The role of alternative splicing in cancer: From oncogenesis to drug resistance

Drug Resistance Updates, Год журнала: 2020, Номер 53, С. 100728 - 100728

Опубликована: Сен. 28, 2020

Alternative splicing is a tightly regulated process whereby non-coding sequences of pre-mRNA are removed and protein-coding segments assembled in diverse combinations, ultimately giving rise to proteins with distinct or even opposing functions. In the past decade, whole genome/transcriptome sequencing studies revealed high complexity regulation, which occurs co-transcriptionally influenced by chromatin status mRNA modifications. Consequently, profiles both healthy malignant cells display diversity alternative was shown be widely deregulated multiple cancer types. particular, mutations regulatory sequences, regulators modifiers, as well differential expression factors important contributors pathogenesis. It has become clear that these aberrations contribute many facets cancer, including oncogenic transformation, progression, response anticancer drug treatment resistance therapy. this respect, perturb broad spectrum relevant genes involved uptake/metabolism (i.e. SLC29A1, dCK, FPGS, TP), activation nuclear receptor pathways GR, AR), regulation apoptosis MCL1, BCL-X, FAS) modulation immunotherapy (CD19). Furthermore, aberrant constitutes an source novel biomarkers spliceosome machinery represents attractive target for rapidly expanding class therapeutic agents. Small molecule inhibitors targeting SF3B1 splice factor kinases were highly cytotoxic against wide range models, drug-resistant cells. Importantly, effects enhanced specific subsets, such factor-mutated c-MYC-driven tumors. pre-clinical report synergistic modulators combination conventional antitumor These strategies based on use low dose could shift window towards decreased toxicity tissues. Here we provide extensive overview latest findings field molecular mechanisms harness drive oncogenesis evade splicing-based vulnerabilities can opportunities. discuss current challenges arising from genome-wide detection prediction methods splicing, unravelling functional relevance plethora cancer-related alterations.

Язык: Английский

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Comprehensive Study of the Clinical Phenotype of GermlineBAP1Variant-Carrying Families Worldwide

JNCI Journal of the National Cancer Institute, Год журнала: 2018, Номер 110(12), С. 1328 - 1341

Опубликована: Авг. 31, 2018

The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary caused by germline pathogenic variants in BAP1 encoding suppressor associated with uveal melanoma, mesothelioma, cutaneous renal cell carcinoma, and BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors yet to be determined. Improved understanding BAP1-TPDS crucial for appropriate clinical management variant carriers their families, including genetic counseling surveillance new We collated status, diagnoses, information on immunohistochemistry or loss somatic heterozygosity 106 published 75 unpublished variant-positive families worldwide better characterize genotypes phenotypes BAP1-TPDS. Tumor ages onset were compared between missense null variants. All statistical tests two-sided. 181 carried 140 unique data confirmed core showed that some carrying can exhibit this phenotype. A variety noncore -associated found carriers. Median types lower than all combined (P < .001), mesothelioma melanoma nonmelanoma skin cancer .001). This analysis substantially increases number refines It highlights need curated registry proper assessment phenotype pathogenicity variants, thus guiding patients informing areas requiring further research.

Язык: Английский

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A pan-cancer analysis of synonymous mutations

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Июнь 12, 2019

Synonymous mutations have been viewed as silent mutations, since they only affect the DNA and mRNA, but not amino acid sequence of resulting protein. Nonetheless, recent studies suggest their significant impact on splicing, RNA stability, folding, translation or co-translational protein folding. Hence, we compile 659194 synonymous found in human cancer characterize properties. We provide user-friendly, comprehensive resource for cancer, SynMICdb ( http://SynMICdb.dkfz.de ), which also contains orthogonal information about gene annotation, recurrence, mutation loads, association, conservation, alternative events, mRNA structure a score. Notably, missense are depleted at 5'-end coding well ends internal exons independent mutational signatures. For patient-derived oncogene KRAS, indicate that single point can relevant expression secondary structure.

Язык: Английский

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RNA Splicing and Cancer

Trends in cancer, Год журнала: 2020, Номер 6(8), С. 631 - 644

Опубликована: Май 17, 2020

Язык: Английский

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Best practices for bioinformatic characterization of neoantigens for clinical utility

Genome Medicine, Год журнала: 2019, Номер 11(1)

Опубликована: Авг. 28, 2019

Neoantigens are newly formed peptides created from somatic mutations that capable of inducing tumor-specific T cell recognition. Recently, researchers and clinicians have leveraged next generation sequencing technologies to identify neoantigens create personalized immunotherapies for cancer treatment. To a vaccine, must be computationally predicted matched tumor-normal data, then ranked according their capability in stimulating response. This candidate neoantigen prediction process involves multiple steps, including mutation identification, HLA typing, peptide processing, peptide-MHC binding prediction. The general workflow has been utilized many preclinical clinical trials, but there is no current consensus approach few established best practices. In this article, we review recent discoveries, summarize the available computational tools, provide analysis considerations each step, prediction, prioritization, delivery, validation methods. addition reviewing state analysis, practical guidance, specific recommendations, extensive discussion critical concepts points confusion practice characterization use. Finally, outline necessary areas development, need improve class II typing accuracy, expand software support diverse sources, incorporate response data algorithms. ultimate goal workflows vaccines patient outcomes types.

Язык: Английский

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Towards new horizons: characterization, classification and implications of the tumour antigenic repertoire

Nature Reviews Clinical Oncology, Год журнала: 2020, Номер 17(10), С. 595 - 610

Опубликована: Июнь 22, 2020

Язык: Английский

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Targeting mRNA processing as an anticancer strategy

Nature Reviews Drug Discovery, Год журнала: 2019, Номер 19(2), С. 112 - 129

Опубликована: Сен. 25, 2019

Язык: Английский

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Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects

Nature Reviews Genetics, Год журнала: 2022, Номер 24(4), С. 251 - 269

Опубликована: Дек. 16, 2022

Язык: Английский

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Dysregulation and therapeutic targeting of RNA splicing in cancer

Nature Cancer, Год журнала: 2022, Номер 3(5), С. 536 - 546

Опубликована: Май 27, 2022

Язык: Английский

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Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Март 22, 2023

Abstract Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools ( www.regtools.org ), a computationally efficient, free, open-source software package designed to integrate somatic variants from genomic data with splice junctions bulk or single cell transcriptomic identify cause aberrant splicing. We apply over 9000 tumor samples both DNA RNA sequence data. discovers 235,778 events where splice-associated variant significantly increases the splicing of particular junction, across 158,200 unique 131,212 junctions. To characterize these their associated isoforms, annotate them Variant Effect Predictor, SpliceAI, Genotype-Tissue Expression junction counts compare our results other tools While many corroborated by aforementioned tools, flexibility also allows us known cancer drivers, such as TP53 , CDKN2A B2M genes.

Язык: Английский

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