Exploring The Molecular Mechanism Of Preinvasive Lesions In Lung Adenocarcinoma Based On WES

Objective: Lung cancer is currently the leading cause of cancer-related death worldwide,and it is generally believed that atypical adenomatous hyperplasia(AAH)and adenocarcinoma in situ(AIS)are preinvasive lesions of lung adenocarcinoma.Clarifying the molecular mechanism of gene mutation in lung atypical adenomatous hyperplasia and lung adenocarcinoma in situ is of great significance for understanding the occurrence and development of lung adenocarcinoma.Methods: We collected 26 patients with preinvasive lung adenocarcinoma with no previous history of malignancy,of which 9 cases of AAH had atypical adenomatous hyperplasia in resected lesions as the most malignant diagnosis,and 17 cases of lung adenocarcinoma in situ All were pathologically diagnosed as lung adenocarcinoma in situ after surgery for a single pulmonary nodule,and the surgically resected lesions and corresponding Paracancer were analyzed by whole exome sequencing.The difference in prognosis between the high and low expression groups of the mucin family genes MUC16(CA125 coding gene),MUC4,MUC17 and MUC2 in lung adenocarcinoma was analyzed through the public database.Results: The mutation load of pure AAH lesions is lower than that of AAH lesions combined with more malignant lesions;we found that in 26 samples,the gene with the highest mutation frequency was TTN,and found that there were no extensive typical driver genes in AAH,AIS There were highly consistent mutation genes in AAH lesions,EGFR gene mutations were not detected in all AAH lesions,and EGFR was not the most important mutation in AIS;there was no significant difference between the increase and decrease of CNV in AAH,and the decrease of CNV in AIS was significantly higher than Increase of CNV;AAH main mutation signature is B,AIS main mutation signature is A and C,the known mutation signature with the highest correlation with B is Signature＿15,Signature＿15 is related to DNA mismatch repair defect,Signature＿3 is correlation with mutation signature C One of the higher known mutational signatures,Signature＿3,is associated with failure of DNA double-strand break repair by homologous recombination;mucin family genes were found to be multiple highly mutated genes in preinvasive lung adenocarcinoma specimens,and these mucin Most of the family genes are known driver genes or predicted mutation genes;finally,we found that the mucin family genes MUC16(CA125 coding gene),MUC4,MUC17 and MUC2,in lung adenocarcinoma,the survival time of the high expression group was significantly lower than that of the low expression group.Conclusions: 1.The tumor mutation load of AAH in multiple nodules is significantly higher than that of simple AAH lesions,which indicates that AAH in multiple nodules may have gene mutations of subsequent lesions;2.There is no EGFR mutation in AAH,which begins to occur in the AIS stage A wide range of driver gene mutations,and the types and mutation rates of driver gene mutations in different patients are more consistent with subsequent microinvasive adenocarcinoma and invasive adenocarcinoma,which means that tumor cells in different patients at the AIS stage have higher 3.The genes with a mutation rate of more than 80% in the AIS stage include TTN(16/17)and MUC16(14/17);4.The reduction of CNV is significantly higher than that of The increase of CNV may be an evidence of tumor progression to AIS;5.MUCs may play an important role in the occurrence and development of preinvasive lesions in lung adenocarcinoma.