Modena Piergiorgio, Lualdi Elena, Facchinetti Federica, Galli Lisa, Teixeira Manuel R, Pilotti Silvana, Sozzi Gabriella
Unit of Molecular Cytogenetics, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
Cancer Res. 2005 May 15;65(10):4012-9. doi: 10.1158/0008-5472.CAN-04-3050.
Epithelioid sarcoma is a rare soft tissue neoplasm of uncertain lineage that usually arises in the distal extremities of adults, presents a high rate of recurrences and metastases and frequently poses diagnostic dilemmas. The recently reported large-cell "proximal-type" variant is characterized by increased aggressiveness, deep location, preferential occurrence in proximal/axial regions of older patients, and rhabdoid features. Previous cytogenetic studies indicated that the most frequent alterations associated with this tumor entity affect chromosome 22. In this study, combined spectral karyotyping, fluorescence in situ hybridization, and array-based comparative genomic hybridization analyses of two proximal-type cases harboring a rearrangement involving 10q26 and 22q11 revealed that the 22q11 breakpoints were located in a 150-kb region containing the SMARCB1/INI1 gene, and that homozygous deletion of the gene was present in the tumor tissue. The SMARCB1/INI1 gene encodes for an invariant subunit of SWI/SNF chromatin remodeling complex and has been previously reported to act as a tumor suppressor gene frequently inactivated in infantile malignant rhabdoid tumors. We analyzed SMARCB1/INI1 gene status in nine additional epithelioid sarcoma cases (four proximal types and five conventional types) and altogether we identified deletions of SMARCB1/INI1 gene in 5 of 11 cases, all proximal types. We confirmed and further extended the number of cases with SMARCB1/INI1 inactivation to 6 of 11 cases, by real-time quantitative PCR analysis of mRNA expression and by SMARCB1/INI1 immunohistochemistry. Overall, these results point to SMARCB1/INI1 gene involvement in the genesis and/or progression of epithelioid sarcomas. Analysis of larger series of epithelioid sarcomas will be necessary to highlight putative clinically relevant features related to SMARCB1/INI1 inactivation.
上皮样肉瘤是一种谱系不明的罕见软组织肿瘤，通常发生于成人的四肢远端，复发和转移率高，且常造成诊断上的难题。最近报道的大细胞“近端型”变体具有侵袭性增加、位置较深、在老年患者的近端/轴位区域优先发生以及横纹肌样特征等特点。先前的细胞遗传学研究表明，与该肿瘤实体相关的最常见改变影响22号染色体。在本研究中，对两例涉及10q26和22q11重排的近端型病例进行联合光谱核型分析、荧光原位杂交和基于芯片的比较基因组杂交分析，结果显示22q11断点位于一个包含SMARCB1/INI1基因的150 kb区域，且肿瘤组织中存在该基因的纯合缺失。SMARCB1/INI1基因编码SWI/SNF染色质重塑复合体的一个不变亚基，先前有报道称其在婴儿恶性横纹肌样肿瘤中常作为肿瘤抑制基因失活。我们分析了另外9例上皮样肉瘤病例（4例近端型和5例传统型）的SMARCB1/INI1基因状态，在总共11例病例中，我们在5例（均为近端型）中鉴定出SMARCB1/INI1基因缺失。通过对mRNA表达进行实时定量PCR分析以及SMARCB1/INI1免疫组化，我们证实并进一步将SMARCB1/INI1失活的病例数扩展至11例中的6例。总体而言，这些结果表明SMARCB1/INI1基因参与上皮样肉瘤的发生和/或进展。有必要分析更多系列的上皮样肉瘤，以突出与SMARCB1/INI1失活相关的假定临床相关特征。
