Lasota Jerzy, Wozniak Agnieszka, Kopczynski Janusz, Dansonka-Mieszkowska Agnieszka, Wasag Bartek, Mitsuhashi Tomoko, Sarlomo-Rikala Marrit, Lee Jeffrey R, Schneider-Stock Regine, Stachura Jerzy, Limon Janusz, Miettinen Markku
Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
Lab Invest. 2005 Feb;85(2):237-47. doi: 10.1038/labinvest.3700218.
Mutational activation of KIT or PDGFRA is considered an early step in pathogenesis of gastrointestinal stromal tumors (GISTs); however, other nonrandom genetic changes have also been identified. At least three common regions of deletions on chromosome 22q, which may harbor putative tumor suppressor genes, have been defined. However, mapping of these regions has been inconsistent. It has also been speculated that GI autonomous nerve tumors (GANTs), GISTs with ultrastructural features suggestive of autonomic nerve differentiation, are characterized by a specific deletion involving 22q13 cytogenetic region. This study was undertaken to evaluate loss of heterozygosity (LOH) on chromosome 22q in 50 GISTs, including 10 GANTs. Four tumors were incidental minimal lesions <or=10 mm in diameter. LOH was evaluated using 20 PCR-based microsatellite markers and capillary gel electrophoresis. In all, 15 (30%) cases showed LOH of more than 75% of informative markers, suggesting loss of chromosome 22q. A total of 24 GISTs (50%) revealed LOH of one to seven informative markers clustered in different loci suggesting simultaneous involvement of different regions. The highest frequency of LOH was seen at D22S922 and D22S425, mapped to 22q13.33 and 22q11.22, respectively. However, LOH at other regions including IL2RB and NF2 locus was also found. No NF2 mutations were identified in four analyzed tumors. LOH on chromosome 22q was more frequent among intestinal than among gastric GISTs; however, there was no difference between LOH pattern seen in tumors defined by different histologic, ultrastructural (GANT) and molecular features (KIT and PDGFRA mutations). Although minimal GISTs revealed LOH on chromosome 22q, there was a higher LOH frequency in malignant than in benign tumors. An isolated LOH at D22S425 was equally found in both benign and malignant tumors. These observations may suggest that LOHs on chromosome 22q in GISTs play a role in early stages of tumor formation as well as in late tumor progression.
KIT或PDGFRA的突变激活被认为是胃肠道间质瘤（GIST）发病机制中的早期步骤；然而，也已发现其他非随机的基因改变。已确定22号染色体长臂上至少有三个常见的缺失区域，这些区域可能含有假定的肿瘤抑制基因。然而，这些区域的定位并不一致。也有人推测，胃肠道自主神经肿瘤（GANT），即具有提示自主神经分化超微结构特征的GIST，其特征是涉及22q13细胞遗传学区域的特定缺失。本研究旨在评估50例GIST（包括10例GANT）中22号染色体长臂上的杂合性缺失（LOH）情况。4例肿瘤为偶然发现的微小病变，直径≤10 mm。使用20个基于聚合酶链反应（PCR）的微卫星标记和毛细管凝胶电泳评估LOH。总共有15例（30%）病例显示超过75%的信息性标记存在LOH，提示22号染色体长臂缺失。总共24例GIST（50%）显示1至7个信息性标记的LOH聚集在不同位点，提示不同区域同时受累。在分别定位于22q13.33和22q11.22的D22S922和D22S425处观察到最高的LOH频率。然而，在包括IL2RB和NF2位点在内的其他区域也发现了LOH。在4例分析的肿瘤中未发现NF2突变。22号染色体长臂上的LOH在小肠GIST中比在胃GIST中更常见；然而，在由不同组织学、超微结构（GANT）和分子特征（KIT和PDGFRA突变）定义的肿瘤中观察到的LOH模式之间没有差异。尽管微小GIST显示22号染色体长臂上存在LOH，但恶性肿瘤中的LOH频率高于良性肿瘤。在良性和恶性肿瘤中均同样发现了D22S425处的孤立LOH。这些观察结果可能表明，GIST中22号染色体长臂上的LOH在肿瘤形成的早期阶段以及肿瘤晚期进展中均起作用。
