APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas

Selenica, Pier; Marra, Antonio; Gazzo, Andrea; Falcon, Christina; Patel, Juber; Pei, Xin; Zhu, Yingjie; Ng, Charlotte K.Y.; Curry, Michael; Heller, Glenn; Zhang, Y.-K.; Berger, Mike F.; Ladanyi, Marc; Rudin, Charles M.; Chandarlapaty, Sarat; Lovly, Christine M.; Reis‐Filho, Jorge S.; Yu, Helena A.

doi:10.1016/j.annonc.2022.09.151

Cited by 35 publications

(31 citation statements)

References 42 publications

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“…More recent studies also detected TRIM24-BRAF and AGK-BRAF fusions identified with first line osimertinib or with later-line osimertinib (10) as is the case reported here with the novel BTN2A1-BRAF fusion (6). Other BRAF fusions have recently been described in EGFR-mutant osimertinib resistant NSCLC and are related to apolipoprotein b mRNA editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature (11).…”

supporting

confidence: 76%

Acquired BRAF gene fusions in Osimertinib resistant EGFR-mutant non-small cell lung cancer

Rosell¹,

González‐Cao²,

Codony-Servat³

et al. 2023

Transl Cancer Res

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supporting

confidence: 76%

Acquired BRAF gene fusions in Osimertinib resistant EGFR-mutant non-small cell lung cancer

Rosell¹,

González‐Cao²,

Codony-Servat³

et al. 2023

Transl Cancer Res

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“…Besides testing search algorithms, we benchmarked Katdetectr using PELT and five publicly available kataegis detection packages which were recently published and used for supporting kataegis research [2, 5, 14, 15]. Since no consensus benchmark was available, we aimed to get insight into the performance of these tools.…”

Section: Discussionmentioning

confidence: 99%

“…Kataegis is the most commonly used term for local hypermutations and has historically been defined as a cluster of at least six variants, of which the mean IMD is less or equal to 1000 base pairs [1, 16]. However, this definition has been altered recently, making the formal definition of kataegis ambiguous [2, 4, 5, 14]. For instance, another type of clustered mutations is called Omikli, which refers to clusters smaller than kataegis, generally containing three or four variants [17].…”

Section: Discussionmentioning

confidence: 99%

Katdetectr: An R/Bioconductor package utilizing unsupervised changepoint analysis for robust kataegis detection

Hazelaar

Riet

Hoogstrate

et al. 2022

Preprint

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Motivation: Kataegis refers to the occurrence of regional hypermutation in cancer genomes and is a phenomenon that has been observed in a wide range of malignancies. Robust detection of kataegis is necessary to advance research regarding the origins and clinical impact of kataegis. Multiple kataegis detection packages are publicly available; however, the performance of their respective approaches have not been evaluated extensively. Here, we introduce katdetectr, an R-based, open-source, computationally fast, and robust package for the detection, characterisation and visualisation of kataegis. Results: The performance of katdetectr and five publicly available packages for kataegis detection were evaluated using an in-house generated synthetic dataset and an a priori labelled pan-cancer dataset of whole genome sequenced malignancies. The performance evaluation revealed that katdetectr has the highest accuracy and normalized Matthews Correlation Coefficient for kataegis classification on both the synthetic and the a priori labelled dataset. Katdetectr is in particularly more robust for kataegis detection within samples with a high tumour mutational burden. Availability and Implementation: Katdetectr imports standardised variant calling formats (MAF and VCF) as well as standard Bioconductor classes (GRanges and VRanges). Katdetectr segments genomic variants utilising unsupervised changepoint detection and the Pruned Exact Linear Time search algorithm. Kataegis foci are flagged based on the historical definition, namely that a kataegis foci is a continuous segment harbouring ≥6 variants and has a mean intermutation distance ≤1000 bp. Additionally, the implementation of changepoint detection utilised by katdetectr results in fast computation. Furthermore, katdetectr is available on Bioconductor which ensures reliability, and operability on common operating systems (Windows, macOS and Linux). Katdetectr is available on Bioconductor at https://www.bioconductor.org/packages/devel/bioc/html/katdetectr.html and on GitHub at https://github.com/ErasmusMC-CCBC/katdetectr. All code used for the performance evaluation is available on GitHub at: https://github.com/ErasmusMC-CCBC/evaluation_katdetectr

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“…The fraction of genome altered (FGA; ie, the number of copy number segments which are not copy neutral divided by the total number of copy number segments26), and the tumour mutation burden (TMB; ie, the number of mutations divided by the total genomic region assessed by MSK-IMPACT, per megabase), were retrieved from cBioPortal. Mutational signatures were inferred using SigMA,27 using all synonymous and non-synonymous somatic mutations in BCs with at least five single nucleotide variants, as previously described 28 29. In addition, we retrieved the raw MSK-IMPACT sequencing data (ie, FASTQ files) and reprocessed them using our validated bioinformatics pipeline30 31 for two cases with paired primary and metastatic samples to infer the copy number alterations and cancer cell fraction using ABSOLUTE 32…”

Section: Methodsmentioning

confidence: 99%

KITgenetic alterations in breast cancer

Vahdatinia

Derakhshan²,

Paula³

et al. 2022

J Clin Pathol

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AimsActivating somatic mutations or gene amplification ofKITresult in constitutive activation of its receptor tyrosine kinase, which is targetable in various solid tumours. Here, we sought to investigate the presence ofKITgenetic alterations in breast cancer (BC) and characterise the histological and genomic features of these tumours.MethodsA retrospective analysis of 5,575 BCs previously subjected to targeted sequencing using the FDA-authorised Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay was performed to identify BCs withKITalterations. A histological assessment ofKIT-altered BCs was conducted, and their repertoire of genetic alterations was compared with that of BCs lackingKITgenetic alterations, matched for age, histological type, oestrogen receptor/HER2 status and sample type.ResultsWe identified 18 BCs (0.32%), including 9 primary and 9 metastatic BCs, with oncogenic/likely oncogenic genetic alterations affectingKIT, including activating somatic mutations (n=4) or gene amplification (n=14). AllKIT-altered BCs were of high histological grade, although no distinctive histological features were observed. When compared with BCs lackingKITgenetic alterations, no distinctive genetic features were identified. In two metastaticKIT-altered BCs in which the matched primary BC had also been analysed by MSK-IMPACT, theKITmutations were found to be restricted to the metastatic samples, suggesting that they were late events in the evolution of these cancers.ConclusionsKITgenetic alterations are vanishingly rare in BC.KIT-altered BCs are of high grade but lack distinctive histological features. Genetic alterations inKITmight be late events in the evolution and/or progression of BC.

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APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas

Cited by 35 publications

References 42 publications

Acquired BRAF gene fusions in Osimertinib resistant EGFR-mutant non-small cell lung cancer

Acquired BRAF gene fusions in Osimertinib resistant EGFR-mutant non-small cell lung cancer

Katdetectr: An R/Bioconductor package utilizing unsupervised changepoint analysis for robust kataegis detection

KITgenetic alterations in breast cancer

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