Antonelli Manila, Raso Alessandro, Mascelli Samantha, Gessi Marco, Nozza Paolo, Coli Antonella, Gardiman Marina P, Arcella Antonietta, Massimino Maura, Buttarelli Francesca R, Giangaspero Felice
*Department of Radiological, Oncological and Anatomo-Pathological Sciences **Department of Neurological Sciences, Sapienza University §Institute of Pathology, Catholic University, Rome †Dipartimento Testa-Collo e Neuroscienze, Istituto Giannina Gaslini, Genoa ∥Department of Surgical Oncological and Gastroenterological Sciences, Urology University of Padova, Padova ¶IRCCS Neuromed, Pozzilli (IS) #Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy ‡Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
Am J Surg Pathol. 2017 Jan;41(1):56-61. doi: 10.1097/PAS.0000000000000741.
Chordomas arise in the skull base and spine and usually occur in adults and are rare in the pediatric population. Cases of chordoma in pediatric age are often poorly differentiated, showing cytologic atypia, increased cellularity, and mitosis, and their aggressive behavior is associated with a high incidence of metastatic spread and a short patient survival. Recent studies have described loss of SMARCB1/INI1 protein in poorly differentiated chordomas associated not with point mutations but with SMARCB1/INI1 gene deletions instead. In this study, we considered immunohistochemistry and SMARCB1/INI1 mutational status to examine SMARCB1 status in a series of pediatric chordomas (7 classic and 1 poorly differentiated). We performed immunohistochemical tests for INI1, brachyury, S100, and cytokeratins and conducted a genetic analysis on the SMARCB1 coding sequence (NM_003073) using the Sanger method and multiplex ligation-dependent probe amplification to detect abnormal copy numbers of the gene locus. All 8 cases were positive for brachyury, whereas there was no nuclear SMARCB1/INI1 expression in 4 of the 8 cases, including the poorly differentiated chordoma. Genetic analysis identified a missense mutation in 2 cases and a nonsense mutation associated with loss of SMARCB1/INI1 protein and features of poorly differentiated tumor in 1. These mutations were novel variants occurring in heterozygosity, and they were judged to be pathogenic by 3 different bioinformatic tools. In 7 of 8 cases we performed multiplex ligation-dependent probe amplification, and 3 cases showed deletions at the SMARCB1 locus. Our results confirm the pathogenic involvement of SMARCB1/INI1 in childhood chordoma. We also describe 3 novel pathogenic mutations.
脊索瘤起源于颅底和脊柱，通常发生于成年人，在儿童群体中较为罕见。儿童期脊索瘤病例往往分化程度低，表现为细胞异型性、细胞增多和有丝分裂，其侵袭性行为与高转移率和患者短生存期相关。最近的研究描述了在低分化脊索瘤中SMARCB1/INI1蛋白缺失，这并非与点突变相关，而是与SMARCB1/INI1基因缺失有关。在本研究中，我们通过免疫组织化学和SMARCB1突变状态来检测一系列儿童脊索瘤（7例经典型和1例低分化型）中的SMARCB1状态。我们对INI1、brachyury、S100和细胞角蛋白进行了免疫组织化学检测，并使用桑格法和多重连接依赖探针扩增对SMARCB1编码序列（NM_003073）进行基因分析，以检测该基因座的异常拷贝数。所有8例病例brachyury均呈阳性，而8例中有4例，包括低分化脊索瘤，无核SMARCB1/INI1表达。基因分析在2例中鉴定出一个错义突变，在1例中鉴定出一个与SMARCB1/INI1蛋白缺失及低分化肿瘤特征相关的无义突变。这些突变是杂合状态下出现的新变体，通过3种不同的生物信息学工具判断它们具有致病性。在8例中的7例中我们进行了多重连接依赖探针扩增，3例显示SMARCB1基因座存在缺失。我们的结果证实了SMARCB1/INI1在儿童脊索瘤中的致病作用。我们还描述了3种新的致病突变。
