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Christoffer Flensburg

Bio: Christoffer Flensburg is an academic researcher from Walter and Eliza Hall Institute of Medical Research. The author has contributed to research in topics: Venetoclax & Germline. The author has an hindex of 5, co-authored 10 publications receiving 351 citations.
Topics: Venetoclax, Germline, MBD4, Gene, Exome

Papers
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Journal ArticleDOI
TL;DR: The first description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients is provided, providing new insights into the pathobiology of venetclax resistance and provides a potential biomarker of impending clinical relapse.
Abstract: The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry. It was first detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affinity of BCL2 for venetoclax by ∼180-fold in surface plasmon resonance assays, thereby preventing the drug from displacing proapoptotic mediators from BCL2 in cells and conferring acquired resistance in cell lines and primary patient cells. This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse. SIGNIFICANCE: Why CLL recurs in patients who achieve remission with the BCL2 inhibitor venetoclax has been unknown. We provide the first description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients. The mutation reduces venetoclax binding and is sufficient to confer resistance.See related commentary by Thangavadivel and Byrd, p. 320.This article is highlighted in the In This Issue feature, p. 305.

263 citations

Journal ArticleDOI
TL;DR: SuperFreq is a cancer exome sequencing analysis pipeline that integrates identification of somatic single nucleotide variants (SNVs) and copy number alterations (CNAs) and clonal tracking for both and can be applied in many different experimental settings for the analysis of exomes and other capture libraries.
Abstract: Analysing multiple cancer samples from an individual patient can provide insight into the way the disease evolves. Monitoring the expansion and contraction of distinct clones helps to reveal the mutations that initiate the disease and those that drive progression. Existing approaches for clonal tracking from sequencing data typically require the user to combine multiple tools that are not purpose-built for this task. Furthermore, most methods require a matched normal (non-tumour) sample, which limits the scope of application. We developed SuperFreq, a cancer exome sequencing analysis pipeline that integrates identification of somatic single nucleotide variants (SNVs) and copy number alterations (CNAs) and clonal tracking for both. SuperFreq does not require a matched normal and instead relies on unrelated controls. When analysing multiple samples from a single patient, SuperFreq cross checks variant calls to improve clonal tracking, which helps to separate somatic from germline variants, and to resolve overlapping CNA calls. To demonstrate our software we analysed 304 cancer-normal exome samples across 33 cancer types in The Cancer Genome Atlas (TCGA) and evaluated the quality of the SNV and CNA calls. We simulated clonal evolution through in silico mixing of cancer and normal samples in known proportion. We found that SuperFreq identified 93% of clones with a cellular fraction of at least 50% and mutations were assigned to the correct clone with high recall and precision. In addition, SuperFreq maintained a similar level of performance for most aspects of the analysis when run without a matched normal. SuperFreq is highly versatile and can be applied in many different experimental settings for the analysis of exomes and other capture libraries. We demonstrate an application of SuperFreq to leukaemia patients with diagnosis and relapse samples.

33 citations

Posted ContentDOI
30 Jul 2018-bioRxiv
TL;DR: SuperFreq is a cancer exome sequencing analysis pipeline that integrates identification of somatic single nucleotide variants (SNVs) and copy number alterations (CNAs) and clonal tracking for both and can be applied in many different experimental settings for the analysis of exomes and other capture libraries.
Abstract: Motivation Analysing multiple tumour samples from an individual cancer patient allows insight into the way the disease evolves. Monitoring the expansion and contraction of distinct clones helps to reveal the mutations that initiate the disease and those that drive progression; therefore, the ability to identify and track clones using genomics data is of great interest. Existing approaches for clonal tracking typically require the user to combine multiple tools that are not purpose-made. Furthermore, most methods require a matched normal (non-tumour) sample, which limits the scope of application. Results We have built superFreq, a cancer exome sequencing analysis tool that calls and annotates somatic SNVs and CNAs and attributes them to clones. SuperFreq makes use of unrelated control samples and does not require matched normal samples. We demonstrate the ability of superFreq to track clones by combining real samples in known proportions to simulating a multi-sample analysis. In addition, we compared superFreq to other somatic SNV callers and CNA callers on exome sequencing data from cancer-normal pairs, including 304 participants gathered from 33 cancer types in The Cancer Genome Atlas (TCGA). SuperFreq offers a reliable platform to identify somatic mutations and to track clones. SuperFreq recalled 91% of somatic SNVs identified by a consensus of four other methods, with a median of 1 additional somatic SNV per sample that was not found by any other method. CNA calls from superFreq showed good agreement with those generated by Sequenza, or those from ASCAT generated using matched SNP arrays. Using our simulated data set for testing multi-sample clonal tracking, we found that superFreq identified 93% of clones with a cellular fraction of at least 50%, and mutations were assigned to clones with high recall and close to 100% precision. In addition, SuperFreq maintained a similar level of performance for most aspects of the analysis without a matched normal control. SuperFreq is a highly adaptable method and has already been used in multiple different projects. Availability SuperFreq is implemented in R and available on github at https://github.com/ChristofferFlensburg/superFreq.

22 citations


Cited by
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Journal ArticleDOI
TL;DR: The main pathways that regulate apoptosis as well as other signalling pathways that interact with them are presented, highlighting actionable molecular targets for anticancer therapy and an overview of therapeutic agents exploiting apoptosis currently in clinical translation and known mechanisms of resistance to these agents are provided.
Abstract: For over three decades, a mainstay and goal of clinical oncology has been the development of therapies promoting the effective elimination of cancer cells by apoptosis. This programmed cell death process is mediated by several signalling pathways (referred to as intrinsic and extrinsic) triggered by multiple factors, including cellular stress, DNA damage and immune surveillance. The interaction of apoptosis pathways with other signalling mechanisms can also affect cell death. The clinical translation of effective pro-apoptotic agents involves drug discovery studies (addressing the bioavailability, stability, tumour penetration, toxicity profile in non-malignant tissues, drug interactions and off-target effects) as well as an understanding of tumour biology (including heterogeneity and evolution of resistant clones). While tumour cell death can result in response to therapy, the selection, growth and dissemination of resistant cells can ultimately be fatal. In this Review, we present the main apoptosis pathways and other signalling pathways that interact with them, and discuss actionable molecular targets, therapeutic agents in clinical translation and known mechanisms of resistance to these agents.

908 citations

Journal ArticleDOI
07 Jul 2022-Blood
TL;DR: This update includes a revised ELN genetic risk classification, revised response criteria, and treatment recommendations for acute myeloid leukemia in adults, which are widely recognized among physicians and investigators.

404 citations

Journal ArticleDOI
TL;DR: A primary gastric cancer organoid biobank that comprises normal, dysplastic, cancer, and lymph node metastases from 34 patients, including detailed whole-exome and transcriptome analysis, provides a useful resource for studying both cancer cell biology and precision cancer therapy.

393 citations

Journal ArticleDOI
TL;DR: Regulators of lymphoid transcription and cellular energy metabolism are identified as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples.

179 citations