Large Scale Detection Of Lung Cancer Mutation Sites And Analysis Of Susceptibility Genes In Han Chinese Population

Lung cancer is the deadliest cancer in the world.It has become the most common malignant tumor with high incidence in China.Patients with lung cancer accounts for a very high proportion of both male and female cancer patients,and the five-year survival rate of lung cancer patients was less than20%.Various subtypes and complicated carcinogenesis mechanisms make it difficult to cure lung cancer.In recent years,with the development of sequencing technology,personalized medicine has become more and more popular,and it also helps personalized treatment of lung cancer.In this paper,we focused on the germline mutations in Han Chinese lung cancer population,using the next-generation sequencing technology and other analysis tools to determine the susceptibility genes and mutation sites related to lung cancer risk.In this study,we first detected germline mutations in 780 sporadic Han lung cancer patients using targeted panel sequencing.The results showed that a total of 1017 mutations were detected,which were distributed in 68 gene regions.BRCA2,ATM and FANCA were the most frequently mutated genes.The mutation spectrum showed that variants detected in lung adenocarcinoma(LUAD),lung squamous cell carcinoma(LUSC),small cell lung cancer(SCLC)and adenosquamous lung carcinoma(ASC)had no significant bias in gene selection;SCLC had a high incidence in male patients than in females,and this phenomenon also occurred in LUSC patients.Four subtypes of lung cancer did not show obvious clustering in a certain age.57.4% of non-synonymous mutations occurred in DNA damage related genes.Our analysis of gene co-occurrence and mutual exclusion showed that gene ATM and MSH6 were significantly mutually exclusive in lung cancer(Fisher’s P = 0.003,q-value = 0.04).After the detection of germline mutations,we analyzed the enrichment of the mutant genes in GO functions and KEGG pathways.Go analysis showed that the mutated genes participated in the processes of DNA damage repair.KEGG analysis showed that the mutated genes in three subtypes of lung cancer,including adenocarcinoma,squamous cell carcinoma and small cell lung cancer,were significantly enriched in ‘Fanconi anemia pathway’,and also in ‘Homologous recombination’.In the chapters 4 and 5 of this thesis,after the pathogenicity analysis of high recurrent frequency mutations,we sequenced these pathogenicity loci in1113 healthy controls to determined the susceptible site of lung cancer by case-control analysis.Correlation analysis for LUAD showed that 13 mutation sites showed significant correlations with LUAD after FDR correction;independent correlation analysis showed that 9 mutation sites had significant correlation with LUSC and 3 mutation sites showed significant correlations with SCLC after FDR correction.In conclusion,our studies showed that a large number of germline mutations were detected in Han Chinese lung cancer population,and the mutual exclusion between gene ATM and MSH6 revealed that the co expression of mutations in these two genes might have negative selection effects on lung cancer tumor cells.At the same time,we have verified dozens of variants that were significantly related to the risk of lung cancer.After further functional verification,these sites could provide new targets for the treatment of lung cancer.