Sandrine Boyault's research while affiliated with Centre Léon Bérard and other places
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Publications (116)
Background: Clonal hematopoiesis (CH) refers to the identification of clonal expansion of hematopoietic cells due to somatic mutations in leukemia-associated genes without evidence of hematologic anomalies. CH, particularly with variant allele frequency (VAF) ≥ 10%, has been associated with adverse outcomes, including reduced survival in advanced m...
BACKGROUND: Previous studies suggested that bio-behavioral models explain part of the variability of cancer-related fatigue, and pro-inflammatory and age-related processes emerged as contributors to persistent fatigue. However, the biological underpinnings of this complex symptom, including its relevant genomic correlates, are still poorly understo...
Introduction
The objective was to determine the added value of comprehensive molecular profile by whole‐exome and RNA sequencing (WES/RNA‐Seq) in advanced and refractory cancer patients who had no molecular‐based treatment recommendation (MBTR) based on a more limited targeted gene panel (TGP) plus array‐based comparative genomic hybridization (aCG...
Introduction: With the increasing complexity of current diagnostic investigations, the integration of clinical, pathological and genomic characteristics is crucial for the management of patients (pts) with cancers of unknown primary (CUP). A national multidisciplinary tumor board (NatCUPMTB) was created in July 2020 in France to discuss the diagnos...
Background:
MOST-plus is a multicenter, randomized, open-label, adaptive Phase II trial evaluating the clinical benefit of targeted treatments matched to molecular alteration in advanced/metastatic solid tumors. Sorafenib was tested on patients with tumors harboring sorafenib-targeted genes.
Methods:
The MOST-plus trial used a randomized discont...
e13666
Background: With the increasing complexity of current diagnostic investigations, the integration of clinical, pathological and genomic characteristics is crucial for the management of patients (pts) with cancers of unknown primary (CUP). A national multidisciplinary tumor board (NatCUPMTB) was created in July 2020 in France to discuss the di...
Background: MOST-plus is a multicenter, randomized, open-label, adaptive Phase II trial evaluating the clinical benefit of targeted treatments matched to molecular alteration in advanced/metastatic solid tumors. Sorafenib was tested on patients with tumors harboring sorafenib-targeted genes Methods: The MOST-plus trial used a randomized discontinua...
Gynecologic carcinosarcomas (CS) are biphasic neoplasms composed of carcinomatous (C) and sarcomatous (S) malignant components. Because of their rarity and histologic complexity, genetic and functional studies on CS are scarce and the mechanisms of initiation and development remain largely unknown.
Whole-genome analysis of the C and S components re...
Introduction: With the increasing complexity of current diagnostic investigations, the integration of clinical, pathological and molecular characteristics is crucial for the management of patients (pts) with cancers of unknown primary (CUP). A national multidisciplinary tumor board (NatCUPMTB) was created 2 years ago in France to discuss the diagno...
Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts fo...
Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature1. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures...
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...
Purpose:
Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.
Experimental design:
SAFIR02-Lung was an open-label, randomized, phase...
Introduction
Epithelial-to-mesenchymal transition (EMT) is associated with tumor aggressiveness, drug resistance, and poor survival in non-small cell lung cancer (NSCLC) and other cancers. The identification of immune-checkpoint ligands (ICPLs) associated with NSCLCs that display a mesenchymal phenotype (mNSCLC) could help to define subgroups of pa...
1554
Background: Precision oncology aims to guide patient (pts) treatment decisions by matching biological features with available drugs. Extensive genomic analysis allows to identify an actionable alteration in 40-60% of patients. In a recent study of 50 pts with advanced refractory diseases included in PROFILER (NCT01774409), whole exome and fusi...
Background: Up to 35% BC survivors who receive adjuvant treatment (tx) experience severe CRCI, which has a significant impact on quality of life, disrupting daily functioning as well as self-esteem, self-confidence, and work ability. However, limited tools exist to predict the risk of CRCI. We aimed to develop a comprehensive model of severe CRCI,...
Background: Weight management is an integral part of survivorship care. Excess weight in BCS is associated with worse clinical outcomes and quality of life. Early identification of BCS at risk of gaining substantial weight could lead to prompt and tailored interventions. We aimed at developing a predictive model of weight gain that integrates clini...
Background: We previously developed a clinico-behavioral model of CRF and reported an increased risk of severe CRF among survivors of breast cancer (BC) receiving adjuvant hormonal therapy (HT) (Di Meglio A, ASCO 2021). We now aim to comprehensively explore the contribution of relevant serum proteins in explaining CRF. We adopted a multimodal appro...
Background
Chemotherapy, anti-HER2 and PD-1 antibodies are standard treatments but only a minority of patients derive long-term benefit from these agents.
Methods
In this report we describe the mutational landscape and outcome of patients with gastroesophageal cancers enroled in the ProfiLER program.
Results
Adenocarcinoma (n = 86, 59%), signet-c...
Malignant Pleural Mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Using the largest series of whole-genome sequencing data integrated with transcriptomic and epigenomic data using multi-omic factor analysis, we demonstrate that MPM heterogeneity arises from four sources of variation: tumor cell...
9095
Background: Targeted therapies (TT) are approved in NSCLC based on a limited number of oncogenic drivers. Numerous additional TT can be matched to other molecular alterations found in comprehensive profiles. We investigated the effect of 8 TT compared to SoC as a maintenance strategy after chemotherapy in pts with metastatic NSCLC. Methods: In...
Simple Summary
Pancreatic ductal adenocarcinoma (PDAC) patient care lacks well-established molecular characterization of the tumors, which would allow for better-personalized treatment selection if improved. To overcome this problem, preclinical models are frequent-ly adopted tools used to elucidate the molecular characterization of PDAC tumors. Un...
Understanding the dynamics of the immune microenvironment is critical to the development of immuno-based strategies for the prevention of oral potentially malignant disorders transformation to oral squamous cell carcinoma (OSCC). We used laser capture microdissection and RNA-sequencing to profile the expression of 13 matched pairs of epithelial ver...
Background
We aimed at predicting fatigue after breast cancer treatment using machine learning on clinical covariates and germline genome-wide data.
Methods
We accessed germline genome-wide data of 2799 early-stage breast cancer patients from the Cancer Toxicity study (NCT01993498). The primary endpoint was defined as scoring zero at diagnosis and...
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG...
We present Butler, a computational tool that facilitates large-scale genomic analyses on public and academic clouds. Butler includes innovative anomaly detection and self-healing functions that improve the efficiency of data processing and analysis by 43% compared with current approaches. Butler enabled processing of a 725-terabyte cancer genome da...
Background:
Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, with no effective therapeutic options.
Methods:
We undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, with no assumption of discreteness. Using immunohistochemistry, we performed an orthogonal validation on a subset of 103 sam...
The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung...
11515
Background: Many BC survivors report fatigue. The relevant genomic correlates of fatigue after BC are not well understood. We applied a previously validated machine learning methodology (Oh 2017) to GWAS data to identify biological correlates of fatigue induced after tx. Methods: We analyzed 3825 BC pts with GWAS data (Illumina InfiniumExome2...
Background:
Antitumor activity of molecular-targeted agents is guided by the presence of documented genomic alteration in specific histological subtypes. We aim to explore the feasibility, efficacy and therapeutic impact of molecular profiling in routine setting.
Patients and methods:
This multicentric prospective study enrolled adult or pediatr...
In the Methods section of this Article, ‘greater than’ should have been ‘less than’ in the sentence ‘Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample. ’. The Article has not been corrected.
Causes of high mortality of prostate cancer in men of African ancestry living in the French West Indies are still debated, between suspicions of environmental factors and genetic susceptibility. We report an integrated genomic study of 25 tumour tissues from radical prostatectomy of aggressive (defined by International Society of Urological Patholo...
Background:
Management of localized prostate cancer (PCa) is a major clinical challenge since most of these cancers would not evolve but a majority of patients will still undergo a life-changing radical surgery. Molecular studies have shown that PCa can be classified according to their genomic alterations but none of the published PCa molecular cl...
Background:
Patients with follicular lymphoma have heterogeneous outcomes. Predictor models to distinguish, at diagnosis, between patients at high and low risk of progression are needed. The objective of this study was to use gene-expression profiling data to build and validate a predictive model of outcome for patients treated in the rituximab er...
The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger seque...
Approximately 1–5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/B...
The recent thriving development of biobanks and associated high-throughput phenotyping studies requires the elaboration of large-scale approaches for monitoring biological sample quality and compliance with standard protocols. We present a metabolomic investigation of human blood samples that delineates pitfalls and guidelines for the collection, s...
Table S3. COSMIC Cancer Genes Containing Mutations with Positive Variant Allele Fraction Difference in ER-ve Cancers
Disordered transcriptomes of cancer encompass direct effects of somatic mutation on transcription, coordinated secondary pathway alterations, and increased transcriptional noise. To catalog the rules governing how somatic mutation exerts direct transcriptional effects, we developed an exhaustive pipeline for analyzing RNA sequencing data, which we...
Purpose:
The tumor genomic copy number profile is of prognostic significance in neuroblastoma (NB) patients. We have studied the genomic copy number profile of cell free DNA (cfDNA) and compared this to primary tumor aCGH at diagnosis.
Experimental design:
In 70 patients, cfDNA genomic copy number profiling was performed using the OncoScan® plat...
List of somatic SNVs in genes.
HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full...
Supplementary Figures 1-17
Frequently amplified genes.
Characterisation of the 99 samples of the HER2+ cohort. Sequencing, clinical, anatomo-pathological and biological characterisation.
We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have di...
Background: HER2-positive (HER2+) breast cancers are defined by the amplification and/or overexpression of the human epidermal growth factor receptor (HER2/ERBB2) gene on chromosome region 17q12. Although anti-HER2 targeted therapies have greatly improved treatment of HER2+ breast cancer, the magnitude of benefit varies widely between patients. Dec...
While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median surviv...
Background:
Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted age...
All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 d...
All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here...
Citations
... Several studies analyzing the molecular characteristics of gynecologic CS have been published in recent years. The majority of these reports included both uterine and ovarian tumors, with the former constituting the majority of cases [3][4][5][6][7]; reviewed in [8], though two more recent studies have analyzed only ovarian CS [9,10]. Of the latter, one study analyzed both ovarian and extra-ovarian tumors [9], whereas the most recent study focused on the ovarian tumors [10]. ...
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... Earlier work identified discrete molecular groups, but more recently the benefits of viewing PM tumors on a histopathologic epithelial mesenchymal (EM) gradient have been demonstrated (Alcala et al., 2019;Blum et al., 2019). A recent multi-omics approach also identified ploidy and methylation as additional important discriminating features (Mangiante et al., 2023). ...
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... The tumor homologous recombination deficiency (HRD) genomic instability score (GIS) calculated by combining three factors, LOH, telomeric allelic imbalance, and large-scale state transitions, was of 15, below the validated threshold of 42 in the context of ovarian cancers [19]. Platinum drug treatment mutational signature SBS35 according to the COSMIC classification [20] contributed to 22% of somatic variants while SBS5 signature of unknown etiology and SBS1 spontaneous deamination of 5-methylcytosine signature contributed to 63% and 15% of somatic variants respectively. No SBS3 nor SBS8 homologous recombination deficiency signature was observed. ...
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... Human malignancies are characterized by chromosome CNVs, which include genes that are in hundreds or thousands [3,17]. According to a growing amount of evidence, CNVs are recurring in several cancer types, with some of them having a probability of appearing in the early tumorigenesis stages, demonstrating that some cancer-associated CNVs may serve as human cancers drivers [30,31]. CNAs can speed up tumor growth by changing the gene expression levels whose location is at regions of the impacted genomic [32]. ...
... Structural variations (SVs) are large-size genetic variations in the human genome, and include insertion, deletion, duplication, inversion, and translocation. SVs have been associated with different traits and with various diseases, including breast cancer [4][5][6]. They contribute to gene fusion, oncogene amplification, tumor suppressor gene deletion and other complex alterations leading to evolution of the cancer genome. ...
... P-values were computed using t-statistics from linear regression in the R package Matrix eQTL [29]. We used a two-step multiple-testing correction procedure, as described in [30]. First, for each gene, we correct for the number of variants tested using Bonferroni correction. ...
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... Genomic alterations have been ranked based on their recurrence and on their functional consequences, finally developing a clustering methodology to discriminate between potential driver events [46]. The extension of the sequencing to intergenic regions allowed evaluation of the burden of putative driver mutations in noncoding regions: on the pan-cancer database, 13% of all mutations were represented by driver point-mutation events in an intergenic region, with 25% of all PCAWG cancers analysed bearing at least one, one-third of which occurred in the TERT promoter, confirming its role in cancer [73][74][75][76][77][78][79]. On the counterpart, 91% of all cancers harboured a somatic driver event in a coding region of a gene (Fig. 3). ...
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... Pre-mutational factors, speci cally hypoxia and altered intracellular pH, are crucial for creating a conducive microenvironment for transformational changes, leading to the accumulation of genetic alterations. Importantly, a correlation between higher levels of hypoxia, pH, and a higher number of driver mutations has been observed in various types of cancer [45][46][47] . ...
... 39 For pathway enrichments, we aggregated consistently curated FlyBase-associated genesets using the modEnrichr project. 40 We then used the ActivePathways gene set enrichment tool 41 Processing single-cell RNA sequencing data and cell-type-specific differential gene expression analysis ...
... LncRNAs are involved in multiple developmental processes, including the regulation of Hox genes (Rinn et al. 2007), the regulation of chromatin accessibility in dosage compensation mechanisms (Loda and Heard 2019), and the development of organs such as the brain (Bernard et al. 2010) and heart (Klattenhoff et al. 2013). Alterations in the expression of lncRNAs have also been described for several diseases, including cancer (Huarte 2015;Carlevaro-Fita et al. 2020), cardiovascular diseases (Poller et al. 2018) and neurological disorders (Sunwoo et al. 2017). In fact, the public database LncRNADisease v2.0 currently describes more than 1,700 experimentally validated lncRNA-disease associations (Bao et al. 2019), highlighting lncRNAs as potential tools to understand the mechanisms and prognosis of multiple diseases. ...
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