摘要
目的探讨胃肠道间质瘤(gastrointestinal stromal tumors,GIST)中c-Kit/PDGFRA基因突变与临床病理特征、免疫表型及预后的关系。方法采用直接测序法检测185例GIST标本中c-Kit和PDGFRA基因突变类型。结果 c-Kit基因突变中,外显子11突变最常见,以缺失突变、点突变及混合突变为主,并见3例双外显子突变。外显子9在小肠GIST中的突变率显著高于胃GIST,且均为A502-Y503串联重复突变,提示小肠GIST有独特的基因型。PDGFRA在上皮样细胞型和混合细胞型GIST中的突变率显著高于梭形细胞型GIST。c-Kit基因外显子11缺失突变的中高危GIST易出现术后复发转移,且复发转移患者中发生二次突变率较高,表现为c-Kit基因外显子13、14、17或18点突变,以13号外显子V654A最为常见。CD117和DOG1的表达与基因突变之间无相关性,不能作为预测疾病基因突变的指标。单因素分析结果显示,肿瘤直径、核分裂象、Ki-67增殖指数、危险程度分级、术后复发和转移是影响GIST预后的重要因素,术后靶向药物治疗可一定程度改善预后。c-Kit基因外显子11缺失突变和外显子9突变的GIST患者预后较差。结论 c-Kit基因9号外显子在小肠GIST中突变率较高,PDGFRA基因在上皮样细胞型和混合细胞型GIST中突变率较高。c-Kit基因外显子11缺失突变的中高危GIST易发生二次突变导致术后复发转移,外显子11缺失突变可作为GIST预后不良的独立影响因素之一。
Purpose To investigate the characteristics of c-Kit and PDGFRA gene mutations in gastrointestinal stromal tumor(GIST)and their associations with clinicopathological features and immunohistochemistry.Methods 185 GIST patients with complete clinical data confirmed by histopathology and immunohistochemical staining were analyzed retrospectively.Mutation of c-Kit exons 9,11,12,13,14,17,18 and PDGFRA exons 12,14,18 were detected by PCR amplification and direct sequencing.The relationship between gene mutations and clinicopathological features and immunohistochemistry was analyzed.Results The most common gene mutation of 185 GISTs was c-Kit exon 11,including deletion mutation,point mutation and hybrid mutation.Double exon mutations were detected in 3 cases of GIST.In small intestine GIST,the mutation rate of c-Kit exon 9 was significantly higher than that in stomach(P<0.05)and the mutation type was exclusively A502_Y503dup,which suggested that small intestinal GIST had a unique mutation type.PDGFRA mutation rate in epithelioid and mixed morphology was obviously higher than that in spindle morphology(P<0.01).Intermediate to high risk GIST patients with exon 11 deletion mutation of c-Kit was prone to secondary gene mutations,and secondary gene mutation rate in the patients with recurrence and metastasis was higher.Most secondary gene mutations were point mutation of exons 13,14,17,or 18,and mutation V654A in exon 13 was the most common type.CD117 and DOG1 are sensitive markers for the diagnosis of GIST,however there was no significant difference between the expression of CD117 and DOG1 and mutation of c-Kit and PDGFRA in GIST samples.CD117 and DOG1 could not be used as markers to predict gene mutation of GIST.Single factor analysis showed that tumor diameter,mitotic index,Ki-67 index,NIH risk classification,recurrence and metastasis were main factors influencing the prognosis of GIST patients,while targeted therapy could improve the prognosis of patients.The prognosis of GIST patients with exon 11 deletion mutation or exon 9 mutation of c-Kit was poor.Conclusion Small intestinal GIST has higher c-Kit exon 9 mutation rate,while GIST with epithelioid and mixed morphology has higher PDGFRA mutation rate.The intermediate to high risk GIST patients with exon 11 deletion mutation of c-Kit are prone to secondary gene mutations,which lead to postoperative recurrence and metastasis.The exon 11 deletion mutation might be an independent factor for the poor prognosis of GIST.
作者
李军
蔡航航
王渝
LI Jun;CAI Hang-hang;WANG Yu(Department of Pathology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China;Department of Pathology,School of Basic Medicine,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China)
出处
《临床与实验病理学杂志》
CAS
CSCD
北大核心
2018年第8期834-839,共6页
Chinese Journal of Clinical and Experimental Pathology
基金
国家自然科学基金青年科学基金(81302114)
