we found a higher rate of rare tumors including malignant peripheral nerve sheath tumor, anaplastic pleomorphic xanthoastrocytoma and thymoma. Some of these subjects developed cancer before displaying other classic VCP disease manifestations. We also present cases of common cancers; however, we did not find an increased rate compared to the general population. This could be related to the early mortality associated with this disease, since most patients die in their 50-60 s due to respiratory failure or cardiomyopathy which is earlier than the age at which most cancers appear.
This is the first study that expands the phenotype of VCP disease to potentially include rare cancers and highlights the importance of further investigation of the role of VCP in cancer development. The results of this study in VCP disease patients suggest that patients may be at an increased risk for rare tumors. A larger study will determine if patients with VCP disease develop cancer at a higher rate than the general population. If that is the case, they should be followed up more frequently and screened for recurrence and metastasis of their cancer.