胃肠道间质瘤分子靶向治疗继发性耐药基因突变的研究

Gastrointestinal stromal tumor molecular targeted treatment for secondary resistance mutations

目的探讨胃肠道间质瘤(GIST)患者酪氨酸激酶受体(KIT)和血小板源性生长受体(PDGFRA)基因突变的特点,以及伊马替尼的继发耐药机制。方法对98例GIST患者肿瘤组织进行DNA抽提、聚合酶链反应(PCR)扩增和直接测序,检测KIT基因外显子9、11、13、17和PDGFRA基因12、18外显子突变;并对伊马替尼继发耐药的65例患者进行2次检测。结果 98例患者中,KIT突变79例(80.6%),其中外显子11突变61例(62.2%),外显子9突变18例(18.4%);PDGFRA突变3例(3.1%)。不同性别、年龄以及晚期GIST患者和潜在恶性的GIST患者间突变比较差异无统计学意义(P>0.05);而不同部位GIST的KIT外显子11突变发生率差异有统计学意义(P<0.05)。65例继发耐药病例中,4例患者发生二次突变,表现为KIT基因第17外显子密码子第2467位点的T为G所替换(T2467G),导致823密码子编码氨基酸由酪氨酸转变为天冬氨酸。结论 KIT基因突变在GIST患者中常见,不同部位间KIT外显子11突变发生率差异有统计学意义。伊马替尼继发耐药可能与KIT基因第17外显子密码子第2467位点T为G所替换(T2467G)相关。

Objective To investiate the gastrointestinal stromal tumor（GIST）patients with tyrosine kinase receptor（KIT）and platelet-derived growth factor receptor（PDGFRA）gene mutation characteristics,as well as secondary imatinib resistance mechanisms.Methods 98 cases of patients with GIST tumor were examed with tissue for DNA extraction,polymerase chain reaction（PCR）amplification and direct sequencing to detect KIT exon 9,11,13,17 and PDGFRA gene mutation in exon 12,18;and secondary second test were performed in 65 imatinib-resistant patients.Results In the 98 patients,KIT mutations were found in 79 cases（80.6%）,of which exon 11 mutations in 61 cases（62.2%）,exon 9 mutations in 18 cases（18.4%）;PDGFRA mutations in 3 cases（3.1%）.Gender,age,and among patients with advanced GIST GIST patients and potentially malignant mutation was with no significant difference（P 0.05）;while different parts of GIST KIT exon 11mutation incidence was significantly（P0.05）.In 65 cases of secondary resistant cases,four patients developed a secondary mutation,gene expression of KIT exon 17 codon 2467 point T is replaced by G（T2467G）,resulting in 823 amino acids encoded by the codons casein converted to aspartic acid.Conclusion It demonstrated that the KIT mutations are common in GIST patients,between different parts of the KIT exon 11 mutation rate difference was statistically significant.Secondary imatinib resistance may be associated with KIT exon 17 of the gene codon 2467 point T is replaced by G（T2467G）related.