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Clinker: visualizing fusion genes detected in RNA-seq data

ABSTRACT: Genomic profiling efforts have revealed a rich diversity of oncogenic fusion genes, and many are emerging as important therapeutic targets. While there are many ways to identify fusion genes from RNA-seq data, visualising these transcripts and their supporting reads remains challenging. Clinker is a bioinformatics tool written in Python, R and Bpipe, that leverages the superTranscript method to visualise fusion genes. We demonstrate the use of Clinker to obtain interpretable visualizations of the RNA-seq data that lead to fusion calls. In addition, we use Clinker to explore multiple fusion transcripts with novel breakpoints within the P2RY8-CRLF2 fusion gene in B-cell Acute Lymphoblastic Leukaemia (B-ALL).

ORGANISM(S): Homo sapiens

PROVIDER: GSE113504 | GEO | 2018/04/23

REPOSITORIES: GEO

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Project description:Background Children with Down Syndrome have an augmented risk for B-cell acute lymphoblastic leukaemia (DS-ALL), which is associated with a survival lower than in non-DS ALL, due to increased chemotherapy-related toxicity and a higher relapse rate, thus demanding new tailored therapeutic strategies. Cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while alterations in CRLF2 and IKZF1 genes are increased. Aim of the study was to evaluate in DS-ALL children the incidence and prognostic value of the Philadelphia Chromosome-Like (Ph-like) status and the “IKZF1plus” profile, both associated with poor outcome in non-DS ALL and therefore introduced in current therapeutic protocols for BCP-ALL. Method Seventy DS-ALL patients at diagnosis treated in Italian centres from 2000 to 2014 were evaluated for their cytogenetic status, including the Ph-like ALL profile, while the IKZF1plus feature was investigated in a larger cohort of 134 patients treated in Italian and German centres from 2000 to 2011. Findings Forty-six out of 70 (65•7%) AIEOP DS-ALL patients displayed the Ph-like ALL gene expression signature, mostly characterized by CRLF2 (n=33) and IKZF1 (n=16) alterations (13 had both alterations); only one case was positive for an ABL-class and one for a PAX5 fusion gene. In the Italian and German joint cohort, we observed 35•6% patients positive for P2RY8::CRLF2 fusion, 24•8% for IKZF1 deletion and 18% for IKZF1plus feature. Unexpectedly, a higher IKZF1 expression and activity were observed in IKZF1plus than IKZF1 wt DS-ALL patients. Ph-like signature and IKZF1 deletion were associated with poor outcome, which further worsens when IKZF1 deletion was co-occurring with P2RY8::CRLF2, qualifying for the IKZF1plus definition. Interpretation These subgroups, which for the most part are not associated with other high risk features, need new and tailored therapeutic strategies, not only focussed on the use of drugs that restore IKZF1 function.

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Clinker: visualizing fusion genes detected in RNA-seq data

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