The “Aging, Prenylation and Cancer” team, gathers 4 groups with distinct but tightly linked research axes oriented on aging, cancer, spermatogenesis and networks/systems biology.


The involvement of aberrantly accumulated or activated prenylated proteins (with Farnesyl or Geranyl‐geranyl hydrophobic C terminus anchors) in all these disease categories (genetically determined premature aging (progeroid) syndromes (PS) and lipodystrophies, cancer, human physiological and pathological spermatogenesis) serves as a focus and common denominator of our scientific research strategies. The department “Aging, Prenylation & Cancer” is unique in France and will increase collaborations with French, EU and international teams currently working on premature aging, laminopathies and prenylated proteins-associated cancers with the major aim of developing translational research.

We propose to use the exploration of both in vitro and in vivo models:
1) to further delineate and enlarge the clinical spectrum of diseases characterized by premature aging/ lipodystrophy/cancer development/altered human spermiogenesis, possibly associated to dysfunction of prenylated proteins or functional interactors;
2) to dissect the molecular mechanisms underlying these syndromes, allowing to identify therapeutic targets;
3) to develop pre-clinical proofs of concepts;
4) to extrapolate the generated knowledge aiming to improve healthy aging, by verifying whether the identified mechanisms apply to similar “natural” aging-associated morbidities;
5) to improve our knowledge on cancers involving prenylated proteins’ dysfunction towards identifying therapeutic targets and ameliorate patients’ healthcare;
6) to launch novel therapeutic trials.

The main long-term objective of the team is indeed the transposition of our discoveries to address and implement care in premature aging syndromes, age-related morbidities, natural aging and cancers. A strategy combining several approaches will lead to the pursuit of the following objectives in the field of “Prenylopathies”.



Group leader: Nicolas Lévy

Since we and others discovered the involvement of the LMNA gene encoding the nuclear proteins Lamins A/C, in Hutchinson-Gilford Progeria Syndrome (OMIM #176670), one of the best known premature aging syndromes (De Sandre-Giovannoli et al., Science 2003), our team focuses on translational research on premature aging (progeroid) syndromes (PS), nuclear protein-linked lipodystrophies, as well as other premature aging diseases, with or without an identified molecular basis. Our research aims to identify novel genes involved in these syndromes, increase our understanding of their pathophysiological mechanisms and to develop new therapeutic approaches using patients’ cell lines or mouse models as our main preclinical tools.


PS are a group of rare genetic disorders characterized by many clinical features that mimic those associated to physiological aging. Many PS share the dysfunction of a prenylated protein. This is the case in Hutchinson-Gilford Progeria Syndrome (HGPS) and related PS, where prenylated progerin or prelamin A aberrantly accumulate in cells’ nuclei, exerting multiple toxic effects and ultimately leading to the systemic severe phenotypes observed in patients. Besides, several other PS have been discovered as being caused by activating mutations in genes encoding permanently prenylated proteins of the RAS‐MAPK pathways. Among these “RASopathies”, research on Costello syndrome, due to H-RAS mutations, will be part of this project. Finally, several lines of evidence suggest that progerin production may also be involved in natural aging pathomechanisms.

Our research has focused until now on the following axes:

a. Extend the clinical spectrum of syndromes associated with prelamin A deficient processing.
We identified several novel or related syndromes mainly characterized by premature aging 7-25 or lipodystrophy / metabolic syndrome 9, 26 linked to mutations of LMNA or functionally related genes; as well as previously undiscovered genetic associations 10.

b. Produce in vitro and in vivo models for studying rare progeroid syndromes
A large panel of data and primary fibroblast cell lines from children affected with typical Progeria or atypical PS, and progeroid RASopathies have been collected through national and international collaborations and are stored in the Biological Resources Center (CRB-TAC), at La Timone hospital, Marseille. Human iPS cell lines (hiPSC) have also been derived and used to study the pathophysiology of the syndrome 27 or compare ongoing or proposed treatments 28. Primary endothelial cells and progenitors issued from human umbilical vein or cord blood were also used as in vitro models to study HGPS pathophysiology 29. Importantly, in collaboration with Pr Lopez-Otin in Oviedo, we generated the mouse model of progeria which most closely mimics the human disease (Knock-In LmnaG609G/G609G) by reproducing the same aberrant splicing mechanism leading to progerin production 30. Additionally, we are involved in a consortium with the mouse clinical institute and the medical genetics team in Bordeaux, to explore a KI model of CS carrying the most common H-RAS p.G12S mutation, based on a project  funded by the ANR (Cf. Appendix 7).

 c. Identify disease mechanisms in progeroid syndromes

  • We demonstrated a common toxic pathway involving prenylated prelamin A accumulation in many PS ranging from restrictive dermopathy and MAD-B to HGPS-like syndromes 8, 12, 24, 25, 31-36.
  • We showed that the microRNA miR‐9 negatively controls lamin A and progerin expression in HGPS­hiPSC derived neural cells 27, 28, having a protective effect on the patients’ central nervous system, which is clinically spared.
  • A miRNome analysis by qRT-PCR on dermal fibroblasts of 5 HGPS patients and 5 healthy individuals at early and late passages, allowed the identification of 29 deregulated miRNAs (15 overexpressed, 14 underexpressed; Frankel et al., publication in preparation). Based on these in vitro results, the potential benefit of miRNA-based therapeutic approaches (antagomiRs or mimics) in HGPS is under evaluation.
  • We contributed to scientific reviews on progeroid laminopathies and related syndromes 7, 8, 37
  • We reported H­RAS mutations in CS patients, confirming the involvement of the activated prenylated RAS proteins 38 in RASopathies, shown to trigger senescence in vitro 39.

d. Establish preclinical proofs of principle for therapeutic approaches and launch clinical trials

  • We demonstrated the synergistic effect of pravastatin (statin) and zoledronate (N-BisPhosphonate) (ZoPra) and its effectiveness in reducing prenylation and rescuing HGPS cells defects and progeroid phenotypes in Zmpste24-/- mice 40.
  • this preclinical work allowed our clinical team to design, and conduct a phase II therapeutic trial (ClinicalTrials.gov, NCT00731016) using zoledronate and pravastatin to evaluate its safety and efficacy in 12 HGPS patients included for 3.5 years each, with partially positive results on primary and secondary endpoints and without severe adverse effects (De Sandre‐Giovannoli, Sigaudy et al, submitted). An Orphan drug designation for this drug combination, “ZoPra”, was also obtained from EMA for progeria, under patent with an exclusive licence to ProGeLife, a spin-off of our academic team, cf. Appendix 6.
  • We showed an efficient reduction of progerin production in vitro at the mRNA and protein levels and phenotypic rescue in the LmnaG609G/G609G mice, using systemic antisense oligonucleotide (AON) treatment 41, providing the first preclinical proof of principle in vivo of the efficacy of this novel and promising approach.
  • We further provided a preclinical proof of principle for the use of a similar, but personalized antisense treatment in patients affected with HGPS-like and type B Mandibuloacral Dysplasia syndromes 42, who may therefore also be eligible for inclusion in a therapeutic trial based on this approach, together with classical HGPS patients.
  • We collaborated in preclinical studies using high-throughput screening of already marketed compounds with HGPS-derived iPS-MSC, leading to the identification of potential novel drugs 43, 44 or comparisons of the efficacy of treatments being tested in clinical trials 28.

Importantly, we recently identified that a specific class of proteasome inhibitors, including MG132, are able to reduce progerin levels by inducing both its degradation through autophagy and inhibition of its production by mRNA splicing modulation45. These findings pave the way for the development of a novel promising class of drugs for the treatment of patients affected with Hutchinson-Gilford Progeria and related syndromes. They may as well find larger applications in diseases involving the accumulation of prenylated proteins or natural aging. This discovery was patented and is co-exploited by ProGeLife (co-owner) and SATT-Sud Est (SATT-SE).

Our future research will be developed on similar strategies:

  • Pursue the data and biological samples’ collection from patients affected with PS and RASopathies stored in the labelled Biological Resource Center (CRB TAC), Department of Medical Genetics, Timone Hospital of Marseille; by establishing iPSC lines which are undergoing differentiation in cell lines of interest, depending on the patient’s phenotypes (collaboration with X. Nissan, iSTEM and F. Magdinier, U910 iPSC platform), by developing future CRISPR mutated iPS cell lines with mutations of interest. Our center also participates to the National registry “OPALE” (https://epidemiologie-france.aviesan.fr/epidemiologie-france/fiches/observatoire-des-patients-atteints-de-laminopathies-et-emerinopathies), collecting longitudinal informations on patients affected with laminopathies and carrying mutations of the LMNA gene.
  • Identify further biomarkers and pathophysiological pathways of premature aging: To dissect the mechanisms of aging caused by dysfunctions of prenylated proteins, we will combine OMICs data (genome, transcriptome/miRNome, proteome, and microbiome), with bioinformatics and systems’ biology interpretation tools. We aim to identify disease biomarkers, pro-and anti-aging factors, and druggable targets using primary fibroblasts from HGPS, Atypical Progeroid Syndromes (APS) due to LMNA mutations, CS patients and age and sex-matched controls; fibroblast-derived hiPSCs cells; 2) iPS-derived differentiated cells (coll. F. Magdinier) from selected APS patients and compared to similar age-matched HGPS and control cells; 3) mouse tissues or tail-tip fibroblast cultures of HGPS (LmnaG609G/G609G) and CS (HrasG12S/G12S) models and controls (wild type mice from the same crosses).
  • Identify and validate Proof-of-Concepts for molecules exhibiting a therapeutic potential in cellular and animal models:  we propose a multi-step, sequential translational approach from patients’ cells explorations to the preclinical validation of compounds in order to advance with solid bases towards novel clinical trials. Both pharmacologic and gene therapy approaches are under study in the team. Concerning the first approach, we recently identified that MG132 and other aldehyde compounds of the same class of proteasome inhibitors are able to dramatically reduce progerin intranuclear levels and ameliorate several disease parameters in HGPS patients’ cell lines. These molecules act by preventing progerin synthesis and increasing progerin degradation both in vitro (HGPS fibroblasts, iPS-MSC and iPS-VSMC from HGPS iPSC) and in vivo (muscles of LmnaG609G/G609G mice)45. Preliminary in vivo pilot studies indicate that the systemic administration of MG132 will require the formulation of a novel galenic form to increase its half-life: this work will be developed in collaboration with industrial and academic partners.In this research axis, the different compounds that are found efficient alone will be tested in combination. Their ability to improve classical disease biomarkers in vitro will be evaluated, with dose-response studies. This study will be completed in vivo, exploring: the drug pharmacokinetics, safety/toxicity, the effects on progerin levels and OMICS studies to validate drug activity and to search for side-effects.
    Interestingly, since progerin has been shown to accumulate in cells’ nuclei during natural aging 3, the proposed research on HGPS and related syndromes may have spinoffs in the field of natural aging.
  • Identification of novel genes involved in premature aging syndromes:  Efforts will be continued towards: 1) identifying novel causal genes in patients affected with sporadic PS or lipodystrophy syndromes of unknown origin (ex. Wiedemann­Rautenstrauch, Hallermann-Streiff syndromes, atypical progeroid syndromes…), and genomic modulators that account for phenotypic variability in PS with extreme phenotypes
  • Functional characterization of pathogenic variants in Lamin A and LINC complex proteins in nuclear protein-linked lipodystrophies: Recent studies have revealed the important role played by the nuclear envelope (NE) in the cell response to various external environmental constraints. In particular, A-type Lamins and proteins of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex are key actors of nucleo-cytoskeletal coupling, playing a role in nuclear signal mechanotransduction 46. We’ll use patients’ cells to investigate the relationship between NE and LINC complex proteins and pathologies.

Group leader: Michael Mitchell

In the age of Assisted Reproductive Technology (ART), where defective gametogenesis is no longer a barrier to procreation, it is crucial to understand how the genome is normally processed in germ cells, detect cases where processing is abnormal and determine the consequences of anomalies for genome stability. We will thus characterize the nuclear lamina during human spermatogenesis, and discover proteins required for nuclear remodelling by searching for genetic causes of abnormal sperm head development (teratozoospermia) and the creation of specific knockout mouse models. Our group has a strong clinical component and enjoys close collaborations with La Conception and La Timone Hospital sites: the Reproductive Biology Laboratory, Centre for the study and conservation of human oocytes and sperm (CECOS, directed by C. Metzler-Guillemain), the Molecular Genetics Laboratory in the Department of Medical Genetics and the Germethèque, a labelled Biobank. We also have a collection of normal testicular material, from patients with brain death, deposited in the Germethèque Biobank and authorized by the Biomedicine Agency (ABM).

Over the last four years, we have characterised the nuclear lamina (NL) and its associated proteins during spermiogenesis and in the mature spermatozoon, in human. During spermiogenesis the round spermatids differentiate into highly-specialised motile spermatozoa, involving dramatic remodelling of the chromatin and the nucleus. We have therefore focused our attention on defining the interface between the NL and the chromatin. Our aims were to improve understanding of the roles of the NL during spermatogenesis and to identify biomarkers of gamete quality.

  • We have determined the composition of the NL in human spermatids. This had previously only been investigated in rodents 47, 48. We have shown that, in human, the NL is composed exclusively of type-B lamins, including lamin B3, a spermatid-specific isoform of lamin B2. We showed that lamin B3 destabilises the NL and induces deformation of the nucleus when expressed in HeLa cells, indicating that lamin B3 may facilitate nuclear remodelling in spermatids by rendering the NL less rigid 49.
  • The NL has been shown to be linked to chromatin in somatic cells by LBR and LEM-domain proteins interacting with the chromatin protein BAF 50, 51. We have explored the NL-chromatin interface during spermiogenesis by studying LBR, seven LEM-domain proteins, and two BAF proteins during spermiogenesis. Only LAP2 had previously been studied during spermiogenesis, in rodents 52. We showed that five of these proteins LAP2, LEMD1, LEMD2 (a short isoform only), BAF and BAF-L, are present in the round spermatid nucleus, but retreat to the posterior pole of the nucleus as the acrosome spreads. We determlined that the full-length isoform of LEMD2, known to contribute to nuclear integrity in somatic cells, was absent from spermatids. Only BAF and BAF-L were retained in elongated spermatids and were detected at the posterior pole of the spermatozoa nucleus by immunofluorescence, and by Western blot. In somatic cells, BAF is known to be required for the re-assembly of the nuclear envelope after mitosis 53, 54. We have therefore proposed that BAF, together with BAF-L, could play roles in the ordered condensation of the spermatid chromatin, its decondensation in the oocyte and the reassembly of the nuclear membrane around the male pronucleus after fertilisation. (Elkhatib et al., 2017, Reproduction – doi: 10.1530/REP-17-0358).
  • We have investigated the localisation of the proteins that we find in normal human spermatozoa and in spermatozoa from infertile men with teratozoospermia. We have completed a first study of spermatozoa from men with globozoospermia due to mutations in the DPY19L2 gene. The sperm in these men have a round head, detached acrosome and retain histones 55. We found that lamin B1 is retained throughout the nuclear periphery of globozoospermic spermatozoa, but that neither BAF nor BAF-L is detectable. Furthermore the mRNA for BAF, which we have shown is normally absent from spermatozoa, was detected in RNA extracted from globozoospermic spermatozoa, suggesting that the BAF transcript could be a biomarker of abnormal chromatin remodelling in human spermatozoa. (Paci et al., submitted).
  • Finally we have launched whole exome analysis to identify genetic causes of sperm head anomalies found in infertile men. Preliminary results have been encouraging with identification of a homozygous loss-of-function variant in a spermatid-specific nuclear envelope protein in an infertile man who produces spermatozoa with enlarged sperm heads. We have also identified the second reported case of a loss of SUN5 function in men with decapitated spermatozoa syndrome, establishing that SUN5 is required for the formation of the sperm nucleus-flagellum junction. (Elkhatib et al., 2017, Human Molecular Genetics, doi: 10.1093/hmg/ddx200)

We have thus established a solid basis of knowledge concerning the structure and behaviour of the NL during human spermiogenesis, on which we have built our project. An important focus will be the condensation and decondensation of the paternal genome before and after fertilisation, processes of vital importance for male fertility, and for the stable transmission of the human genetic and epigenetic identity to future generations.

Our current scientific objectives are: 

1) Determine the role of the NL, BAF and BAF-L in nuclear remodelling during spermiogenesis and the formation of the male pronucleus in the oocyte after fertilisation.
To gain insights into nuclear remodelling, we will identify protein partners of lamin B1, lamin B3, BAF and BAF-L in spermatids and spermatozoa. Knockout mouse models are underway to identify proteins with key functions in the nuclear remodelling that occurs before and after fertilisation. We will use ChIP seq to define the genomic regions to which BAF and BAF-L are bound in the sperm nucleus.

2) Define new biomarkers for human spermatozoa quality. We have identified specific B-type lamins and lamin partners that are present on human ejaculated spermatozoa. We will evaluate these proteins as biomarkers by measuring their presence or absence on quality-selected spermatozoa and different types of teratozoospermic spermatozoa.


3) Characterize the NL and the NL-chromatin interface during meiosis.
In rats, the spermatocyte NL is composed of lamin B1 and lamin C2, a meiotic specific isoform 56. The lamin C2 appears in the form of discontinuous domains associated with meiotic telomeres 57. In mice expressing lamin A/C but lacking lamin C2, spermatogenesis blocks during meiosis 58. In humans, there is no published data on the nature of the NL and partner proteins in male meiosis. We will identify specific lamin isoforms and NL-associated proteins in human meiotic cells, and follow their localisation in spermatocytes through each step of human meiosis.


4) Use exome analyses to identify causal mutations in men with abnormal sperm heads. Recruitment through the Reproductive Biology Laboratory is around 10-15 cases per year. Based on phenotype, pre-screening will exclude cases with causal mutations in AURKC (macrocephalic sperm), DPY19L2 and SPATA16 (globozoospermia) (estimated 30-50% of cases). Variants in genes encoding components of the nuclear envelope will be validated by modelling in the mouse.
By exome analysis, we have identified a homozygous loss-of-function variant predicted to inactivate a spermatid-specific component of the nuclear envelope, in a man with macrocephalic haploid spermatozoa in which histones have not been replaced by protamines. We will create and characterise a mouse model to gain insights into the role of the nuclear envelope in chromatin remodelling during spermiogenesis.

 

Group leader: Sylviane Olschwang

The cancer project focuses on the identification of genetic variants that contribute either to increase the risk of digestive cancer or to aggravate their evolution, according to 2 main axes:

  • Pharmacogenetics and therapeutic evaluation in digestive oncology
  • Hereditary predispositions to digestive cancers

A third axis "genetics of sarcomas and related tumors" was initiated this year
Joining Nicolas Lévy's team, the research projects have been re-centered on tumors impairing pathways involved in premature aging, mainly RAS and TGFB, to identify potential therapeutic targets useful in in both conditions. The pancreatic cancerogenesis of mucinous cysts has been chosen as study model.

Past results

The projects of the group focused on the study of gastrointestinal tumorigenesis mechanisms to identify genetic variations or mutations that contribute to or increase their risk, or impact their evolution. The clinical objective was to better integrate into medical practice DNA analyses, which take a special place in various aspects of oncology, prevention, early diagnosis and therapeutic evaluation. In the past, we described the genetic alterations responsible for major genetic predispositions to digestive cancer and their relationship with the main phenotypic characteristics. The molecular analyses have been progressively transferred to hospital laboratories and integrated to the medical care of patients. We coordinate the data collection of germ line mutations identified in the French labeled laboratories in national mutations databases and permanently implement these LSDBs with functional data allowing variants classification. Furthermore, the study of somatic genetic alterations in colorectal cancer, to which we contributed, identified two alternative pathways of colon cancer, linked to different prognostic risks. The allelic loss frequencies and the complexity of their associations, as well as the difficulty of finding a major event in tumor progression prompted us to undertake a comprehensive genomic characterization of colorectal cancer combining genome and transcriptome analysis. The direct responsibility of the WNT pathway via the APC gene appeared the most probable hypothesis that was specifically explored 59. To document the existence of genes predisposing to the development of metastases based on genotype-phenotype associations, we set up a national group of clinicians and researchers to collect such case-control series and were able to describe the first locus involved in the metastatic process 60, where a non-coding RNA was then identified by another group 61, 62.
An interface contract with the Institut Paoli-Calmettes allowed us to develop a regional laboratory that contributes to the diagnostic and therapeutic evaluation of cancer.

Project

Joining Nicolas Lévy's team, the group will re-direct its research projects on tumors impairing pathways also involved in premature aging, mainly RAS and TGFB, to identify potential therapeutic targets in pathways involved in both conditions. Since 2006, targeted therapies have been developed to improve solid tumors treatment, like anti-EGFR and Tyrosine kinase inhibitors that are now used in metastatic colorectal and lung cancers. Anti-EGFRs have been first demonstrated as ineffective in case of K-RAS gene activation, and their use has been restricted to tumors without K-RAS somatic mutations. Subsequently, a systematic molecular analysis of tumor cells has been introduced in cancer patients’ management, and the EGFR pathway has been more extensively characterized to document the mechanisms of drug resistance. Similar observations have been made in cases of N-RAS, BRAF or PTEN mutations as examples. Drugs targeting other steps of the pathway have been tested and the use of prenylation inhibitors revealed promising directions to manage devastating tumors such pancreatic, lung and ovarian cancers 63, 64 for reviews. The use of xanthohumol, a prenylated chalcone, is able to induce cell cycle arrest and apoptosis by inhibiting phosphorylation of STAT3, together with expression of downstream targets cyclin D1 and survivin in cell lines and xenografts of pancreatic cancer 65. Combined geranylgeranyltransferase 1 and farnesyltransferase inhibitors liposomal delivery induces G1 cycle cell arrest by p21CIP1/WAF1 in human pancreatic and lung cancer cell lines 66. Zoledronic acid on lung cancer and melanoma cells with NRAS mutation inhibited prenylation, supressing downstream RAS and EGFR signaling. This effect has been reversed using geranylgeraniol and farnesol, confirming the specific prenylation inhibition 67, 68. In combination with paclitaxel, which showed promising results in pancreatic cancer, synergistic effects could be obtained. Blocking the mevalonate pathway with statins also shows interference with post-translational modification of KRAS inducing antiproliferative phenotype of ovarian cancer cells from xenografts 69, suppression of proliferation linked to endocrine resistance resulting from the accumulation of senescent cells after radio/chemotherapy of breast and prostate cancer 70, 71. Isoprenoid biosynthetic pathway inhibitors also showed Rap1A alteration in metastatic prostate cancer cells 72.

Pancreatic cancer is one of the most lethal human cancers, exhibiting RAS pathway activation in more than 80% of cases. The unique treatment consists in chemotherapy based on 5FU or gemcitabine solely or in combination with irinotecan and/or oxaliplatine, adjuvant to surgery in less than 20% of cases, often used as palliative. Clinical trials currently introduce other molecules without any positive result. Pancreatic cancer also takes part of the tumor spectrum of several genetic disorders highly predisposing to cancer (BRCA, Lynch, Peutz-Jeghers, Cowden, Von Hippel Lindau syndromes as the most frequent). Precancerous lesions have been described, particularly pancreatic cysts with mucinous component, known at high risk for cancer. These tumors were retained as an interesting model to extensively study the EGFR/RAS pathway, looking for targetable modifications. A collaborative consortium has been set up in Marseille, including all interventional digestive endoscopy units and the corresponding surgical departments (AP-HM hospitals Timone and Nord, St-Joseph hospital, European Hospital, Institut Paoli-Calmettes), and two expert centers in Lyon (Mermoz hospital) and Paris (Les Peupliers hospital). We plan to collect samples of cystic fluid and analyze“circulating” DNA from surrounding epithelial cells. As blood circulating tumor cells showed their ability to reveal molecular alterations as cancer diagnostics or recurrence markers, tumor cells are initially present in cystic fluids and can be collected for further molecular investigations 73, 74.

A pilot study has just been funded, which will test the feasibility of a systematic approach comparing the molecular profiles of cysts in pre-operative echoendoscopic biopsies and per-operative samples of 10 patients, thus validating the preoperative approach as applicable to a larger series, as echoendoscopic biopsies are systematically performed before surgery to confirm the clinical indication of pancreatectomy. Sample processing and NGS sequencing will be done within U910. Nucleic acids will be extracted and sequenced on a panel of 70 genes involved in pancreatic tumorigenesis and targeting the RAS signaling pathway, MAPK, AKT, JAK-STAT signaling pathway, WNT, TGFB, TP53 and repair BRCA, ATM. The selected sequencing technology (HaloPlexHS®, Agilent), through the incorporation of random nucleic acid sequences (10 nucleotides) during the libraries preparation, enables detection of alleles present in a 1% proportion. This new technical approach that combines high sensitivity and specificity is also compatible with degraded DNA and/or small amounts (less than 50 ng). It therefore appears as an appropriate technique for this type of samples with an expected important degradation and nucleic clonal heterogeneity. Bioinformatics analysis will detect somatic variations and define their allelic frequency as well as CNVs. A comparison of the molecular profiles of pre- and post-operative samples will be performed, then faced with the pathologic and biological characteristics. The identification of a molecular profile indicating a precancerous condition would be helpful for the surgical decision, which consists in a (cephalic) pancreatectomy, now performed twice more than a posteriori required. The characterization of the very early recurrent molecular alterations would also be helpful to refine targeted therapies, and to test cell models exhibiting similar pathways disorders.
At the same time, the group, in collaboration with French clinical oncogenetics units, is currently collecting families with aggregation of breast/pancreatic cancer without known germline alterations to define through exomes analyses a set of candidate genes that could be involved in such predispositions. Variations identified by this approach will be compared to those enlightened in the previous part, to document the genetic alterations responsible for the very early steps of pancreatic tumorigenesis.
Finally, as multichemotherapy is currently the single therapeutic approach in pancreatic cancer, the group drives pharmacogenetics studies to possibly add new parameters useful in dosage adjustment in collaboration with the oncology units of the university hospital. This year, clinical files of 98 patients have been registered and 87 have been genotyped on 1636 SNPs of 231 genes using the DMET chip (Affymetrix). Associations with toxicity have been identified for genes participating to phases I and II metabolism enzymes and transporters. The set of data will be extended, genotyping 279 patients included in the national clinical trial PRODIGE35 in collaboration with the Fédération Française de Cancérologie Digestive (FFCD) to validate primary results.

 

Group leader: Anaïs Baudot

The group Networks and Systems Biology for Diseases focuses on untangling the genotype-phenotype relationships of human disorders. Disease complexity is the consequence of the intricate cellular functioning of genes and proteins. Indeed, biological molecules do not act alone, but rather interact with each other to perform their functions in protein complexes, signalling pathways or metabolic reactions. The disease phenotypes are thus resulting not from perturbations of isolated genes or proteins, but of complex networks of molecular interactions.
In this context, thanks to network modeling and large-scale interactome and -omics mining, our group studies genes and proteins in their cellular contexts, towards a better understanding of their perturbations in diseases. We further investigate the relationships between different diseases, in particular disease comorbidities, and aim to improve diagnostic and therapeutic predictions.

Disease complexity is the consequence of the intricate cellular functioning of genes and proteins. Indeed, biological molecules do not act in isolation, but rather interact with each other to perform their functions in protein complexes, signaling pathways or metabolic reactions, for instance. The disease phenotypes are thus resulting not from perturbations of isolated genes or proteins, but of complex networks of molecular interactions.

Systems Biology, which consider biological systems as networks of interactions between biological components, offer a new approach to link the genotypes (e.g., the genes and the proteins, as the components of the systems) to the phenotypes (the merging properties of the systems), and in particular the diseased phenotypes. Our group is active in the fields of systems biology with both the development of mathematical and computational tools grounded on network theory and their application to biological questions, with the ultimate goal of untangling the genotype-phenotype relationships of human disorders. 

Axis 1 Methodological developments: Systems Biology and Network Theory

Large-Scale Interactomes and Multiplex Networks

Thanks to the scaling of the experimental techniques allowing interaction discovery, recent years have witnessed the accumulation of thousands of physical and functional interactions of various nature. These interaction data are usually represented as networks, but as biological interaction sources are diverse, some networks contain few interactions of high relevance, while others, prone to noise, contain thousands or even millions of interactions. Overall, -omics interaction data offer unprecedented opportunities to study disease-associated cellular perturbations. However, while their production is becoming easier and more cost-effective, interpretation and integration of these diverse data still face major challenges.

We are involved for many years in the development of tools to extract knowledge from large-scale interactomes. We develop in particular clustering algorithms for community identification. This leading network approach, revealing subnetwork communities of tightly linked genes and proteins, provides access to the landscape of cellular functions. Recently, we extended these approaches to multiplex networks, i.e., networks composed of many layers of physical or functional interactions between genes and proteins.
We are also working on guilt-by-association strategies to study gene and protein functions. In particular, we are now extending the random walk with restart algorithm to multiplex networks.

Integrative Biology: -omics data integration
One of the goals of the group is to develop tools to use networks as scaffold to integrate other type of large-scale -omics data. We aim at combining heterogeneous datasets, such as interactions, mutation and expression. In particular, we work to contextualize networks, and to predict the activity status of cellular biological processes in the different tissues.
Dynamical Network Modeling
We are also involved in the development of mathematical models to study human diseases. To build a model, we start by constructing a regulatory graph encompassing activating and inhibiting interactions between genes and proteins of interest (e.g., genes mutated or pathway implicated in diseases). The logical formalism then allows creating explanatory and predictive models from the regulatory graph, to study the dynamics of biological systems behaviors in healthy or diseased contexts.

Axis 2 Applications to untangle human disorders


Thanks to network modeling and large-scale interactome and -omics mining, our group study genes and proteins functioning in their cellular contexts, towards a better understanding of their perturbations in diseases.

Common diseases
In common diseases, such as cancers, many factors are jointly contributing to the disease emergence and phenotype. These diseases are then often studied thanks to networks, to understand the combined effect of genes, proteins and their interactions. We are involved for many years in the application of network approaches to study the functions of the genes and proteins implicated in cancer.


Rare diseases
Rare diseases are also associated to a very high heterogeneity and complexity. In this context, we study the network vicinity of disease genes to identify modifier genes and understand the influence of the genetic background. We are also interested in developing diagnosis tools based on network approaches, for instance to rank variants according to their proximities with genes whose mutations lead to diseases with similar phenotypes. Finally, the group is working on drug repurposing strategies, leveraging networks to integrate the many-to-many relationships between drugs and targets.


Disease relationships and comorbidities
We are also interested in the investigation of disease-disease molecular and comorbidity relationships. The group will develop analyses of disease-disease relationships in the context of the rare and common diseases. Indeed, higher-than-expected association of rare diseases with apparently common multifactorial diseases is often observed, as well as, in some cases, lower-than-expected associations.

 

Sánchez-Valle, J.  et al. 2017

A molecular hypothesis to explain direct and inverse co-morbidities between Alzheimer's Disease, Glioblastoma and Lung cancer

Epidemiological studies indicate that patients suffering from Alzheimer's disease have a lower risk of developing lung cancer, and suggest a higher risk of developing glioblastoma. Here we explore the...
Sci Rep - issue: 1 - volume: 7 - pages: 4474.

Tabarés-Seisdedos, R.  et al. 2016

Editorial: Direct and Inverse Comorbidities Between Complex Disorders


Front Physiol - issue: - volume: 7 - pages: 117.

Lo Cicero, A.  et al. 2016

A High Throughput Phenotypic Screening reveals compounds that counteract premature osteogenic differentiation of HGPS iPS-derived mesenchymal stem cells

Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal genetic disorder that causes systemic accelerated aging in children. Thanks to the pluripotency and self-renewal properties of induced...
Sci Rep - issue: - volume: 6 - pages: 34798.

Hamadou, WS.  et al. 2016

Mutational analysis of JAK2, CBL, RUNX1, and NPM1 genes in familial aggregation of hematological malignancies

Familial aggregation of hematological malignancies has been reported highlighting inherited genetic predisposition. In this study, we targeted four candidate genes: JAK2 and RUNX1 genes assuring a...
Ann. Hematol. - issue: 7 - volume: 95 - pages: 1043-1050.

Ambrosi, P.  et al. 2016

A novel overlapping phenotype characterized by lipodystrophy, mandibular dysplasia, and dilated cardiomyopathy associated with a new mutation in the LMNA gene

WOS:000372530700078
Int. J. Cardiol. - issue: - volume: 209 - pages: 317-318.

Hamadou, WS.  et al. 2016

Familial hematological malignancies: ASXL1 gene investigation

Familial aggregation among patients with several hematological malignancies has been revealed. This emphasizes the importance of genetic factors. Only few genes predisposing to familial hematological...
Clin. Transl. Oncol. - issue: 4 - volume: 18 - pages: 385-390.

Sevy, A.  et al. 2016

Improving molecular diagnosis of distal myopathies by targeted next-generation sequencing

WOS:000371328100020
J. Neurol. Neurosurg. Psychiatry - issue: 3 - volume: 87 - pages: 340-U116.

Grandval, P.  et al. 2016

Consideration surrounding incidental findings throughout multigene panel testing in cancer genetics

WOS:000368806900019
Clin. Genet. - issue: 2 - volume: 89 - pages: 267-268.

Blondel, S.  et al. 2016

Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene...
Cell Death Dis. - issue: - volume: 7 - pages: e2105.

Roca, E.  et al. 2016

Detection of EpCAM-positive microparticles in pleural fluid: A new approach to mini-invasively identify patients with malignant pleural effusions

Pleural biomarkers allowing to mini-invasively discriminate benign from malignant pleural effusions are needed. Among potential candidates, microparticles (MPs) are extracellular vesicles that...
Oncotarget - issue: 3 - volume: 7 - pages: 3347-3356.

Didier, G.  et al. 2015

Identifying communities from multiplex biological networks

Various biological networks can be constructed, each featuring gene/protein relationships of different meanings (e.g., protein interactions or gene co-expression). However, this diversity is...
PeerJ - issue: - volume: 3 - pages: e1525.

Movahedi, M.  et al. 2015

Obesity, Aspirin, and Risk of Colorectal Cancer in Carriers of Hereditary Colorectal Cancer: A Prospective Investigation in the CAPP2 Study

Purpose In the general population, increased adiposity is a significant risk factor for colorectal cancer (CRC), but whether obesity has similar effects in those with hereditary CRC is uncertain. This...
J. Clin. Oncol. - issue: 31 - volume: 33 - pages: 3591-+.

Flobak, .  et al. 2015

Discovery of Drug Synergies in Gastric Cancer Cells Predicted by Logical Modeling

Discovery of efficient anti-cancer drug combinations is a major challenge, since experimental testing of all possible combinations is clearly impossible. Recent efforts to computationally predict drug...
PLoS Comput. Biol. - issue: 8 - volume: 11 - pages: e1004426.

Tripathi, S.  et al. 2015

The gastrin and cholecystokinin receptors mediated signaling network: a scaffold for data analysis and new hypotheses on regulatory mechanisms

BACKGROUND: The gastrointestinal peptide hormones cholecystokinin and gastrin exert their biological functions via cholecystokinin receptors CCK1R and CCK2R respectively. Gastrin, a central regulator...
BMC Syst Biol - issue: - volume: 9 - pages: 40.

Nectoux, J.  et al. 2015

Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing

Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and in Bardet-Biedl syndrome. Few cases have been described to date in LGMD2H/STM, but...
Eur. J. Hum. Genet. - issue: 7 - volume: 23 - pages: 929-934.

van Kuilenburg, ABP.  et al. 2015

Frequent intragenic rearrangements of DPYD in colorectal tumours

Dihydropyrimidine dehydrogenase is a crucial enzyme for the degradation of 5-fluorouracil (5FU). DPYD, which encodes dihydropyrimidine dehydrogenase, is prone to acquire genomic rearrangements because...
Pharmacogenomics J. - issue: 3 - volume: 15 - pages: 211-218.

Roca, E.  et al. 2015

Detection of procoagulant and profibrinolytic epcam-positive microparticles in pleural fluid: a new approach for the diagnosis of the tumoral origin of pleural effusions

WOS:000356426902034
J. Thromb. Haemost. - issue: - volume: 13 - pages: 215-215.

Danjou, F.  et al. 2015

A genetic score for the prediction of beta-thalassemia severity

Clinical and hematologic characteristics of beta(beta)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and...
Haematologica - issue: 4 - volume: 100 - pages: 455-460.

Elkhatib, R.  et al. 2015

Nuclear envelope remodelling during human spermiogenesis involves somatic B-type lamins and a spermatid-specific B3 lamin isoform

The nuclear lamina (NL) is a filamentous protein meshwork, composed essentially of lamins, situated between the inner nuclear membrane and the chromatin. There is mounting evidence that the NL plays a...
Mol. Hum. Reprod. - issue: 3 - volume: 21 - pages: 225-236.

Grandval, P.  et al. 2015

Genomic variations integrated database for MUTYH-associated adenomatous polyposis

WOS:000346344000004
J. Med. Genet. - issue: 1 - volume: 52 - pages: 25-27.

Joly, P.  et al. 2014

Beta-thalassemias: molecular, epidemiological, diagnostical and clinical aspects

Beta-thalassemia is one of most common autosomal recessive disorders worldwide. In France, 5 to 10 new major or intermedia forms are diagnosed annually and the global prevalence is about 500 cases....
Ann. Biol. Clin. - issue: 6 - volume: 72 - pages: 639-668.

Doyen, J.  et al. 2014

High-resolution analysis of DNA copy number alterations in rectal cancer Correlation with metastasis, survival, and mRNA expression

Background and purpose. This study aimed to determine the candidate genes and chromosomal imbalances capable of predicting occurrences of metastasis in patients with rectal cancer. Patients and...
Strahlenther. Onkol. - issue: 11 - volume: 190 - pages: 1028-1036.

Bushby, K.  et al. 2014

Ataluren Treatment of Patients with Nonsense Mutation Dystrophinopathy

Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in...
Muscle Nerve - issue: 4 - volume: 50 - pages: 477-487.

Yahiaoui, OI.  et al. 2014

Constitutive AKT activation in follicular lymphoma

Background: The phosphoinositide 3-kinase (PI3K) pathway is involved in the growth of various human cancers, including lymphoid malignancies. However its role in the pathogenesis of follicular...
BMC Cancer - issue: - volume: 14 - pages: 565.

Hadj-Rabia, S.  et al. 2014

A New Lamin A Mutation Associated with Acrogeria Syndrome

WOS:000339126100031
J. Invest. Dermatol. - issue: 8 - volume: 134 - pages: 2274-2277.

Badens, C.  et al. 2014

Complex Diagnostics in Hemoglobinopathies

WOS:000337244300037
Int. J. Lab. Hematol. - issue: - volume: 36 - pages: 15-16.

Thompson, BA.  et al. 2014

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for...
Nature Genet. - issue: 2 - volume: 46 - pages: 107-+.

Ibáñez, K.  et al. 2014

Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers detected by transcriptomic meta-analyses

There is epidemiological evidence that patients with certain Central Nervous System (CNS) disorders have a lower than expected probability of developing some types of Cancer. We tested here the...
PLoS Genet. - issue: 2 - volume: 10 - pages: e1004173.

Beau-Faller, M.  et al. 2014

A Multicenter Blinded Study Evaluating EGFR and KRAS Mutation Testing Methods in the Clinical Non-Small Cell Lung Cancer Setting-IFCT/ERMETIC2 Project Part 1 Comparison of Testing Methods in 20 French Molecular Genetic National Cancer Institute Platforms

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors have limited use as first-line treatment for mutated EGFR metastatic non-small cell lung cancer. The French National Cancer Institute...
J. Mol. Diagn. - issue: 1 - volume: 16 - pages: 45-55.

Ozcan, D.  et al. 2013

A Collodion Baby with Facial Dysmorphism, Limb Anomalies, Pachygyria and Genital Hypoplasia: A Mild Form of Neu-Laxova Syndrome or a New Entity?

Neu-Laxova syndrome is a rare, lethal, autosomal recessive disorder characterized by intrauterine growth retardation, central nervous system anomalies, skin findings, such as ichthyosis, edema,...
Ann. Dermatol. - issue: 4 - volume: 25 - pages: 483-488.

Pujol, P.  et al. 2013

Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests

Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in...
Breast Cancer Res. Treat. - issue: 1 - volume: 141 - pages: 135-144.

Spinelli, L.  et al. 2013

Clust&See: a Cytoscape plugin for the identification, visualization and manipulation of network clusters

BACKGROUND AND SCOPE: Large networks, such as protein interaction networks, are extremely difficult to analyze as a whole. We developed Clust&See, a Cytoscape plugin dedicated to the identification,...
BioSystems - issue: 2 - volume: 113 - pages: 91-95.

Zufferey, F.  et al. 2013

Acro-osteolysis, keloid like-lesions, distinctive facial features, and overgrowth: Two newly recognized patients with premature aging syndrome, penttinen type

We report on two unrelated patients with a rare progeroid syndrome first described by Penttinen. Patients presented with prematurely aged appearance, delayed dental development, acro-osteolysis,...
Am. J. Med. Genet. A - issue: 7 - volume: 161A - pages: 1786-1791.

Grandval, P.  et al. 2013

Design of a Core Classification Process for DNA Mismatch Repair Variations of A Priori Unknown Functional Significance

WOS:000319278500016
Hum. Mutat. - issue: 6 - volume: 34 - pages: 920-922.

Neri, M.  et al. 2013

A patient with limb girdle muscular dystrophy carries a TRIM32 deletion, detected by a novel CGH array, in compound heterozygosis with a nonsense mutation

Limb girdle muscular dystrophy 2H is a rare autosomal recessive muscular dystrophy, clinically highly variable, caused by mutations in the TRIM32 gene. Here we describe a 35-years-old who experienced...
Neuromusc. Disord. - issue: 6 - volume: 23 - pages: 478-482.

Milano, G.  et al. 2013

A French multifactorial prospective study of tumor protein and genetic markers in stage I-III colorectal cancer (CRC): Highlight on molecular characteristics related to mismatch repair (MMR) status

WOS:000335419601331
J. Clin. Oncol. - issue: 15 - volume: 31 - pages: .

Andre, F.  et al. 2013

Array CGH and DNA sequencing to personalize targeted treatment of metastatic breast cancer (MBC) patients (pts): A prospective multicentric trial (SAFIR01)

WOS:000335419600016
J. Clin. Oncol. - issue: 15 - volume: 31 - pages: .

Oudot, C.  et al. 2013

Desmoid tumors in children: current strategy

Desmoid tumor (DT) or aggressive fibromatosis is a histologically benign-appearing neoplasms of the soft tissues, arising from connective tissues, the fascial sheaths and musculoaponevrotic structures...
Bull. Cancer - issue: 5 - volume: 100 - pages: 518-528.

Marisa, L.  et al. 2013

Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value

Background: Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical...
PLos Med. - issue: 5 - volume: 10 - pages: e1001453.

Agouti, I.  et al. 2013

Analytical evaluation of the Capillarys 2 Flex piercing for routine haemoglobinopathies diagnosis

To evaluate the analytical performance of a new capillary electrophoresis instrument, the Capillarys 2 Flex piercing (Sebia, France), allowing the separation and quantitative estimation of the...
Int. J. Lab. Hematol. - issue: 2 - volume: 35 - pages: 217-221.

Rahner, N.  et al. 2013

Clinical utility gene card for: Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM) - update 2012

WOS:000312492500001
Eur. J. Hum. Genet. - issue: 1 - volume: 21 - pages: .

Herbaux, C.  et al. 2012

A NEW ATRX MUTATION IN A PATIENT WITH ACQUIRED alpha-THALASSEMIA MYELODYSPLASTIC SYNDROME

Acquired alpha-thalassemia (alpha-thal) myelodysplastic syndrome (ATMDS) is a rare acquired syndrome characterized by a somatic point mutation in the ATRX gene in patients with chronic myeloid...
Hemoglobin - issue: 6 - volume: 36 - pages: 581-585.

Mathers, JC.  et al. 2012

Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial

Background Observational studies report that higher intake of dietary fibre (a heterogeneous mix including non-starch polysaccharides and resistant starches) is associated with reduced risk of...
Lancet Oncol. - issue: 12 - volume: 13 - pages: 1242-1249.

Grandval, P.  et al. 2012

Is the controversy on breast cancer as part of the Lynch-related tumor spectrum still open?

Several studies report an increased risk of breast/pancreatic cancer in MMR (DNA mismatch repair) mutation carriers that has significant consequences on standard cancer screening in such population....
Fam. Cancer - issue: 4 - volume: 11 - pages: 681-683.

Eyrnard, B.  et al. 2012

Diagnostic strategy for limb-girdle muscular dystrophies

Limb-girdle muscular dystrophies represent a major chapter of genetic myopathies. Many different entities have been identified, most of them with recessive transmission, a minority with dominant...
Rev. Neurol. - issue: 12 - volume: 168 - pages: 919-926.

Doubaj, Y.  et al. 2012

An inherited LMNA gene mutation in atypical Progeria syndrome

HutchinsonGilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis...
Am. J. Med. Genet. A - issue: 11 - volume: 158A - pages: 2881-2887.

Laibe, S.  et al. 2012

A Seven-Gene Signature Aggregates a Subgroup of Stage II Colon Cancers with Stage III

Colorectal cancer is one of the most common cancers in the world. Histological staging is efficient, but combination with molecular markers may improve tumor classification. Gene expression profiles...
OMICS - issue: 10 - volume: 16 - pages: 560-565.

De Sandre-Giovannoli, A.  et al. 2012

Antisense based therapeutic approaches in Hutchinson-Gilford Progeria

WOS:000310364400085
Hum. Gene Ther. - issue: 10 - volume: 23 - pages: A27-A27.

Grandval, P.  et al. 2012

Colon-specific phenotype in Lynch syndrome associated with EPCAM deletion

WOS:000305129600017
Clin. Genet. - issue: 1 - volume: 82 - pages: 97-99.

Bertucci, F.  et al. 2012

8q24 Cancer Risk Allele Associated with Major Metastatic Risk in Inflammatory Breast Cancer

Background: Association studies have identified low penetrance alleles that participate to the risk of cancer development. The 8q24 chromosomal region contains several such loci involved in various...
PLoS One - issue: 5 - volume: 7 - pages: e37943.

Levy, N.  et al. 2012

Development of synergies and partnerships on rare diseases: Model of a scientific cooperation foundation

WOS:000305168100008
Presse Med. - issue: - volume: 41 - pages: S23-S25.

Ayme, S.  et al. 2012

Conclusions of RARE 2011 and prospects for RARE 2013

WOS:000305168100023
Presse Med. - issue: - volume: 41 - pages: S65-S66.

Compagnone, M.  et al. 2012

KRAS Mutation Spectrum Notably Diverges between Non-small Cell Lung and Colorectal Carcinomas

WOS:000301866500026
J. Thorac. Oncol. - issue: 4 - volume: 7 - pages: 773-774.

Birnbaum, DJ.  et al. 2012

Expression Profiles in Stage II Colon Cancer According to APC Gene Status

Colorectal cancer is one of the most common cancers in the world. Histoclinical staging is efficient, but combination with molecular markers may improve the classification of stage II cancers. Several...
Transl. Oncol. - issue: 2 - volume: 5 - pages: 72-76.

Sakr, L.  et al. 2012

Cytology-based treatment decision in primary lung cancer: Is it accurate enough?

Accurate distinction of lung cancer types has become increasingly important as recent trials have shown differential response to chemotherapy among non-small cell lung carcinoma (NSCLC) subtypes....
Lung Cancer - issue: 3 - volume: 75 - pages: 293-299.

Kichine, E.  et al. 2012

HSFY genes and the P4 palindrome in the AZFb interval of the human Y chromosome are not required for spermatocyte maturation

BACKGROUND: Recurrent AZFb deletions on the human Y chromosome are associated with an absence of ejaculated spermatozoa consequent to a meiotic maturation arrest that prevents the progression of germ...
Hum. Reprod. - issue: 2 - volume: 27 - pages: 615-624.

Maalouf, D.  et al. 2012

A Novel Mutation in the PORCN Gene Underlying a Case of Almost Unilateral Focal Dermal Hypoplasia

Background: Focal dermal hypoplasia (also known as Goltz syndrome) is an X-linked dominant syndrome characterized by patchy hypoplastic skin with soft-tissue, skeletal, dental, and ocular defects that...
Arch. Dermatol. - issue: 1 - volume: 148 - pages: 85-88.

Faguer, S.  et al. 2011

A 10 Mb duplication in chromosome band 5q31.3-5q33.1 associated with late-onset lipodystrophy, ichthyosis, epilepsy and glomerulonephritis

We report here a 44 years-old patient with late-onset partial lipodystrophy, mental retardation, epilepsy, ichtyosis and glomerulonephritis, carrying a 10 Mb duplication of the chromosome...
Eur. J. Med. Genet. - issue: 3 - volume: 54 - pages: 310-313.

Aubourg, P.  et al. 2005

Assignment of a new congenital fibrosis of extraocular muscles type 3 (CFEOM3) locus, FEOM4, based on a balanced translocation t(2;13) (q37.3;q12.11) and identification of candidate genes

WOS:000227470300010
J. Med. Genet. - issue: 3 - volume: 42 - pages: 253-259.