Nicolas Servant

Institut Curie · Bioinformatics platform

Myotonic dystrophy type 1 (DM1) exhibits highly heterogeneous clinical manifestations caused by an unstable CTG repeat expansion reaching up to 4,000 CTG. The dynamics of CTG repeats and clinical variability depends on the CTG repeat number, CNG repeat interruptions, DNA methylation, somatic mosaicism, but also gene modifiers. Around 10% of the DM1...

Metastatic urothelial carcinoma (mUC) is a lethal cancer, with limited therapeutic options. Large-scale studies in early settings provided critical insights into the genomic and transcriptomic characteristics of non-metastatic UC. The genomic landscape of mUC remains however unclear. Using Whole Exome (WES) and mRNA sequencing (RNA-seq) performed o...

The reverse transcriptase subunit of telomerase, TERT, is frequently activated in high‐grade dysplasia and invasive cancers of the uterine cervix. Telomerase activation through hypomethylation of the TERT promoter holds promise as a biomarker for cervical cancer progression, however, specific CpG sites involved in cervical cancer risk remain to be...

Recent studies have established a reciprocal causal link between aging and the activation of transposable elements, characterized in particular by a de-repression of LINE-1 retrotransposons. These LINE-1 elements represent 21% of the human genome, but only a minority of these sequences retain the coding potential essential for their mobility. LINE-...

Recent studies have established a reciprocal causal link between aging and the activation of transposable elements, characterized in particular by a de-repression of LINE-1 retrotransposons. These LINE-1 elements represent 21% of the human genome, but only a minority of these sequences retain the coding potential essential for their mobility. LINE-...

Syntologous long noncoding RNAs (lncRNAs) are loci with conserved genomic positions that often show little or no sequence similarity. Despite diverging primary sequences, lncRNA syntologs from distant species can carry out similar functions. However, determinants underlying conserved functions of syntologous lncRNA transcripts with no sequence simi...

Background Copy number alterations (CNA) are acquired during the evolution of cancers from their early stage to metastatic stage. This study aims at analysing the clinical value of the identified metastasis-associated CNAs both in metastatic breast cancers (mBCs) and early breast cancers (eBCs). Methods Single-nucleotide polymorphism (SNP)-array w...

Metastatic carcinoma of presumed renal origin (rCUP) has recently emerged as a new entity within the heterogeneous entity of Cancers of Unknown Primary (CUP) but their biological features and optimal therapeutic management remain unknown. We report the molecular characteristics and clinical outcome of a series of 25 rCUP prospectively identified wi...

INTRODUCTION Medulloblastoma (MB) is one of the most prevalent embryonal malignant brain tumors, divided into four distinct molecular subgroups (WNT, SHH, group 3, and group 4) with its individual prognosis. A more extensive classification of MB has recently been provided, identifying numerous subtypes, some with poor prognosis, leading to a signif...

Glioblastoma (GBM) is a highly lethal type of cancer. GBM recurrence following chemoradiation is typically attributed to the regrowth of invasive and resistant cells. Therefore, there is a pressing need to gain a deeper understanding of the mechanisms underlying GBM resistance to chemoradiation and its ability to infiltrate. Using a combination of...

Background: There are significant parallels between CC cell lines (CCCL) and newly diagnosed tumors, the most prominent being HPV infection/integrations and PI3K as well as epigenetic pathway alterations. Objectives: Identify genomic alterations associated with resistance to specific drug families in pharmacological profiles in Cell Lines (CL) and...

Background: Cervical cancer (CC) remains a leading cause of gynecological cancer related mortality worldwide and constitutes the third most common malignancy in women. We have previously reported a “metagene” of genomic markers in the PI3K pathway and epigenetic regulators associated with poor outcome. Immune therapy recently showed promising resul...

Introduction: Head and neck squamous cell carcinoma (HNSCC) is characterized by substantial intratumor heterogeneity (ITH) at the molecular level that may foster tumor evolution, adaptation, and therapeutic failure. Personalized-medicine strategies mostly rely on single tumor-biopsy samples which might not capture the mutational burden of heterogen...

Background: Cancers of unknown primary (CUP) is a heterogenous group of malignancies characterized by distant metastases in the absence of detectable primary. Specifics subgroups of CUP that share similarities with cancers of known primary beneficiate from tissue-tailored therapeutic strategies. The objective of this study was to characterize the c...

Background: The PEVOsq basket trial (NCT04357873) evaluated the efficacy of pembrolizumab and vorinostat (P+V) in patients (pts) with advanced squamous cell carcinoma (SCC) of different locationsAmong 112 pts included, 66 were HPV-positive (HPV+). Here we report HPV ctDNA monitoring in these pts. Methods: ctDNA before treatment (T0) and at first im...

Background: Epigenetic modulation plays a major role in escaping tumor immunosurveillance. PEVOsq (NCT04357873) was an open-label, non-randomized, multi-center, basket phase II trial evaluating the efficacy of pembrolizumab (P) and the vorinostat (V) HDAC inhibitor in 112 patients (pts) with recurrent and/or metastatic squamous cell carcinoma (SCC)...

In placental females, one copy of the two X chromosomes is largely silenced during a narrow developmental time window, in a process mediated by the non-coding RNA Xist ¹ . Here, we demonstrate that Xist can initiate X-chromosome inactivation (XCI) well beyond early embryogenesis. By modifying its endogenous level, we show that Xist has the capacity...

Background High tumor mutational burden (TMB) was reported to predict the efficacy of immune checkpoint inhibitors (ICIs). Pembrolizumab, an anti-PD-1, received FDA-approval for the treatment of unresectable/metastatic tumors with high TMB as determined by the FoundationOne®CDx test. It remains to be determined how TMB can also be calculated using...

Background: To identify patients most likely to respond to everolimus, a mammalian target of rapamycin (mTOR) inhibitor, a prospective biomarker study was conducted in hormone receptor-positive endocrine-resistant metastatic breast cancer patients treated with exemestane-everolimus therapy. Methods: Metastatic tumor biopsies were processed for i...

Recent studies have established a reciprocal causal link between aging and the activation of transposable elements, characterized in particular by a de-repression of LINE-1 retrotransposons. These LINE-1 elements represent 21% of the human genome, but only a minority of these sequences retain the coding potential essential for their mobility. LINE-...

Transcript isoforms generated by intronic polyadenylation (IPA) are widely regulated in various biological processes and often encode protein isoforms. Microproteins are small proteins translated from small open reading frames (sORFs) in noncoding RNAs and mRNAs, but their production by IPA isoforms is unknown. Using 3’-seq and long-read RNA-seq an...

Glioblastoma (GB) is one of the deadliest types of human cancer. Despite a very aggressive treatment regime-including resection, chemo-radiation, its recurrence rate is more than 90%. Recurrence is mostly caused by highly resistant and invasive cells that spread from tumor bulk and are not removed by resection. To develop an effective therapeutic a...

Atypical teratoid rhabdoid tumors (ATRT) are divided into MYC, TYR and SHH subgroups, suggesting diverse lineages of origin. Here, we investigate the imaging of human ATRT at diagnosis and the precise anatomic origin of brain tumors in the Rosa26-CreERT2::Smarcb1flox/flox model. This cross-species analysis points to an extra-cerebral origin for MYC...

Uveal melanoma is the most common primary intraocular malignancy in adults. Up to 50% of UM patients develop metastatic disease, usually in the liver. When metastatic, the prognosis is poor, and few treatment options exist. Here, we investigated the feasibility of establishing patient-derived xenografts (PDXs) from a patient’s tumor in order to scr...

BACKGROUND Glioblastoma (GB) is one of the deadliest types of human cancer. Despite a very aggressive treatment regime, including resection of the tumor, radiation, and chemotherapy, the recurrence rate is more than 90%. Recurrence is mostly caused by the regrowth of highly invasive and resistant cells that have spread from the tumor bulk and are n...

Uveal melanoma (UM) is a rare cancer resulting from the transformation of melanocytes in the uveal tract. Integrative analysis has identified four molecular and clinical subsets of UM. To improve our molecular understanding of UM, we performed extensive multi-omics characterization comparing two aggressive UM patient-derived xenograft models with n...

Intronic polyadenylation (IPA) leads to the production of transcript isoforms with alternative last exons in thousands of mammalian genes. Widespread regulation of IPA isoforms was observed during oncogenic transformation and in tumours versus healthy tissues, and several IPA isoforms were involved in oncogenesis. However, little is known about the...

Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial (NCT03298893) is designed to determine the safety/tolerance profile and the recommended phase-II dose of nivolumab with and following concurrent...

BRCA1 and BRCA2 are tumour suppressor genes that have been characterised as predisposition genes for the development of hereditary breast and ovarian cancers among other malignancies. The molecular diagnosis of this predisposition syndrome is based on the detection of inactivating variants of any type in those genes. But in the case of structural v...

Inflammation is a complex physiological process triggered in response to harmful stimuli¹. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2–4. The molecular bases underlying inflammatory responses are not...

Random X-chromosome inactivation (XCI) is a hallmark of female mammalian somatic cells. This epigenetic mechanism, mediated by the long non-coding RNA Xist, occurs in the epiblast and is stably maintained to ensure proper dosage compensation of X-linked genes during life. However, this silencing is lost during primordial germ cell (PGC) development...

Introduction: Cell-free tumor DNA (ctDNA) is an emerging biomarker in head and neck squamous cell carcinoma (HNSCC) for disease staging, patients’ recurrence risk stratification and early detection of relapse. We aimed to compare variants identified in ctDNA versus surgical tumor specimen, and to study the evolution of the mutational landscape of c...

OBJECTIVE Chordomas are rare bone neoplasms characterized by a high recurrence rate and no benefit from any approved medical treatment to date. However, the investigation of molecular alterations in chordomas could be essential to prognosticate, guide clinical decision-making, and identify theranostic biomarkers. The aim of this study was to provid...

The recognition of polyadenylation signals (PAS) in eukaryotic pre-mRNAs is usually coupled to transcription termination, occurring while pre-mRNA is chromatin-bound. However, for some pre-mRNAs, this 3'-end processing occurs post-transcriptionally, i.e., through a co-transcriptional cleavage (CoTC) event downstream of the PAS, leading to chromatin...

Background: Data on the role of the microbiota in cancer have accumulated in recent years, with particular interest in intratumoral bacteria. Previous results have shown that the composition of intratumoral microbiome is different depending on the type of primary tumour and that bacteria from the primary tumour could migrate to metastatic sites....

Neuronal DNA modifications differ from those in other cells, including methylation outside CpG context and abundant 5-hydroxymethylation whose relevance for neuronal identities are unclear. Striatal projection neurons expressing D1 or D2 dopamine receptors allow addressing this question, as they share many characteristics but differ in their gene e...

Human TRIAP1 (TP53-regulated inhibitor of apoptosis 1; also known as p53CSV for p53-inducible cell survival factor) is the homolog of yeast Mdm35, a well-known chaperone that interacts with the Ups/PRELI family proteins and participates in the intramitochondrial transfer of lipids for the synthesis of cardiolipin (CL) and phosphatidylethanolamine....

Cancer progression is driven in part by genomic alterations¹. The genomic characterization of cancers has shown interpatient heterogeneity regarding driver alterations², leading to the concept that generation of genomic profiling in patients with cancer could allow the selection of effective therapies3,4. Although DNA sequencing has been implemente...

The genome stability of adult stem cells is of particular importance as these cells maintain long-term self-renewal capacity and can contribute extensively to adult tissues. During development and aging, genome mutation leading to loss of heterozygosity (LOH) can uncover recessive phenotypes and be propagated within tissue compartments. This phenom...

Intronic polyadenylation (IPA) isoforms, which contain alternative last exons, are widely regulated in various biological processes and by many factors. However, little is known about their cytoplasmic regulation and translational status. In this study, we provide the first evidence that the genome-wide patterns of IPA isoform regulation during a b...

The field of genomics and genome-wide analysis has exploded since around 2008 with the development of high-throughput omics approaches, largely driven by the emergence of the next-generation sequencing technologies. Among the different biological applications supported by recent sequencing technologies, ChIP-seq (Chromatin ImmunoPrecipitation follo...

In precision oncology, tailored treatment decisions are largely driven by genomic alterations in a patient’s tumor. To support epidemiological research, we initiated a registry that enrolls patients diagnosed with a solid tumor and profiled with NGS. Collecting and standardizing variables of interest across the patient journey is critical for data...

The fast advances in molecular biology have led to the discovery of new genetic and epigenetic driver events that play a key role in the pathogenesis of central nervous system (CNS) tumors. These data showed the importance of molecular biology, and in particular methylation profiling and fusion detection, to complete the histological examination. E...

Atypical teratoid rhabdoid tumors (ATRT) are divided in three molecular subgroups, the so-called MYC, TYR and SHH subgroups. This heterogeneity suggests some diversity in the cells of origin, which remain hypothetical thus far. A careful radiological review of 55 MRI at diagnosis was performed in parallel with a careful analysis of mouse tumor orig...

Pre-mRNA 3'-end processing by cleavage and polyadenylation (CPA) is a nuclear process in which RNA polymerase II (Pol II) transcripts are cleaved at the polyadenylation site (PAS cleavage) before addition of a poly(A) tail. While PAS cleavage is usually coupled to transcription termination, for some pre-mRNAs it occurs post-transcriptionally, i.e....

A prevalence of around 26% of Human Papillomavirus (HPV) in Head and Neck Squamous Cell Carcinoma (HNSCC) has been previously reported. HPV induced oncogenesis mainly involves E6 and E7 viral onco‐proteins. In some cases, HPV viral DNA has been detected to integrate in the host genome and possibly contribute to carcinogenesis by affecting gene expr...

The interplay between the topological organization of the genome and the regulation of gene expression remains unclear. Depletion of molecular factors (e.g. CTCF) underlying topologically associating domains (TADs) leads to modest alterations in gene expression, while genomic rearrangements involving TAD boundaries disrupt normal gene expression an...

Inflammation is a complex physiological process triggered in response to harmful stimuli. It involves specialized cells of the immune system able to clear sources of cell injury and damaged tissues to promote repair. Excessive inflammation can occur as a result of infections and is a hallmark of several diseases. The molecular basis underlying infl...

Uveal Melanoma (UM) is a rare cancer resulting from the transformation of melanocytes residing in the uveal tract. Integrative analysis has identified four molecular and clinical subsets in UM. To improve our understanding of UM we performed extensive multi-omics characterization comparing pure melanoma populations obtained from two aggressive UM p...

With the advent of high-throughput biotechnological platforms and their ever-growing capacity, life science has turned into a digitized, computational and data-intensive discipline. As a consequence, standard analysis with a bioinformatics pipeline in the context of routine production has become a challenge such that the data can be processed in re...

The interplay between the topological organization of the genome and the regulation of gene expression remains unclear. Depletion of molecular factors underlying genome topology, such as CTCF and cohesin, leads to modest alterations in gene expression, while genomic rearrangements involving boundaries of topologically associating domains (TADs) dis...

Background Oral cavity is the most prevalent site of head and neck squamous cell carcinomas (HNSCCs). Most often diagnosed at a locally advanced stage, treatment is multimodal with surgery as the cornerstone. The aim of this study was to explore the molecular landscape of a homogenous cohort of oral cavity squamous cell carcinomas (OCSCCs), and to...

With the advent of high-throughput biotechnological platforms and their ever-growing capacity, life science has turned into a digitized, computational and data-intensive discipline. As a consequence, standard analysis with a bioinformatics pipeline in the context of routine production has become a challenge such that the data can be processed in re...

Precision oncology is currently based on pairing molecularly targeted agents (MTA) to predefined single driver genes or biomarkers. Each tumor harbors a combination of a large number of potential genetic alterations of multiple driver genes in a complex system that limits the potential of this approach. We have developed an artificial intelligence...

Extracranial rhabdoid tumours (ECRT) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRT can harbour the alternative inactivation of SMARCA4 (ECR...

Squamous cell carcinomas (SCCs) are among the most frequent solid tumors in humans. SCCs, related or not to the human papillomavirus, share common molecular features. Immunotherapies, and specifically immune checkpoint inhibitors, have been shown to improve overall survival in multiple cancer types, including SCCs. However, only a minority of patie...

The adaptation of Hi-C protocols to enable the investigation of chromosome organization in single cells opens new avenues to study the dynamics of this process during embryogenesis. However, the analysis of single-cell Hi-C data is not yet standardized and raises novel bioinformatic challenges. Here we describe a complete workflow for the analysis...

Background Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality with infection by human papilloma virus (HPV) being the most important risk factor. We analysed the association between different viral integration signatures, clinical parameters and outcome in pre-treated CCs. Methods Different integration signatur...

Chromatin modifications orchestrate the dynamic regulation of gene expression during development and in disease. Bulk approaches have characterized the wide repertoire of histone modifications across cell types, detailing their role in shaping cell identity. However, these population-based methods do not capture cell-to-cell heterogeneity of chroma...