The identification of gene fusions from RNA sequencing data is a routine task in cancer research and precision oncology. However, despite the availability of many computational tools, fusion ...detection remains challenging. Existing methods suffer from poor prediction accuracy and are computationally demanding. We developed Arriba, a novel fusion detection algorithm with high sensitivity and short runtime. When applied to a large collection of published pancreatic cancer samples (
= 803), Arriba identified a variety of driver fusions, many of which affected druggable proteins, including ALK, BRAF, FGFR2, NRG1, NTRK1, NTRK3, RET, and ROS1. The fusions were significantly associated with
wild-type tumors and involved proteins stimulating the MAPK signaling pathway, suggesting that they substitute for activating mutations in
In addition, we confirmed the transforming potential of two novel fusions,
-
and
-
, in cellular assays. These results show Arriba's utility in both basic cancer research and clinical translation.
Soft-tissue sarcomas (STS) are a heterogeneous group of mesenchymal tumors for which response to immunotherapies is not well established. Therefore, it is important to risk-stratify and identify STS ...patients who will most likely benefit from these treatments.
To reveal shared and distinct methylation signatures present in STS, we performed unsupervised deconvolution of DNA methylation data from the TCGA sarcoma and an independent validation cohort. We showed that leiomyosarcoma can be subclassified into three distinct methylation groups. More importantly, we identified a component associated with tumor-infiltrating leukocytes, which suggests varying degrees of immune cell infiltration in STS subtypes and an association with prognosis. We further investigated the genomic alterations that may influence tumor infiltration by leukocytes including RB1 loss in undifferentiated pleomorphic sarcomas and ELK3 amplification in dedifferentiated liposarcomas.
In summary, we have leveraged unsupervised methylation-based deconvolution to characterize the immune compartment and molecularly stratify subtypes in STS, which may benefit precision medicine in the future.
Abstract
Summary
Piwi-interacting RNAs (piRNAs) are a class of small non-coding RNAs which guide endonucleases to mRNAs of actively transcribed transposons in order to prevent their translation. The ...resulting mRNA fragments induce a positive feedback loop (the 'ping-pong cycle'), which reinforces piRNA production and hence the transposon-silencing effect. PingPongPro is a command-line tool to scan small RNA-Seq data for signs of ping-pong cycle activity. It implements a novel algorithm that combines empirical probabilities in a multi-factor model to accurately identify transposons which are suppressed through the ping-pong cycle.
Availability and implementation
Source code, a user manual, and binaries for Microsoft Windows and Linux are available at https://github.com/suhrig/pingpongpro under the GPLv3 license.
Supplementary information
Supplementary data are available at Bioinformatics online.
The widespread use of high-throughput sequencing techniques is leading to a rapidly increasing number of disease-associated variants of unknown significance and candidate genes. Integration of ...knowledge concerning their genetic, protein as well as functional and conservational aspects is necessary for an exhaustive assessment of their relevance and for prioritization of further clinical and functional studies investigating their role in human disease. To collect the necessary information, a multitude of different databases has to be accessed and data extraction from the original sources commonly is not user-friendly and requires advanced bioinformatics skills. This leads to a decreased data accessibility for a relevant number of potential users such as clinicians, geneticist, and clinical researchers. Here, we present aRgus (https://argus.urz.uni-heidelberg.de/), a standalone webtool for simple extraction and intuitive visualization of multi-layered gene, protein, variant, and variant effect prediction data. aRgus provides interactive exploitation of these data within seconds for any known gene of the human genome. In contrast to existing online platforms for compilation of variant data, aRgus complements visualization of chromosomal exon-intron structure and protein domain annotation with ClinVar and gnomAD variant distributions as well as position-specific variant effect prediction score modeling. aRgus thereby enables timely assessment of protein regions vulnerable to variation with single amino acid resolution and provides numerous applications in variant and protein domain interpretation as well as in the design of in vitro experiments.
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Multiple myeloma (MM) is a hematological malignancy originating from malignant and clonally expanding plasma cells. MM can be molecularly stratified, and its clonal evolution deciphered based on the ...Ig heavy and light chains of the respective malignant plasma cell clone. Of all MM subtypes, IgE type MM accounts for only <0.1% of cases and is associated with an aggressive clinical course and consequentially dismal prognosis. In such malignancies, adoptive transfer of autologous lymphocytes specifically targeting presented (neo)epitopes encoded by either somatically mutated or specifically overexpressed genes has resulted in substantial objective clinical regressions even in relapsed/refractory disease. However, there are no data on the genetic and immunological characteristics of this rare and aggressive entity. Here, we comprehensively profiled IgE type kappa MM on a genomic and immune repertoire level by integrating DNA- and single-cell RNA sequencing and comparative profiling against non-IgE type MM samples. We demonstrate distinct pathophysiological mechanisms as well as novel opportunities for targeting IgE type MM. Our data further provides the rationale for patient-individualized neoepitope-targeting cell therapy in high tumor mutation burden MM.
Combined hepatocellular-cholangiocarcinoma (cHCC/CCA) represents a rare type of primary liver cancer with a very limited prognosis. Although just recently genomic studies have contributed to a better ...understanding of the disease’s genetic landscape, therapeutic options, especially for advanced-stage patients, are limited and often experimental, as no standardized treatment protocols have been established to date. Here, we report the case of a 38-year-old male patient who was diagnosed with extensive intrahepatic cHCC/CCA in an otherwise healthy liver without signs of chronic liver disease. An interdisciplinary stepwise therapeutic approach including locoregional liver-targeted therapy, systemic chemotherapy, liver transplantation, surgical pulmonary metastasis resection, and next-generation sequencing-based targeted therapy led to a prolonged overall survival beyond 5 years with an excellent quality of life. This case report comprises several provocative treatment decisions that are extensively discussed in light of the existing literature on this rare but highly aggressive malignancy.
We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 ...patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with
wild-type (
) tumors (4 of 17). These alterations included recurrent
rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with
-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of
tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC.
Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as
fusions as disease-driving events in
tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity.
.
Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept ...data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle–related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.
•Ex vivo drug profiling captures disease-relevant features and relevant sensitivity to therapeutic agents in ALL.•A subset of drug-resistant T-ALL without mutations in ABL1 is highly responsive to dasatinib, which provides a rationale for drug repurposing.
Abstract
Background
Cholangiocarcinoma (CCA) is a primary malignancy of the biliary tract with a dismal prognosis. Recently, several actionable genetic aberrations were identified with significant ...enrichment in intrahepatic CCA, including
FGFR2
gene fusions with a prevalence of 10–15%. Recent clinical data demonstrate that these fusions are druggable in a second-line setting in advanced/metastatic disease and the efficacy in earlier lines of therapy is being evaluated in ongoing clinical trials. This scenario warrants standardised molecular profiling of these tumours.
Methods
A detailed analysis of the original genetic data from the FIGHT-202 trial, on which the approval of Pemigatinib was based, was conducted.
Results
Comparing different detection approaches and displaying representative cases, we described the genetic landscape and architecture of
FGFR2
fusions in iCCA and show biological and technical aspects to be considered for their detection. We elaborated parameters, including a suggestion for annotation, that should be stated in a molecular diagnostic
FGFR2
report to allow a complete understanding of the analysis performed and the information provided.
Conclusion
This study provides a detailed presentation and dissection of the technical and biological aspects regarding
FGFR2
fusion detection, which aims to support molecular pathologists, pathologists and clinicians in diagnostics, reporting of the results and decision-making.
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