A5049196945- Ocular Oncology and Treatments
- Immunotherapy and Immune Responses
- Cancer Genomics and Diagnostics
- Advanced biosensing and bioanalysis techniques
- Microtubule and mitosis dynamics
- Nanoplatforms for cancer theranostics
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Retinal Development and Disorders
- Epigenetics and DNA Methylation
- Chromatin Remodeling and Cancer
- RNA Research and Splicing
- Cutaneous Melanoma Detection and Management
- PARP inhibition in cancer therapy
- Cancer Cells and Metastasis
- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- Advanced Fluorescence Microscopy Techniques
- Telomeres, Telomerase, and Senescence
- Genomics and Chromatin Dynamics
- Acute Myeloid Leukemia Research
- Cell Adhesion Molecules Research
- Cancer Immunotherapy and Biomarkers
- Genetic factors in colorectal cancer
- melanin and skin pigmentation
Institut Curie
2016-2025
Université Paris Sciences et Lettres
2016-2024
Inserm
2016-2024
La Ligue Contre le Cancer
2018-2024
Sorbonne Université
2022
Hotspot mutations in the spliceosome gene SF3B1 are reported ∼20% of uveal melanomas. is involved 3'-splice site (3'ss) recognition during RNA splicing; however, molecular mechanisms its mutation have remained unclear. Here we show, using RNA-Seq analyses melanoma, that SF3B1(R625/K666) results deregulated splicing at a subset junctions, mostly by use alternative 3'ss. Modelling differential junctions SF3B1(WT) and cell lines demonstrates splice pattern strictly depends on status...
In nonmetastatic triple-negative breast cancer (TNBC) patients, we investigated whether circulating tumor DNA (ctDNA) detection can reflect the response to neoadjuvant chemotherapy (NCT) and detect minimal residual disease after surgery.Ten milliliters of plasma were collected at 4 time points: before NCT; 1 cycle; surgery; surgery. Customized droplet digital PCR (ddPCR) assays used track protein p53 (TP53) mutations previously characterized in tissue by massively parallel sequencing...
Although most characterized tumor antigens are encoded by canonical transcripts (such as differentiation or tumor-testis antigens) mutations (both driver and passenger mutations), recent results have shown that noncanonical including long noncoding RNAs transposable elements (TEs) can also encode tumor-specific neo-antigens. Here, we investigate the presentation immunogenicity of derived from mRNA splicing events between coding exons TEs. Comparing human non–small cell lung cancer (NSCLC)...
Oncogenesis often implicates epigenetic alterations, including derepression of transposable elements (TEs) and defects in alternative splicing. Here, we explore the possibility that noncanonical splice junctions between exons TEs represent a source tumor-specific antigens. We show mouse normal tissues tumor cell lines express wide but distinct ranges mRNA TEs, some which are specific. Immunopeptidome analyses identified peptides derived from exon-TE splicing associated to MHC-I molecules....
Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present metastatic patient an exceptional high sensitivity to PD-1 inhibitor associated outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic inactivation in the tumor. We identify additional tumors The Cancer Genome Atlas (TCGA) cohorts similar hypermutator profiles patients carrying mutations loss heterozygosity. This MBD4-related phenotype may explain unexpected responses...
Disruption of splicing patterns due to mutations genes coding factors in tumors represents a potential source tumor neoantigens, which would be both public (shared between patients) and tumor-specific (not expressed normal tissues). In this study, we show that the factor SF3B1 uveal melanoma generate such immunogenic neoantigens. Memory CD8+ T cells specific for these neoantigens are preferentially found 20% patients with bearing SF3B1-mutated tumors. Single-cell analyses neoepitope-specific...
A variant erythroferrone contributes to hepcidin modulation and systemic iron accumulation in patients with SF3B1 -mutated myelodysplastic syndrome.
We introduce shallowHRD, a software tool to evaluate tumor homologous recombination deficiency (HRD) based on whole genome sequencing (WGS) at low coverage (shallow WGS or sWGS; ∼1X coverage). The tool, mining copy number alterations profile, implements fast and straightforward procedure that shows 87.5% sensitivity 90.5% specificity for HRD detection. shallowHRD could be instrumental in predicting response poly(ADP-ribose) polymerase inhibitors, which tumors are selectively sensitive....
Abstract SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that mutant ( MUT ) cells selectively sensitive poly (ADP-ribose) polymerase inhibitors (PARPi), independent mutation site. display defective response PARPi-induced replication stress occurs via downregulation the cyclin-dependent kinase 2 interacting protein (CINP), leading increased fork origin...
Abstract Myelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS mutations in other splicing factor genes SRSF2 or U2AF1 . Molecular bases of these divergences are poorly understood. Here we find that -mutated show reduced R-loop formation predominating bodies associated intron retention reduction, not found - MDS. Compared to erythroblasts SRSF2- patients, exhibit augmented DNA synthesis, accelerated replication forks, and...
Abstract Purpose: Uveal melanomas (UM) are genetically simple tumors carrying few copy number alterations (CNA) and a low mutation burden, except in rare MBD4-deficient, hypermutated cases. The genomics of uveal melanoma metastatic progression has not been described. We assessed the genetic heterogeneity primary MBD4-proficient -deficient melanomas. Experimental Design: prospectively collected 75 16 samples from 25 consecutive patients, performed whole-exome sequencing. Results: contained...
Uveal melanoma (UM) arises from malignant transformation of melanocytes in the uveal tract eye. This rare tumor has a poor outcome with frequent chemo-resistant liver metastases. BAP1 is only known predisposing gene for UM. UMs are generally characterized by low mutation burden, but some display high level CpG>TpG mutations associated MBD4 inactivation. Here, we explored incidence germline variants consecutive series 1093 primary UM case patients and 192 tumors monosomy 3 (M3).We performed...
Uveal melanoma (UM) is the most common cancer of eye. The loss chromosome 3 (M3) associated with a high risk metastases. M3 tumors are more infiltrated by T-lymphocytes than low-risk disomic-3 (D3) tumors, contrasting other tumor types in which T cell infiltration correlates better prognosis. Whether these cells represent an antitumor response and how would be primed eye both unknown. Herein, we characterized infiltrating primary UMs. CD8+ Treg were abundant D3 tumors. CD39+PD-1+CD8+...
Progress in the liquid biopsy field, combined with development of droplet digital PCR (ddPCR), has enabled noninvasive monitoring mutations high detection accuracy. However, current assays detect a restricted number per reaction. ddPCR is recognized method for detecting alterations previously characterized tumor tissues, but its use as discovery tool when mutation unknown priori remains limited.We established 2 all genomic within KRAS exon and EGFR 19 hotspots, which are clinical importance...
Background and Aim: Uveal melanoma (UM) is the most common intraocular malignancy in adults. Thus far, germline mutations of two genes have been identified to be predisposing UM with a high penetrance: BAP1, responsible for BAP1 tumor predisposition syndrome (BAP1-TPDS), MBD4, which alterations are associated predisposition, specific mutational signature response immunotherapy. However, only fraction familial bilateral/multifocal forms can explained by these alterations, suggesting existence...
Abstract Genes involved in 3′-splice site recognition during mRNA splicing constitute an emerging class of oncogenes. SF3B1 is the most frequently mutated factor cancer, and mutants corrupt branchpoint leading to usage cryptic sites subsequent aberrant junctions. For a comprehensive determination alterations this pattern, we performed pan-TCGA screening for SF3B1-specific acceptor usage. While patterns were explained by mutations, also detected nine wild-type tumors (including five lung...
The hotspot mutations of SF3B1, the most frequently mutated splicing gene in cancers, contribute to oncogenesis by corrupting mRNA splicing. Further SF3B1 have been reported cancers but their consequences remain unclear. Here, we screened for vicinity region tumors. We then performed in-silico prediction functional outcome followed in-cellulo modelling different mutants. show that cancer-associated present varying are loosely predicted algorithms. Analysis tertiary structure mutants revealed...
Tebentafusp, a bispecific immune therapy, is the only drug that demonstrated an overall survival benefit in patients with metastatic uveal melanoma (MUM). Circulating tumor DNA (ctDNA) has emerged as potential prognostic and predictive marker phase 3 IMCgp100-202 trial using multiplex PCR-based next-generation sequencing (NGS). In this study (NCT02866149), ctDNA dynamics were assessed droplet digital PCR (ddPCR) 69 MUM undergoing tebentafusp treatment. Notably, 61% of exhibited detectable...
Uveal melanoma, a rare malignant tumor of the eye, is predominantly observed in populations European ancestry. A genome-wide association study 259 uveal melanoma patients compared to 401 controls all ancestry revealed candidate locus at chromosome 5p15.33 (region rs421284: OR = 1.7, CI 1.43-2.05). This was replicated an independent set 276 cases and 184 controls. In addition, risk variants from this region were positively associated with higher expression
We report here the results of a prospective study circulating tumor DNA (ctDNA) detection in patients undergoing uveal melanoma (UM) liver metastases resection (NCT02849145).
Conjunctival melanoma (ConjMel) is a potentially deadly ocular melanoma, originating from partially sunlight-exposed mucosa. We explored the mutational landscape of ConjMel and studied correlation with etiological factors. collected 47 primary samples performed next-generation sequencing 400 genes. Hotspot mutations in
Abstract Background Uveal melanoma (UM), a rare malignant tumor of the eye, is predominantly observed in populations European ancestry. UMs carrying monosomy 3 (M3) frequently relapse mainly liver, whereas with disomy (D3) are associated more favorable outcome. Here, we explored UM genetic predisposition factors large genome-wide association study (GWAS) 1142 patients and 882 healthy controls . Methods We combined 2 independent datasets (Global Screening Array) dataset described previously...
Cell lines are being used in preclinical uveal melanoma (UM) research. Because not all cell harbor typical GNAQ or GNA11 hotspot mutations, we aimed at better classifying them and determining whether could find genetic causes to explain the protein mRNA expression profiles of lines.