Transcriptomic Analysis of Metastatic Colorectal Tumor with Low Mutational Burden

Objective:To identify potential drug targets for metastasis colorectal cancer(CRC)patients with low mutational burden by examining differences in immune-related gene expression.Methods:For this study,623 samples were collected from The Cancer Genome Atlas(TCGA)database,comprising tumor mutational burden(TMB),RNA sequencing(RNA-Seq),and clinical data.Differential gene expression analysis,Gene Ontology(GO),and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis of the identified genes were conducted using the R package.Additionally,a comparative analysis of immune infiltrating cell composition in metastatic and non-metastatic groups was performed.Hub genes,exhibiting high levels of interaction,were selected using the Search Tool for the Retrieval of Interacting Genes/Proteins(STRING)database.The Drug Gene Interaction Database(DGIdb)was then utilized to estimate drugs targeting the identified hub genes.Results:The transcriptome data of 326 colorectal cancer patients with low TMB were analyzed,comprising 58 patients with metastasis and 268 patients without metastasis.Among the differential expression in 1,111 genes for patients with metastasis compared to those without metastasis,733 genes were upregulated,and 378 genes were downregulated.KEGG and GO enrichment analysis indicated significant differences in gene expression in CRC metastatic patients with low TMB compared to non-metastasis patients with low TMB.Enriched pathways included humoral immune response,immunoglobulin production,and regulation of AMPA receptor activity.Two genes related to interleukin-12 were identified through secondary enrichment for immune-related genes.Analysis of tumor-infiltrating immune cell data revealed significant differences in memory-activated T cell CD4 and T cell CD8.Conclusions:This analysis of RNA sequencing data and immune-filtrating cell data revealed significant differences between metastatic colorectal cancer patients with low TMB and their non-metastatic counterparts.These distinctions suggest the possibility of identifying more effective drugs or therapies for metastatic colorectal cancer patients with low TMB.

Somatic genetic aberrations in gallbladder cancer: comparison between Chinese and US patients

Background:Gallbladder cancer(GBC)is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis.The five-year survival rate of this cancer when diagnosed at an advanced stage is below 5%,and the median survival time is less than a year with standard gemcitabine-based chemotherapy.Survival benefit with second-line treatment is unknown.Thus,there is an urgent need for novel treatment strategies and targeted therapy based on next generation sequencing(NGS)may be of value.Methods:Comprehensive genomic profiling(CGP)was performed with NGS panel on paraffin-embedded tumors from a cohort of 108 Chinese and 107 US GBC patients.Clinical data were collected using an IRB approved protocol from a single-center in US and from China.Results:In Chinese and US GBC cohorts,an average of 6.4 vs.3.8 genomic alterations(GAs)were identified per patient.The most frequent alterations were TP53(69.4%),CDKN2A/B(26%),ERBB2(18.5%),PIK3CA(17%)and CCNE1(13%)in Chinese cohort,TP53(57.9%),CDKN2A/B(25%),SMAD4(17%),ARID1A(14%),PIK3CA(14%)and ERBB2(13.1%)in US patients.NFE2L2 mutations were present in 6.5%of Chinese patients and not observed in the US cohort.Interestingly,ERBB2 genetic aberrations were significantly associated with better pathological tumor differentiation and tended to co-occurrence with CDKN2A/B mutations in both the Chinese and US GBC cases.Out of the top 9 dysregulated genetic pathways in cancer,Chinese patients harbored more frequent mutations in ERBB genes(30.6%vs.19.0%,P=0.04).High frequency of PI3K/mTOR pathway variations was observed in both Chinese(37%)and US cohort(33%)(P=0.5).Additionally,both Chinese and US GBC patients exhibited a relatively high tumor mutational burden(TMB)(17.6%and 17.0%,respectively).In the Chinese cohort,a significant association was seen between direct repair gene alterations and TMB≥10 muts/Mb(P=0.004).Conclusions:In our study,over 83%Chinese and 68%US GBC patients had actionable alterations that could potentially guide and influence personalized treatment options.The identification of high TMB,ERBB2,CDKN2A/B,PI3K/mTOR pathway and DNA repair mutations indicated that both Chinese and US GBC patients may benefit from targeted or immune checkpoint inhibitors.