【作者】 黄宇；

【导师】 江跃全；

【作者基本信息】 重庆大学 ， 临床医学， 2023， 硕士

【摘要】 目的:多原发肺腺癌与单发肺腺癌在分子生物学、临床特征等方面存在差异,然而目前相关研究较少,临床医生缺乏针对多原发肺腺癌治疗的参考依据。本研究拟通过对多原发肺腺癌(MPLA)基因谱深入分析,并与单原发肺腺癌(SPLA)进行比较,探讨多原发肺腺癌的分子病理学特性,并制定专门针对多原发肺腺癌的治疗策略。方法:2021年6月1日-2022年6月30日期间,对所有手术切除的肺腺癌结节,进行高通量基因检测。将患者分为MPLA组和SPLA组。使用R软件,分析比较两组临床病理学特征及基因突变之间的差异。结果:1.MPLA组女性(77.1%vs 57.0%)及不吸烟(85.4%vs 67.8%)患者比例显著高于SPLA组(p<0.001)。2.MPLA组微小浸润性腺癌比例显著高于SPLA组(44.4%vs 31.9%),而SPLA组最常见的病理学类型为浸润性腺癌(63.5%vs 43.8%)(p<0.001)。3.MPLA组有基因突变的患者比例与SPLA组无显著差异(88.2%vs82.9%,p=0.188),然而MPLA组肿瘤的基因突变率显著低于SPLA组(66.3%vs82.9%,p<0.001)。4.MPLA组最常见EGFR21基因突变(n=80,24.3%),而EGFR19基因突变较易出现于SPLA组(n=187,24.7%)。5.MPLA组多个肿瘤中最常见的相同突变基因是EGFR21,达到20%(13/65),其余基因突变相同的概率极低。6.MPLA组中,肿瘤位于同一肺叶的患者,其基因突变率低于不同肺叶(75.0%vs94.8%,p=0.001)。而同一肺叶的多个肿瘤基因突变相同的比例高于不同肺叶(16.7%vs 11.5%,p=0.001)。结论:MPLA与SPLA在基因突变上存在显著差异:MPLA中EGFR21突变率增高、EGFR19突变率降低;MPLA患者多个肿瘤之间,EGFR21突变相同率达到20%,其他基因突变相同概率极低;肿瘤位于同一肺叶存在基因相同突变的比例较高,但突变率低。根据这些研究结果,在治疗策略上我们推荐:(1)基因检测策略:尽可能对MPLA患者的每一个结节进行高通量基因检测,根据多个结节的基因检测结果选择合适的靶向药物。(2)分子靶向治疗策略:对于MPLA患者,如果仅能切除其中一个肿瘤且切除的肿瘤存在基因突变,不建议根据这一个基因突变结果选择靶向治疗,除非该肿瘤基因突变为EGFR 21号外显子突变,对其他不能切除的结节可以考虑采用3代靶向药物试验性治疗。更多还原

【Abstract】 Objective:There are differences in molecular biology and clinical characteristics between multiple primary lung adenocarcinoma(MPLA)and single primary lung adenocarcinoma(SPLA).However,clinicians lack treatment reference of multiple primary lung adenocarcinoma due to inadequate relevant studies.In this study,we propose to initiate an in-depth analysis of MPLA’s genetic profile and to draw a comparison with SPLA’s,thus investigating the molecular pathological characteristics of MPLA and developing a treatment strategy specifically for MPLA.Methods:Next-generation sequencing(NGS)was performed on all surgically resected lung adenocarcinoma nodules from June 1,2021 to June 30,2022,2022.Patients were divided into MPLA and SPLA groups.Using R software,the differences between the clinicopathological characteristics and gene mutations of the two groups were compared and analyzed.Results:1.The proportion of women(77.1%vs 57.0%)and nonsmokers(85.4%vs67.8%)in the MPLA group was significantly higher than in the SPLA group(p<0.001).2.The proportion of microinvasive adenocarcinoma was prominently higher in the MPLA group than in the SPLA group(44.4%vs.31.9%),while the most common pathological type in the SPLA group was invasive adenocarcinoma(63.5%vs.43.8%)(p<0.001).The proportion of patients with mutations in the MPLA group shared little distinct difference from that in the SPLA group(88.2%vs 82.9%,p=0.188).However,the mutation rate of tumors in the MPLA group was significantly lower than that in the SPLA group(66.3%vs 82.9%,p<0.001).4.EGFR21 mutations were most common in the MPLA group(n=80,24.3%),while EGFR19 mutations were more likely to be found in the SPLA group(n=187,24.7%).5.The most common identical mutated gene in multiple tumors in the MPLA group was EGFR21,reaching 20%(13/65),and the probability of identical mutations in the remaining genes was extremely low.6.In the MPLA group,patients’tumors located in the same lobe had lower mutation rates than those in different lobes(75.0%vs 94.8%,p=0.001).In contrast,the rate of identical mutations in multiple tumors in the same lobe was higher than that in different lobes(16.7%vs 11.5%,p=0.001).Conclusions:There are significant differences in gene mutations between MPLA and SPLA:the rate of EGFR21 mutation increased and that of EGFR19 mutation decreased in MPLA;the mutation identity rate of EGFR21 reached 20%among multiple nodes in MPLA patients,while the probability of other gene mutation identity was extremely low;tumors located in the same lung lobe had higher proportion of gene identity mutation,but its mutation rate was low.Based on these findings,we recommend the following treatment strategies:(1)Genetic testing strategies:NGS is performed on each nodule in MPLA patients in every possible condition with the selection of appropriate targeted drugs in accordance with the genetic testing results of multiple nodules.(2)Molecular targeted therapy strategy:For MPLA patients,if only one of the tumors,which has gene mutation,can be resected,it is not recommended to select targeted therapy based on the results of this one gene mutation,unless the tumor gene mutation is EGFR exon 21mutation.For other unresectable nodes,experimental treatment with 3rd generation targeted drugs can be considered.更多还原