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Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X.

恶性腹膜间皮瘤的基因型分析揭示表观遗传调控基因BAP1、SETD2、DDX3X常见突变

Joseph NM,Chen YY,Nasr A,Yeh I,Talevich E,Onodera C,Bastian BC,Rabban JT,Garg K,Zaloudek C,Solomon DA
阅读:1448 Modern PathologyFeb 2017; 30 (2): 158 - 313:246-254 

Abstract

Malignant mesothelioma is a rare cancer that arises from the mesothelial cells that line the pleural cavity and less commonly from the peritoneal lining of the abdomen and pelvis. Most pleural mesotheliomas arise in patients with a history of asbestos exposure, whereas the association of peritoneal mesotheliomas with exposure to asbestos and other potential carcinogens is less clear, suggesting that the genetic alterations that drive malignant peritoneal mesothelioma may be unique from those in pleural mesothelioma. Treatment options for all malignant mesotheliomas are currently limited, with no known targeted therapies available. To better understand the molecular pathogenesis of malignant peritoneal mesothelioma, we sequenced 510 cancer-related genes in 13 patients with malignant mesothelioma arising in the peritoneal cavity. The most frequent genetic alteration was biallelic inactivation of the BAP1 gene, which occurred in 9/13 cases, with an additional two cases demonstrating monoallelic loss of BAP1. All 11 of these cases demonstrated loss of BAP1 nuclear staining by immunohistochemistry, whereas two tumors without BAP1 alteration and all 42 cases of histologic mimics in peritoneum (8 multilocular peritoneal inclusion cyst, 6 well-differentiated papillary mesothelioma of the peritoneum, 16 adenomatoid tumor, and 12 low-grade serous carcinoma of the ovary) demonstrated intact BAP1 nuclear staining. Additional recurrently mutated genes in this cohort of malignant peritoneal mesotheliomas included NF2 (3/13), SETD2 (2/13), and DDX3X (2/13). While these genes are known to be recurrently mutated in pleural mesotheliomas, the frequencies are distinct in peritoneal mesotheliomas, with nearly 85% of peritoneal tumors harboring BAP1 alterations versus only 20-30% of pleural tumors. Together, these findings demonstrate the importance of epigenetic modifiers including BAP1, SETD2, and DDX3X in mesothelial tumorigenesis and suggest opportunities for targeted therapies.

摘要

恶性间皮瘤是一种罕见的癌症,它起源于胸膜腔的间皮细胞。腹膜腔和盆腔的间皮瘤相对少见。多数胸膜间皮瘤发生于有石棉接触史的病人,腹膜间皮瘤和暴露于石棉以及潜在致癌因子之间的关系尚不明确,这提示造成恶性腹膜间皮瘤的基因改变可能不同于胸膜间皮瘤。由于没有靶向治疗,目前可选择的恶性间皮瘤治疗方法还很有限。为了更好的理解恶性腹膜间皮瘤的分子学发病机制,我们测序了13个患有恶性腹膜间皮瘤患者的510个癌症相关基因。最常见的基因突变是BAP1基因的等位基因失活,9/13例,另外有2例BAP1单等位基因丢失。全部的11例免疫组化均显示核染色阴性,2例没有BAP1基因突变的病例、42例组织学类似腹膜的标本(8例多房性腹膜包涵囊肿,6例分化良好的乳头状腹膜间皮瘤,16例腺瘤样瘤,12例低级别浆液性卵巢癌)均显示了完整的BAP1核着色阳性。恶性腹膜间皮瘤其它常见突变的基因包括NF2 (3/13),SETD2 (2/13)和 DDX3X (2/13)。尽管胸膜间皮瘤的这些基因也经常发生突变,但是同腹膜间皮瘤的突变频率截然不同,后者BAP1的突变频率将近85%而前者仅为20-30%。总之,这些研究证明了表观遗传修改因子——包括BAP1、SETD2和DDX3X——在间皮瘤发生中的重要性,并提示了靶向治疗的可能。

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