A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential
A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential
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DOI：
10.1038/labinvest.3700122
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发表时间：
2004-07-01
影响因子：
5
通讯作者：
Miettinen, M
中科院分区：
文献类型：
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作者：
Lasota, J;Dansonka-Mieszkowska, A;Miettinen, M
胃肠道间质瘤（GIST）是表达KIT的梭形细胞、上皮样和罕见的多形性间叶肿瘤。大多数GIST显示功能获得性KIT突变。然而，没有KIT突变的GIST和免疫组化KIT表达弱或缺乏的GIST也有报道。最近，在PDGFRA的外显子18（激活环）和外显子12（质膜结构域）的功能获得性突变被确定在这样的肿瘤。本研究的目的是验证PDGFRA突变可能定义GIST的特定临床病理亚组的假设。共研究了447例KIT外显子11（质膜结构域）突变阴性的GIST。DNA样品从甲醛固定的石蜡包埋组织中获得。通过PCR扩增和直接测序评估PDGFRA外显子18和12的基因组序列的突变。在346例胃GIST中的122例（35.3%）和75例肠GIST中的2例（2.7%）中发现了PDGFRA外显子18突变。这些突变中的绝大多数代表密码子842处的简单T至A错义突变，导致缬氨酸取代天冬氨酸（D842 V）。然而，在所有外显子18突变中，约23%发现了框内缺失和密码子841-847之间聚集的点突变缺失。PDGFRA外显子12突变仅见于10/170例（5.8%）胃GIST和1/54例（11.9%）肠GIST，KIT外显子11和PDGFRA外显子18突变阴性。在密码子561（V561 D）处有7个天冬氨酸替换为缬氨酸，并且在密码子566和571之间聚集有4个具有点突变的框内缺失。大多数GIST与PDGFRA突变有纯或主要上皮样形态。在81%的分析的GIST中检测到低有丝分裂活性，小于或等于5个有丝分裂/50 HPF，包括较大的> 5cm肿瘤。根据长期随访（平均135个月），大多数（83.5%）PDGFRA突变的GIST遵循良性过程。
Gastrointestinal stromal tumors (GISTs) are KIT expressing spindle cell, epithelioid and rarely pleomorphic mesenchymal tumors. The majority of GISTs show gain-of-function KIT mutations. However, GISTs without KIT mutations and GISTs with weak or lack of immunohistochemical KIT expression have also been reported. Recently, gain-of-function mutations in exon 18 (activation loop) and exon 12 (juxtamembrane domain) of the PDGFRA were identified in such tumors. The purpose of this study was to test the hypothesis that PDGFRA mutation may define a specific clinicopathologic subgroup of GISTs. A total of 447 KIT exon 11 (juxtamembrane domain) mutation-negative GISTs were studied. DNA samples were obtained from formaldehyde-fixed paraffin-embedded tissues. Genomic sequences of PDGFRA exons 18 and 12 were evaluated for the mutations by PCR amplification and direct sequencing. PDGFRA exon 18 mutations were identified in 122 of 346 (35.3%) gastric GISTs and two of 75 (2.7%) intestinal GISTs. A great majority of these mutations represented simple T to A missense mutation at the codon 842 leading to substitution of the valine for aspartic acid (D842 V). However, in-frame deletions and deletions with point mutations clustering between codons 841-847 were found in approximately 23% of all exon 18 mutations. Mutations in PDGFRA exon 12 were found only in 10 of 170 (5.8%) gastric and one of 54 (11.9%) intestinal GISTs negative for KIT exon 11 and PDGFRA exon 18 mutations. There were seven substitutions of aspartic acid for valine at codon 561 (V561 D) and four in-frame deletions with point mutations clustering between codons 566 and 571. The majority of GISTs with PDGFRA mutations had pure or predominant epitheloid morphology. Low mitotic activity, less than or equal to5 mitoses/50HPF was detected in 81% of analyzed GISTs including larger, > 5 cm tumors. Based on long-term follow-up (average 135 months), a majority (83.5%) of GISTs with PDGFRA mutations followed a benign course.