A Study Of Gene Mutation Expression Profiles In Pancreatic Cancer Using Multi-gene Panel And Next-generation Sequencing Technology And Establishment Of Precise Pharmacodynamics Evaluation System

Objective:Pancreatic ductal adenocarcinoma(PDAC)is a highly lethal malignancy with a low early diagnosis rate,poor efficiencyand poor prognosis.Currently,advances in surgery can only partially improve the prognosis.Besides,itcan not bring extra benefits to the patients with PDAC if purely using.the pancreatic tumor resection with expanded clearance.At the same time,for lack of effective chemotherapy and targeted drugs also makes the treatment unimproved.However,it is well-established that the development of PDAC is closely related to gene mutation.Hence,it is possible to improve therapeutic effect of PDAC via applying individualized targeted treatment program which is based on different types of gene mutations in the PDAC patients.Methods:In the present study,high-throughput next-generation sequencing platforms containing 521 gene panels,was used to perform deep sequence analysis of gene mutation from 33 PDAC patients.Firstly,a special capture scheme was designed totarget the region of specific mutations,copy number variation and fusion gene.Then,a high-depth(> 1000X)sequencing protocol was used to performdeep sequence analysis and validate gene mutation profiles.Afterwards,the genomics data was effectively integrated with the gene-related chemotherapy drug database using integration technology.Finally,through rapid and efficient data analysis,we furtherexplored the effective relationship between the genomic data and the clinical data,then improved the predictive efficacy,and ultimately provided guidance for PDAC individualized treatment and provided evidence for PDAC drug development.Results: 1.In 33 cases,all the patients were diagnosed with PDAC on biopsy and then underwent radical resection.There were 28 cases of pancreatic head tumors,5 cases of pancreatic tail tumors,and 15 cases of postoperative complications,but no deaths during hospitalization.2.Mutated genes occurred in all the PDAC samples,the average value reached 200 or more.However,no gene had only one mutation site,in contrast,all the genes had multiple sites or multiple types of mutations.In addition,with the different mutated genes,the mutation sites were also variable in each PDAC patients.3.Meantime,we also detected the mutations of KRAS and EGFR in the PDACtissues.Among them,G12 D mutations of KRAS gene were found in 13 cases of PDAC somatic cells.4.The present study demonstrated that only 21.2%(7/33)patients showed effective after treatment by Gemcitabine,and remaining patients showed poor therapeutic effects or bad side effects.5.Using Lapatinib and Tricotinib combination therapy in the PDAC patients with G12 D mutations of KRAS gene may play an inhibitory effect on the mutation-related tumors.6.The prognosis of the patient with PDAC wasstill closely associated with the clinical stage of disease,the surgical therapy situation and the post-operative general condition of the patient.Conclusions: 1.Surgical safety and perioperative mortality were significantly decreased in the PDAC radical surgery;2.Multiple genes,multiple target mutations and tumor heterogeneity existed in all the PDAC samples;3.There are individual differences in patients with PDAC when treated with chemotherapeutic drugs;4.Combination therapy of Lapatinib and Tricotinib may be effective in the patients with G12 D mutations of KRAS gene 5.It is possible to improve the prognosis of the patientwith PDACif we have a systematic pharmacodynamics evaluation on gene-level before determining the chemthreapy of patient.6.The prognosis of the patient with PDAC wasstill closely associated with the clinical stage of disease,the surgical therapy situation and the post-operative general condition of the patient.