Study On The Relationship Between Gene Characteristics And Immunotherapy And Targeted Therapyin Advanced Gastrointestinal Cancer

BackgroundIn this study,we introduced next-generation liquid biopsy techniques to detect gene variants,copy number variations,and microsatellite instability associated with drug therapeutic targets in the plasma circulating tumor DNA(ct DNA)of patients with advanced gastric and colorectal cancer and mapped the drug-related gene variations of common therapeutic targets in patients with advanced gastric and colorectal cancer in Fujian,China.The relationship between gene variation and programmed death-ligand 1(PD-L1)or microsatellite instability was analyzed,to lay a research foundation for finding a model of targeted therapy combined with immunotherapy for advanced gastric cancer and colorectal cancer.MethodsA total of 46 patients with advanced gastrointestinal cancer(27 cases of gastric cancer and 19 cases of colorectal cancer)diagnosed in our hospital from September 2020 to July2021 were collected,and all enrolled patients underwent “next-generation” sequencing technology(NGS).Blood samples were collected,based on NGS method for 95 genes related to the development and progression of patients’ tumors: the ct DNA from blood were extracted,subjected to library construction,amplified,and subjected to targeted capture enrichment,followed by completion of high-throughput DNA sequencing.Data from the sequence information of the target genes were analyzed.The types of variations detected in the product included single nucleotide variant(SNV),copy number variation(CNV),insertion/deletion(In Del),structure variation(SV),gene fusion,etc.After obtaining the results,draw the gene map of advanced gastrointestinal cancer in Fujian,analyze the preference of various gene variants between the two kinds of cancer and the location of high-frequency mutant genes,and compare them with the mutations of relevant tumor genes in the database.At the same time,we analyzed their correlation with clinicopathological features and prognosis.Data were analyzed using SPSS version 26.0(IBM Corp.,Armonk,NY,USA).Overall survival(OS)curves were produced using the Kaplan-Meier estimator method and compared with the logrank test.Univariable and multivariable analyses of clinical characteristics.All available patient and tumor variables were compared using the χ2 test.All statistical tests were twosided,with a threshold of P<0.05 for statistical significance.Results1)The alleles with the highest frequency of mutation in the population were the genes with the highest frequency of mutation occurrence in the population are TP53(32/46,69.6%),KRAS(12/46,26.1%),APC(11/46,23.9%),PIK3CA(10/46,21.7%),ERBB2(8/46,17.4%),MYC(6/46,13.0%),CDH1(6/46,13.0%),FGFR2(5/46,10.9%),SMAD4(5/46,10.9%),ARID1A(5/46,10.9%),etc.2).The mutation frequency of TP53 gene is very high in both gastric cancer and colorectal cancer(81% vs 53%).The higher mutation frequencies in gastric cancer include ERBB2(22% vs 11%),FGFR2(19% vs 0%),CDH1(19% vs 0%),CCND1(15% vs 0%).Those with higher mutation frequencies in colorectal cancer include APC(19%vs 32%),BRCA1(0% vs 11%),NF2(0% vs 11%),etc.3).In the hot spot genes which are mainly mutated in the form of non-CNV,the lollipop map shows that the mutation sites and the functional domains of the corresponding genes,tumor suppressor genes and protooncogenes,the location of the mutation is not regular distribution.4)The same genes those carried mutations between the gastric cancer cohort of this study,the TCGA gastric cancer cohort,and the COSMIC gastric cancer cohort are: TP53,APC,ARID1 A,PIK3CA.The same genes those carried mutations in the colorectal cancer cohort of this study,the TCGA colorectal cancer cohort and the COSMIC colorectal cancer cohort are:KRAS,TP53,APC,PIK3 CA.5)50% of microsatellite instability(MSI)patients carry MYC gene mutation,while microsatellite stability(MSS)patients do not carry this gene mutation.6)There are co-mutations in PD-L1 positive patients,including FGFR2,ERBB2 amplification,ALK,and other targets of proprietary drug mutations,which improve the theoretical basis for individualized targeted combined immunotherapy.7)Univariate analysis showed that patients with colorectal cancer,less than 60 years old,II-III stage,moderate differentiation,surgical treatment,and postoperative adjuvant chemotherapy had a longer survival time.Multivariate analyses indicated that surgical treatment was an independent factor affecting OS.ConclusionsIn this study,a new type of ct DNA liquid biopsy sequencing was performed in the plasma of patients with advanced gastric cancer and colorectal cancer in Fujian,and the results were similar to those of other Chinese tissue samples.It is suitable for medication guidance for patients with advanced gastrointestinal tumors who cannot obtain biopsy samples.There most common relevant biomarkers: FGFR2,ERBB2 amplifications and ALK mutation in PD-L1 positive patients,which provides theoretical support for targeted combined immunotherapy.Surgical treatment is an independent prognostic factor for the total survival of advanced gastrointestinal tumors.