Genomic Study Of Multiple Primary Lung Cancer

Objectives:Lung cancer is a heterogeneous disease with different genomic and phenotypic characteristics among different patients.Tumor heterogeneity reflects different genetic backgrounds and different carcinogen exposures in different lung cancer patients.It is unclear whether and how to limit genomic heterogeneity during tumor evolution.This topic intends to compare the relative differences and consistency of genetic drivers in the same germline and environmental background by performing whole-exome sequencing(WES)in 10 cases of multiple primary lung cancer(MPLC).To provide a theoretical basis for better discrimination between multiple primary lung cancers and intrapulmonary metastases(IM),and to help guide treatment and prognosis.Methods:Screening for patients who were diagnosed with multiple lung cancer by pathology after surgery at the First Hospital of Jilin University from January 2008 to December 2018.A total of 10 patients who were considered by the pathology department as multiple primary lung cancer were collected.Among them,6 were females and 4 were males.The age range was 50~72 years,2 patients had a history of smoking,9 patients underwent simultaneous resection of multiple primary lung cancer at the same time,and 1 patient underwent surgery of multiple primary lung cancer at three different times.8 patients had 2 lesions and 2 patients had 3 lesions.2lesions in 7 patients were invasive adenocarcinoma,3 lesions in 1 patient were invasive adenocarcinoma,minimally invasive adenocarcinoma,atypical adenomatous hyperplasia,and 2 lesions in 1 patient were invasive adenocarcinoma and invasive squamous cell carcinoma,3 lesions of 1 patient were invasive adenocarcinoma,minimally invasive adenocarcinoma,and invasive adenocarcinoma.Pathological specimens of 22 tumor lesions and paracarcinoma lesions from 10 patients were testedfor WES analysis.Results:1.WES technology was used to analyze 22 tumor lesions in 10 patients.The results suggest that the lung lesions in the same patient were heterogeneous,and the average similarity of somatic mutation patterns was 2.09%(0%~4.73%).It is suggested that there is significant heterogeneity among lung tumors in the same patient.2.System Among all gene mutations,5 significantly mutated genes(SMG)identified as EGFR(72.73%),TP53(36.36%),NBPF1(27.27%),MUC19(27.27%),and BAGE2(22.73%).3.Mutational spectrum analysis suggested that C> T substitutions occurred most frequently in patients with non-smoking history(17/18).4.Enrichment analysis of signal pathways identified 18 signal pathways with statistically significant(p <0.05)mutation enrichment.The first five signal pathways that are most significantly enriched are the Glioma signal pathway,Chronic myeloid leukemia signal pathway,Endocrine resistance signal pathway,Glutamatergic synapse signal pathway and Focal adhesion signal pathway.When analyzing the intracellular regulatory pathway of Focal adhesion,it was found that 2 lung adenocarcinoma lesions in 3 patients had EGFR exon 19 deletion mutation and EGFR exon 21 L858 R mutation,and 19-del mutation lesions were often accompanied by the activation of PI3K-Akt signal pathway,but lesions with L858 R mutations are often accompanied by the activation of the PI3K-Akt signal pathway inhibitory kinase PTEN.5.In the same patient,the tumor mutation burden of squamous cell carcinoma is significantly higher than that of adenocarcinoma.At different stages of tumor development,the tumor mutation burden of atypical adenomatoid hyperplasia,minimally adenocarcinoma and invasive adenocarcinoma is increasing.Conclusions:1.The different lesions of MPLC patients have greater heterogeneity at the genomic level.2.Genetic detection should be performed on each lesion resected by MPLC to understand the mutation status of the target gene,and to develop a more reasonable diagnosis and treatment project for patients.3.The next-generation sequencing provides a reliable method for identifying MPLC and IM,and also provides a technical means for revealing the occurrence and development of multiple primary lung cancer and predicting potential therapeutic targets.