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Tumor Heterogeneity and Drug Resistance in FGFR2-Fusion Cholangiocarcinoma

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.

PROVIDER: phs001830 | dbGaP |

REPOSITORIES: dbGaP

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			Action	DRS
	GapExchange_phs001830.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs001830.FGFR2_Cholangiocarcinoma.v1.p1.MULTI.pdf	Pdf
	manifest_phs001830.FGFR2_Cholangiocarcinoma.v1.p1.c1.DS-CA.pdf	Pdf
	datadict_v2.xsl	Other

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Tumor heterogeneity and acquired drug resistance in FGFR2 fusion-positive cholangiocarcinoma through rapid research autopsy

Project description:Tumor heterogeneity and acquired drug resistance in FGFR2 fusion-positive cholangiocarcinoma through rapid research autopsy

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Tumor heterogeneity and acquired drug resistance in FGFR2 fusion-positive cholangiocarcinoma through rapid research autopsy

Project description:Tumor heterogeneity and acquired drug resistance in FGFR2 fusion-positive cholangiocarcinoma through rapid research autopsy

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Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy.

Project description:Cholangiocarcinoma is a highly aggressive and lethal malignancy, with limited treatment options available. Recently, FGFR inhibitors have been developed and utilized in FGFR-mutant cholangiocarcinoma; however, resistance often develops and the genomic determinants of resistance are not fully characterized. We completed whole-exome sequencing (WES) of 11 unique tumor samples obtained from a rapid research autopsy on a patient with FGFR-fusion-positive cholangiocarcinoma who initially responded to the pan-FGFR inhibitor, INCB054828. In vitro studies were carried out to characterize the novel FGFR alteration and secondary FGFR2 mutation identified. Multisite WES and analysis of tumor heterogeneity through subclonal inference identified four genetically distinct cancer cell populations, two of which were only observed after treatment. Additionally, WES revealed an FGFR2 N549H mutation hypothesized to confer resistance to the FGFR inhibitor INCB054828 in a single tumor sample. This hypothesis was corroborated with in vitro cell-based studies in which cells expressing FGFR2-CLIP1 fusion were sensitive to INCB054828 (IC50 value of 10.16 nM), whereas cells with the addition of the N549H mutation were resistant to INCB054828 (IC50 value of 1527.57 nM). Furthermore, the FGFR2 N549H secondary mutation displayed cross-resistance to other selective FGFR inhibitors, but remained sensitive to the nonselective inhibitor, ponatinib. Rapid research autopsy has the potential to provide unprecedented insights into the clonal evolution of cancer throughout the course of the disease. In this study, we demonstrate the emergence of a drug resistance mutation and characterize the evolution of tumor subclones within a cholangiocarcinoma disease course.

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Expression Profiling of human Fusion-Positive and Fusion-Negative Rhabdomyosarcoma

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

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RNA sequencing to identify fusion transcripts in late-stage relapse patients with estrogen receptor positive breast cancer

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.

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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%).

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