ORCID Profile
0000-0002-1328-5290
Current Organisations
Ligue Nationale Contre le Cancer
,
Université Paris Cité
,
Université Paris Dauphine
,
Université Paris Descartes
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Publications
An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer
Publisher: Springer Science and Business Media LLC
Date: 16-04-2021
DOI: 10.1038/S41467-021-22465-W
Abstract: The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC ( n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation s les using a single s le classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
Community assessment of methods to deconvolve cellular composition from bulk gene expression
Publisher: Cold Spring Harbor Laboratory
Date: 05-06-2022
DOI: 10.1101/2022.06.03.494221
Abstract: Deconvolution methods infer levels of immune and stromal infiltration from bulk expression of tumor s les. These methods allow projection of characteristics of the tumor microenvironment, known to affect patient outcome and therapeutic response, onto the millions of bulk transcriptional profiles in public databases, many focused on uniquely valuable and clinically-annotated cohorts. Despite the wide development of such methods, a standardized dataset with ground truth to evaluate their performance has been lacking. We generated and sequenced in vitro and in silico admixtures of tumor, immune, and stromal cells and used them as ground truth in a community-wide DREAM Challenge that provided an objective, unbiased assessment of six widely-used published deconvolution methods and of 22 new analytical approaches developed by international teams. Our results demonstrate that existing methods predict many cell types well, while team-contributed methods highlight the potential to resolve functional states of T cells that were either not covered by published reference signatures or estimated poorly by some published methods. Our assessment and the open-source implementations of top-performing methods will allow researchers to apply the deconvolution approach most appropriate to querying their cell type of interest. Further, our publicly-available admixed and purified expression profiles will be a valuable resource to those developing deconvolution methods, including in non-malignant settings involving immune cells.
A Consensus Molecular Classification of Muscle-invasive Bladder Cancer
Publisher: Elsevier BV
Date: 04-2020
Identification of Differential Tumor Subtypes of T1 Bladder Cancer
Publisher: Elsevier BV
Date: 10-2020
DOI: 10.1016/J.EURURO.2020.06.048
Abstract: Stage T1 bladder cancers have the highest progression and recurrence rates of all non-muscle-invasive bladder cancers (NMIBCs). Most T1 cancers are treated with bacillus Calmette-Guérin (BCG), but many will progress or recur, and some T1 patients will die from bladder cancer. Particularly aggressive tumors could be treated with early cystectomy. To better understand the molecular heterogeneity of T1 cancers, we performed transcriptome profiling and unsupervised clustering, and identified five consensus subtypes of T1 tumors treated with repeat transurethral resection (reTUR) and induction and maintenance BCG. The T1-LumGU subtype was associated with carcinoma in situ (CIS six/13, 46% of all CIS), had high E2F1 and EZH2 expression, and was enriched in E2F target and G2M checkpoint hallmarks. The T1-Inflam subtype was inflamed and infiltrated with immune cells. While most T1 tumors were classified as luminal papillary, the T1-TLum subtype had the highest median luminal papillary score and FGFR3 expression, no recurrence events, and the fewest copy number gains. T1-Myc and T1-Early subtypes had the most recurrences (14/30 within 24 mo), the highest median MYC expression, and, when combined, had significantly worse recurrence-free survival than the other three subtypes. T1-Early had five (38%) recurrences within the first 6 mo of BCG, and repressed IFN-α and IFN-γ hallmarks and inflammation. We developed a single-patient T1 classifier and validated our subtype biology in a second cohort of T1 tumors. Future research will be necessary to validate the proposed T1 subtypes and to determine if therapies can be in idualized for each subtype. PATIENT SUMMARY: We identified and characterized expression subtypes of high-grade stage T1 bladder cancer that are biologically heterogeneous and have variable responses to bacillus Calmette-Guérin treatment. We validated the subtypes and describe a single-patient classifier.
Tertiary lymphoid structures marker CXCL13 is associated with better survival for patients with advanced-stage bladder cancer treated with immunotherapy
Publisher: Elsevier BV
Date: 05-2021
Reply To Kenneth B. Yatai, Mark J. Dunning, Dennis Wang. Consensus Genomic Subtypes of Muscle-invasive Bladder Cancer: A Step in the Right Direction but Still a Long Way To Go. Eur Urol 2020;77:434–5
Publisher: Elsevier BV
Date: 04-2020
Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors
Publisher: Springer Science and Business Media LLC
Date: 13-03-2018
DOI: 10.1038/S41467-018-03099-X
Abstract: Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic ( n = 60) and transcriptomic ( n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11 / KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1 high / DLL3 high / NOTCH low , type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1 low / DLL3 low / NOTCH high , and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.
Cancer stemness, intratumoral heterogeneity, and immune response across cancers
Publisher: Proceedings of the National Academy of Sciences
Date: 17-04-2019
Abstract: The exclusion of immune cells from the tumor microenvironment has been associated with poor prognosis in the majority of cancers. We report that when considering 21 solid cancer types, immune cell exclusion is widely associated with the presence of a stem cell-like phenotype in tumors (“stemness”). Stemness positively correlates with higher intratumoral heterogeneity, possibly by protecting antigenic clones from elimination by the immune system. The activation of a stemness program appears to limit antitumor immune responses via tumor cell-intrinsic silencing of endogenous retrovirus expression, repression of type I interferon signaling, and up-regulation of immunosuppressive checkpoints. Our work suggests that targeting the stemness phenotype in cancer will promote T cell infiltration and render tumors more responsive to immune control.
Related Organisations
Related Funding Activities
No related grants have been discovered for Aurélien de Reyniès.