Tumor Heterogeneity and Drug Resistance in FGFR2-Fusion Cholangiocarcinoma
Ontology highlight
ABSTRACT:
Whole exome sequencing was performed on blood and tumor specimens (collected from biopsy or rapid research autopsy) from a patient with FGFR2 fusion positive cholangiocarcinoma.
Project description:Genome-wide gene expression in 33 fusion-positive and 25 fusion-negative rhabdomyosarcoma cases was studied using GeneChip Human Genome U133 Plus2 (Affymetrix) Fusion-positive versus fusion-negative rhabdomyosarcoma tumors
Project description:RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor positive (ER+) breast cancer but their role in disease pathogenesis remains unclear. We performed sequencing on RNA extracted from metastatic biopsy samples from patients with ER+ breast cancer to assess the presence of fusion transcripts.
Project description:Genome-wide gene expression in 33 fusion-positive and 25 fusion-negative rhabdomyosarcoma cases was studied using GeneChip Human Genome U133 Plus2 (Affymetrix)
Project description:Purpose: Our laboratory recently identified the most common mechanism of acquired drug resistance in High Grade Serous Ovarian Cancer (HGSOC) to date, SLC25A40-ABCB1 fusions. The primary aim of this study was to examine the transcriptional profile of drug resistant fusion-positive SLC25A40-ABCB1 fusion positive cells. Single cell fusion-positive and negative clones were derived from the human HGSOC cell line AOCS-18.5 Methods: Three independent replicates of RNA was collected from five SLC25A40-ABCB1 fusion-negative AOCS 18.5 clones (B,C, D,E,F) and five SLC25A40-ABCB1 fusion-positive AOCS 18.5 clones (8,9,13, 15B, 18B) and submitted for NextSeq 100bp paired-end, polyA RNA-sequencing. Cells were collected 48-72hrs post seeding. 20 million paired end reads per sample were generated. Reads were mapped to the human reference GRCh37.92 using the STAR two pass method (v2.6.0b). Counts were generated on the ensemble release GRCh37.92 GTF annotation using HTSeq (v0.10.0). Counts were normalized to logged TMM values using edgeR (v3.28.1). TPM expression values were also generated. Differential gene expression analysis was performed using DESeq2 (v1.26.0) on the raw counts. In all, 3333 genes were significantly upregulated (>1.5 log2 fold change, p-adj<0.1) in fusion-positive lines, with 1751 genes significantly downregulated Conclusions: Using a stringent cut-off of >2.0 fold change (n=2238 differentially expressed genes), Metascape pathway analysis revealed that the most significantly enriched pathways in fusion-positive clones included the NABA matrisome associated pathway (160/751 genes, 7.24%), followed by external encapsulating structure organization (102/398 genes, 4.62%) and regulation of cell adhesion (139/734 genes, 6.29%).
Project description:ALK fusion positive tumor constitutes a unique entitiy in lung adenocarcionmas. We compared the allelokaryotypes of ALK fusion positive and negative tumors with SNP array to get insight into the difference of genomic background of them. Copy number analysis with Affymetrix 250K SNP arrays of 35 ALK fusion positive and 95 ALK fusion negative lung adenocarcinomas was performed with annonymous references.
Project description:Fusion of the N-terminus of the mixed-lineage-leukemia (MLL) gene with various partner genes drives acute lymphoblastic leukemia (ALL). Despite the fusion proteins sharing some common attributes, transcriptome heterogeneity of MLL-fusion ALL is observed and the underlying mechanism and biological consequences are unknown. We compared the genome-wide occupancy of MLL-Af4 and MLL-AF9 in human ALL cells expressing FLAG-tagged fusion proteins. Although both oncoproteins retain the same MLL N-terminal domains that mediate chromatin binding, the two fusion proteins displayed largely non-overlapping binding profiles, with MLL-AF9 showing preferential binding at repetitive elements. The binding specificity of each fusion protein was associated with differential global gene activation distinguishing the two ALLs. A subset of prednisolone response genes were among the differentially regulated targets, and the resistance related genes were specifically upregulated in MLL-Af4/AF4 cells. These studies provide evidence that distinct chromatin occupancy of different MLL-fusion proteins is one driving force for transcriptome heterogeneity of MLL-fusion ALL, which could potentially result in the disparate therapeutic outcome of the disease.