Study On The Correlation Of Germline Mutations In Sporadic Colorectal Cancer

Objective:Sporadic colorectal cancer is the most common type of colorectal cancer,accounting for more than 80% of colorectal cancer.Its occurrence and development is a multi-gene,multi-step process of continuous accumulation,and the specific etiology and pathogenesis have not yet been fully understood.In recent years,germline mutations randomly discovered in sporadic colorectal cancer have been continuously reported by scholars,which suggests that we should pay attention to the role of genetic factors in sporadic colorectal cancer,so as to conduct in-depth research on sporadic colorectal cancer on the basis of molecules.In this study,the second-generation sequencing technology was used to detect gene mutations in sporadic colorectal cancer,especially germline gene mutations,in order to improve the genetic susceptibility screening and explore the pathogenesis of sporadic colorectal cancer.By comparing the clinicopathological parameters of the two groups of patients with germline mutations and non-germline mutations,the relationship between germline mutations and clinicopathological characteristics of patients with sporadic colorectal cancer was evaluated.Methods:DNA samples were collected from 32 cases of sporadic colorectal cancer tumor tissue and peripheral blood from the general hospital of Tianjin Medical University from January 2017 to January 2019.DNA samples were sequenced by the second generation sequencing technology,and germline mutations were screened after sequencing data was analyzed by bioinformatics.According to the results of genetic testing,patients were divided into germline mutation group and non-germline mutation group,and the mutation genes and the number of mutations in the two groups were compared.The SPSS 25.0 software was used to analyze the clinical pathology parameters of two groups.When P<0.05,the result was considered statistically different;When P <0.01,the difference was significant.Results:1.A total of 2515 high-quality gene mutations were screened.These mutations were distributed in 1590 genes,of which the most common genes were TP53、APC、KRAS、PIK3CA、AR、ATM、MUC4、TCF7L2、TMEM67、TTN、VKORC1 and FBXW7.The gene with the highest mutation frequency was the TP53 gene(23/32),followed by the APC gene(22/32)and the KRAS gene(11/32).The mutation types of the APC gene were mainly nonsense mutations.In addition,missense mutant genes were mainly: TP53,KRAS,PIK3 CA,ATM,MUC4,TTN.2.This study included 32 patients with sporadic colorectal cancer,including 11 patients with germline mutations,accounting for 34.4% of all patients.A total of 42 germline mutations were selected from these 11 patients,including: 78.6% missense mutations,14.3% insertion deletions and 7.1% nonsense mutations.The gene with the highest mutation frequency was the ATM gene(3/11),followed by the AR,CYP2C19,IDH2,TGFBR2,and UGT1A1 genes(2/11).Except for AR,CYP2C19,FANCD2,MSH6,MUTYH,and SMAD4 genes,the mutation types of other genes were missense mutations.3.Among the selected germline mutations,81.0%(34/42)of the mutations were archived in Clin Var,1000 G or Ex AC databases,and 66.7%(28/42)were pathogenic mutations.These pathogenic germline mutations were mainly related to pathways such as mismatch repair,base excision repair,nucleotide excision repair,and Fanconi anemia pathway.4.After conducting statistical analysis of the clinicopathological parameters of the germline mutation group(n=11)and the non-germline mutation group(n=21),it was found that the age of onset of the germline mutation group was significantly lower than that of the non-germline mutation group(49.45 ± 17.52 vs.64.00 ± 12.77,P=0.027).In addition,patients in the germline mutation group had a larger tumor diameter(P=0.159)and a greater number of gene mutations(P=0.120)than those in the non-germline mutation group.Conclusion:1.This study used next-generation sequencing technology to screen for related gene mutations in sporadic colorectal cancer,confirming the reliability and feasibility of the method.It provided a theoretical basis for the pathogenesis and genetic risk assessment of sporadic colorectal cancer. 2.This study presented the results of genetic mutations in sporadic colorectal cancer enrolled.34.4% of patients had germline mutations,81.0% of germline mutations were archived in Clin Var,1000 G or Ex AC databases,and 66.7% of the mutations were pathogenic mutation.This suggested that we should pay attention to the existence and role of germline mutations in sporadic colorectal cancer.In addition,the pathogenesis of pathogenic germline mutations in sporadic colorectal cancer should be further studied.3.Some new mutations were discovered in this study,which expanded the germline mutation spectrum of susceptibility genes for sporadic colorectal cancer.This finding was helpful for in-depth discussion of candidate susceptibility genes and mutations related to sporadic colorectal cancer,and was of great significance for early diagnosis,genetic counseling and pre-clinical screening of sporadic colorectal cancer.4.Clinical pathology showed that patients with sporadic colorectal cancer carrying genetic susceptibility gene germline mutations were younger,the tumor diameter tended to increase,and the number of gene mutations tended to increase.This suggested that we should pay attention to the screening of tumor genes in such patients,formulate better treatment plans and more rigorous postoperative tumor monitoring,and implement corresponding early prevention work,so as to be alert to the risk of other tumors as early as possible.