Genomic and Transcriptomic Landscape of Tumor Clonal Evolution in Cholangiocarcinoma

Abstract

Cholangiocarcinoma remained a severe threat to human health. Deciphering the genomic and/or transcriptomic profiles of tumor has been proved to be a promising strategy for exploring the mechanism of tumorigenesis and development, which could also provide valuable insights into Cholangiocarcinoma. However, little knowledge has been obtained regarding to how the alteration among different omics levels is connected. Here, using whole exome sequencing and transcriptome sequencing, we performed a thorough evaluation for the landscape of genome and transcriptome in cholangiocarcinoma and illustrate the alteration of tumor on different biological levels. Meanwhile, we also identified the clonal structure of each included tumor sample and discovered different clonal evolution patterns related to patients' survival. Furthermore, we extracted subnetworks that were greatly influenced by tumor clonal/subclonal mutations or transcriptome change. The topology relationship between genes affected by genomic/transcriptomic changes in biological interaction networks revealed that alteration of genome and transcriptome was highly correlated, and somatic mutations located on important genes might affect the expression of numerous genes in close range.

Genomic alterations in cholangiocarcinoma: clinical significance and relevance to therapy

“…In this respect, most studies of genomic profiling of CCA did not report information on the clonal or sub-clonal origin of the identified actionable mutations. In addition, evidence suggests that some CCA carry a considerable portion of sub-clonal mutations [ 142 ]. We might expect that tumors with sub-clonal driver alterations might not respond to matched therapies.…”

Current Advances in Basic and Translational Research of Cholangiocarcinoma

“…The landscape of genome and transcriptome in CCA may facilitate identification of target genes for novel therapies. Whole-exome and transcriptome sequencing for tumor and corresponding peritumor tissue samples of 9 iCCA patients identified an average of 378 somatic single nucleotide variants and 2366 differentially expressed genes in tumor tissues [24]. Interaction networks have shown that somatic mutations are highly correlated with altered gene expression, and mutations in key genes, such as TP53, may alter expression of numbers of genes [24].…”

“…Whole-exome and transcriptome sequencing for tumor and corresponding peritumor tissue samples of 9 iCCA patients identified an average of 378 somatic single nucleotide variants and 2366 differentially expressed genes in tumor tissues [24]. Interaction networks have shown that somatic mutations are highly correlated with altered gene expression, and mutations in key genes, such as TP53, may alter expression of numbers of genes [24]. Whole-exome sequencing for 318 iCCA patients identified 32 mutated genes associated with poor survival rates, which included TP53 and KRAS [25].…”

Evolución de la genómica tumoral

“…La isocitrato deshidrogenasa 1 y 2 (IDH1 y 2) fueron adiciones significativas a la lista de impulsores del glioblastoma, la LMA y el colangiocarcinoma (30)(31)(32). Ambas enzimas convierten el isocitrato en α-cetoglutarato (α-KG), un cofactor de las dioxigenasas α-KG, incluidas las ADN demetilasas de la familia TET, las histonas demetilasas de la familia KDM y muchas otras proteínas (33). Cuando IDH1 o 2 están mutados producen 2-oxiglutarato, un análogo estructural del α-KG que actúa como potente inhibidor de enzimas dependientes de α-KG, las metiltransferasas involucradas en la metilación del ADN y la cromatina.…”