Analyze Gene Changes Characteristics Of Multiple Synchronous Lung Adenocarcinomas Through Targeted Sequencing

Objectives:Simultaneous multiple lung adenocarcinoma refers to the occurrence of two or more primary lung adenocarcinomas at the same time in the same or different parts of the lungs of the same patient.Because the diagnosis and treatment of multiple primary lung adenocarcinomas and metastatic lung cancers are quite different,distinguishing them is a clinical challenge,but it is critical to the treatment and prognosis of patients.On the other hand,lung cancer is a heterogeneous disease,but when the genetic background and environmental background are the same,the genomic heterogeneity between multiple primary lung adenocarcinomas and different tumors is still unclear.This study aims to analyze the genomic characteristics of multiple primary lung adenocarcinomas through targeted sequencing,to better distinguish multiple primary lung adenocarcinomas from lung metastases,and to explore the genomics information of multiple primary lung adenocarcinomas.To better guide the diagnosis and treatment of multiple primary lung adenocarcinomas.Methods:This is a prospective,single-center,phase Ⅱ clinical study(registration number:NCT03764371),approved by the ethics committee of our hospital(ethics number: AF-IRB-030-04).Screening of patients in the Thoracic Surgery Department of Bethune First Hospital of Jilin University between September 2018 and March 2020.After all patients signed the informed consent,a total of 17 cases were included in pathology and genetic screening after surgical treatment.Confirmed to be patients with multiple primary lung adenocarcinomas at the same time.Forty lung adenocarcinoma lesions and 17 para-carcinoma tissues of 17 patients were submitted for 180 panel targeted sequencing and bioinformatics analysis.This study did not intervene in the postoperative treatment of patients.According to the postoperative situation of the patients and their willingness to treat,they were divided into a targeted therapy group(n=7)and a control group(n=10)for systematic follow-up.The technical route is shown in the figure below.Results:1.Among the patients included in this study,5 cases were male(29.4%)and 12 cases were female(70.6%).The median age of onset was 58.2 years ±8.3 years.4 cases(23.5%)were previous smokers and 13 cases(76.5%)had never smoked.Of the 40 tumor samples included,21(52.5%)were in stage IA1,13(32.5%)were in stage IA2,2(5.0%)were in stage IA3,3(7.5%)were in stage IB,and 1(2.5%)were in stage IIB.Six patients(35.3%)had triple multiple synchronous lung adenocarcinomas and 11 patients(64.7%)had double multiple synchronous lung adenocarcinomas.2.Among 40 lung adenocarcinomas in 17 patients,four high-frequency mutated genes with a mutation frequency greater than or equal to 5% were identified,namely EGFR(88.0%),TP53(15.0%),MED12(5.0%),and RBM10(5.0%).3.Analysis of EGFR mutations showed that EGFR expression was different among the same tumor in the same patient,and EGFR expression was also different among different tumors in the same patient.The average similarity of somatic mutations was only 6.1%,suggesting that there was significant heterogeneity within and between lung tumors in the same patient.4.The enrichment analysis of somatic mutation genes in all tumor samples identified 18 pathways with significant statistical significance(P <0.05).The first five pathways with the most significant enrichment are bladder cancer signaling pathway,endometrial cancer signaling pathway,non-small cell lung cancer signaling pathway,glioma signaling pathway and pancreatic cancer signaling pathway.5.The median follow-up time of patients in this study was 20.4 months.There were 7patients(41.2%)who received targeted therapy after surgery,and 10 patients(58.8%)who did not receive treatment after surgery.A total of 1 patient(14.3%)in the targeted therapy group experienced disease recurrence,and 1 patient(10.0%)in the untreated control group experienced disease recurrence.Conclusions:1.In this study,the major mutant genes of MSLAs were EGFR(88.0%),TP53(15.0%),MED12(5.0%)and RBM10(5.0%).2.The heterogeneity of EGFR mutations in MSLAS patients showed that there was heterogeneity between the same individual and the same tumor,and there was heterogeneity between different tumors in the same individual.3.The most significant concentrations in the Bladder cancer pathway,Endometrial cancer pathway,NSCLC pathway,Glioma pathway,and Pancreatic cancer pathway were found in patients with MSLAS.4.The lesions carrying EGFR L858 R are often accompanied by the inhibitory expression of DNA damage signaling pathway,and its downstream genes p21,GADD45,Bax,BAK,p48,and Polk may be potential therapeutic targets of MSLAs.5.In this study,there was no significant statistical difference in postoperative recurrence rate between the targeted therapy group and the control group for MSLAS patients,and no survival benefit was observed in the targeted therapy group.