Iker Sánchez‐Navarro

Universidad Autónoma de Madrid

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JÁ

Juan Ángel Fresno Vara

Instituto de Salud Carlos III

Enrique Espinosa

Instituto de Salud Carlos III

Angelo Gámez‐Pozo

Hospital Universitario Puerta del Mar

Rosário Madero

Hospital Universitario La Paz

Carmen Ayuso

Centre for Biomedical Network Research on Rare Diseases

David Hardisson

Hospital Universitario La Paz

Fiona Blanco‐Kelly

Centre for Biomedical Network Research on Rare Diseases

Marta Mendiola

Centro de Investigación Biomédica en Red de Cáncer

Marta Cortón

Hospital Universitario Fundación Jiménez Díaz

AÁ

Almudena Ávila‐Fernández

Centre for Biomedical Network Research on Rare Diseases

Cooperative Institutions

Universidad Autónoma de Madrid

Instituto de Salud Carlos III

Centre for Biomedical Network Research on Rare Diseases

Hospital Universitario Fundación Jiménez Díaz

Centro de Investigación Biomédica en Red

Hospital Universitario La Paz

Instituto de Investigación de Enfermedades Raras

Hospital La Paz Institute for Health Research

Universidad Complutense de Madrid

Centro de Investigación Biomédica en Red de Cáncer

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Protein phosphorylation analysis in archival clinical cancer samples by shotgun and targeted proteomics approaches

Molecular BioSystems (2011)

Angelo Gámez‐Pozo Iker Sánchez‐Navarro Enrique Calvo Esther Díaz María Miguel-Martín

Protein phosphorylation affects most eukaryotic cellular processes and its deregulation is considered a hallmark of cancer and other diseases. Phosphoproteomics may enable monitoring of altered signaling pathways as a means of stratifying tumors and facilitating the discovery of new drugs. Unfortunately, the development of molecular tests for clinical use is constrained by the limited availability of fresh frozen, clinically annotated samples. Here we report phosphopeptide analysis in human archival formalin-fixed, paraffin-embedded (FFPE) cancer samples based on immobilized metal affinity chromatography followed by liquid chromatography coupled with tandem mass spectrometry and selected reaction monitoring techniques. Our results indicate the equivalence of detectable phosphorylation rates in archival FFPE and fresh frozen tissues. Moreover, we demonstrate the applicability of targeted assays for phosphopeptide analysis in clinical archival FFPE samples, using an experimental workflow suitable for processing and analyzing large sample series. This work paves the way for the application of shotgun and targeted phosphoproteomics approaches in clinically relevant studies using archival clinical samples.

Phosphoproteomics

Phosphopeptide

Shotgun proteomics

Shotgun

10.1039/c1mb05113j

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Citations (40)

Comparison of gene expression profiling by reverse transcription quantitative PCR between fresh frozen and formalin-fixed, paraffin-embedded breast cancer tissues

BioTechniques (2010)

Iker Sánchez‐Navarro Angelo Gámez‐Pozo Manuel González-Barón Álvaro Pinto-Marín David Hardisson

Recent reports demonstrate the feasibility of quantifying gene expression by using RNA isolated from blocks of formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The development of molecular tests for clinical use based on archival materials would be of great utility in the search for and validation of important genes or gene expression profiles. In this study, we compared the performance of different normalization strategies in the correlation of quantitative data between fresh frozen (FF) and FFPE samples and analyzed the parameters that characterize such correlation for each gene. Total RNA extracted from FFPE samples presented a shift in raw cycle threshold (Cq) values that can be explained by its extensive degradation. Proper normalization can compensate for the effects of RNA degradation in gene expression measurements. We show that correlation between normalized expression values is better for moderately to highly expressed genes whose expression varies significantly between samples. Nevertheless, some genes had no correlation. These genes should not be included in molecular tests for clinical use based on FFPE samples. Our results could serve as a guide when developing clinical diagnostic tests based on RT-qPCR analyses of FFPE tissues in the coming era of treatment decision-making based on gene expression profiling.

Reference Genes

Normalization

Database normalization

10.2144/000113388

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Citations (65)

NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases

Human Genetics (2021)

Irene Perea‐Romero Fiona Blanco‐Kelly Iker Sánchez‐Navarro Isabel Lorda‐Sánchez Saoud Tahsin Swafiri

Syndromic retinal diseases (SRDs) are a group of complex inherited systemic disorders, with challenging molecular underpinnings and clinical management. Our main goal is to improve clinical and molecular SRDs diagnosis, by applying a structured phenotypic ontology and next-generation sequencing (NGS)-based pipelines. A prospective and retrospective cohort study was performed on 100 probands with an a priori diagnosis of non-Usher SRDs, using available clinical data, including Human Phenotype Ontology annotation, and further classification into seven clinical categories (ciliopathies, specific syndromes and five others). Retrospective molecular diagnosis was assessed using different molecular and bioinformatic methods depending on availability. Subsequently, uncharacterized probands were prospectively screened using other NGS approaches to extend the number of analyzed genes. After phenotypic classification, ciliopathies were the most common SRD (35%). A global characterization rate of 52% was obtained, with six cases incompletely characterized for a gene that partially explained the phenotype. An improved characterization rate was achieved addressing prospective cases (83%) and well-recognizable syndrome (62%) subgroups. The 27% of the fully characterized cases were reclassified into a different clinical category after identification of the disease-causing gene. Clinical-exome sequencing is the most appropriate first-tier approach for prospective cases, whereas whole-exome sequencing and bioinformatic reanalysis increases the diagnosis of uncharacterized retrospective cases to 45%, mostly those with unspecific symptoms. Our study describes a comprehensive approach to SRDs in daily clinical practice and the importance of thorough clinical assessment and selection of the most appropriate molecular test to be used to solve these complex cases and elucidate novel associations.

Ciliopathies

Proband

Exome

10.1007/s00439-021-02343-7

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Mutations inSCAPERcause autosomal recessive retinitis pigmentosa with intellectual disability

Journal of Medical Genetics (2017)

Yasmin Tatour Iker Sánchez‐Navarro Elana Chervinsky Hákon Hákonarson Haithum Gawi

Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy, with a worldwide prevalence of 1 in 4000 persons. While in most cases of RP, the disease is limited to the eye (non-syndromic), over 40 forms of syndromic RP have been described.To identify the genetic basis for syndromic RP in three unrelated families from Israel and Spain.Whole exome sequencing was conducted in one Israeli and two Spanish families segregating autosomal recessive RP with intellectual disability. Complete ophthalmic examination included best-corrected visual acuity, funduscopy, optical coherence tomography, fluorescein angiography, flash visual evoked potentials, and electroretinography. Reverse transcription (RT)-PCR and immunostaining were used to examine the spatial and temporal expression pattern of SCAPER.In all patients, biallelic SCAPER mutations were observed. Clinically, patients with SCAPER mutations show signs of typical RP. In addition, they have mild to moderate intellectual disability and attention-deficit/hyperactivity disorder. SCAPER was found to be ubiquitously expressed in a wide range of human tissues, including retina and brain. Furthermore, RT-PCR analysis revealed that in both mouse eye and brain, Scaper is expressed as early as embryonic day 14. In the mouse retina, SCAPER is located in multiple layers, including the retinal pigment epithelium, photoreceptor outer and inner segments, the inner plexiform layer and the ganglion cell layer.Deleterious SCAPER mutations were identified in four patients from three unrelated families of different ethnic backgrounds, thereby confirming the involvement of this gene in the aetiology of autosomal recessive syndromic RP.

Electroretinography

10.1136/jmedgenet-2017-104632

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Panel-based NGS Reveals Novel Pathogenic Mutations in Autosomal Recessive Retinitis Pigmentosa

Scientific Reports (2016)

Raquel Pérez-Carro Marta Cortón Iker Sánchez‐Navarro Olga Zurita Noelia Sanchez-Bolivar

Abstract Retinitis pigmentosa (RP) is a group of inherited progressive retinal dystrophies (RD) characterized by photoreceptor degeneration. RP is highly heterogeneous both clinically and genetically, which complicates the identification of causative genes and mutations. Targeted next-generation sequencing (NGS) has been demonstrated to be an effective strategy for the detection of mutations in RP. In our study, an in-house gene panel comprising 75 known RP genes was used to analyze a cohort of 47 unrelated Spanish families pre-classified as autosomal recessive or isolated RP. Disease-causing mutations were found in 27 out of 47 cases achieving a mutation detection rate of 57.4%. In total, 33 pathogenic mutations were identified, 20 of which were novel mutations (60.6%). Furthermore, not only single nucleotide variations but also copy-number variations, including three large deletions in the USH2A and EYS genes, were identified. Finally seven out of 27 families, displaying mutations in the ABCA4, RP1, RP2 and USH2A genes, could be genetically or clinically reclassified. These results demonstrate the potential of our panel-based NGS strategy in RP diagnosis.

ABCA4

Stargardt disease

10.1038/srep19531

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Citations (59)

Author Correction: Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Scientific Reports (2021)

Irene Perea‐Romero Gema Gordo Ionut-Florin Iancu Marta Del Pozo‐Valero Berta Almoguera

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Genetic epidemiology

10.1038/s41598-021-89275-4

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Abstract 379: Predictive profile of pathological response in advanced ovarian carcinoma derived from angiogenesis-related genes

Cancer Research (2010)

Jorge Barriuso Marta Mendiola Andrés Redondo Adrián Mariño‐Enríquez Rosário Madero

Abstract Background: Studies have consistently shown that the volume of residual disease remaining after cytoreductive surgery inversely correlates with survival. Women with optimally resected tumor have, on average, a 20-month improvement in median survival compared to those with suboptimal resection. It is difficult to predict which patients can be optimally debulked. CA 125 level and scoring imaging techniques have been used, however they were not enough accurate to obviate the initial surgical exploration. Several genes involved in angiogenesis proved to have prognosis capacity in advanced ovarian carcinoma. The aim of this study is to find model derived from angiogenesis genes to predict pathological response to treatment. Material and Methods: 34 patients with III/IV FIGO stage ovarian cancer that underwent surgical cytoreduction and received a carboplatin plus paclitaxel chemotherapy regime were included. A second look laparotomy was performed in all the patients. Optimal debulking was defined as ≤1 cm (diameter) residual disease. RNAs were collected from formalin-fixed paraffin-embedded advanced ovarian carcinoma samples. Expression levels of 82 angiogenesis related genes were measured using quantitative real time polymerase chain reaction (qRT-PCR). A logistic regression method was used to build multiple models based on the significant genes in the univariate analysis. The accuracy of the models was evaluated using Receiver Operating Characteristic (ROC) curves. The Akaike Information Criterion based selection was used to find the most accurate one. And Leave-one-out Cross Validation (LOOCV) method was applied to avoid overoptimistic predictions. Results: The median age at diagnosis was 50 years (range, 35 to 79 years). All patients had advanced disease (FIGO stages III/IV). Most of them had FIGO stage III (27, 79.4%), grade 3 tumors (19, 55.9%), and serous histology (23, 67.6%). 20 patients (50.8%) achieved complete response after standard treatment. It was found an independent model able to predict any degree of response to therapy comprising 5 genes with an Area Under the Curve (AUC) of 0.950 (p<0.001). LOOCV was applied to avoid overfitting of the model, obtaining a corrected AUC of 0.846, 95%IC: 0,717-0,976. Conclusions: It is feasible to create a predictive profile for pathological response in AOC derived from genes involved in ovarian angiogenesis. Our profile could be used as predictive tool to enable clinicians to identify those high risk patients who will potentially benefit from alternative drug combinations. Nevertheless, the predictive value of our qRT-PCR based angiogenesis-related gene expression profile should be further evaluated in prospective studies of patients with AOC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 379.

Debulking

Carboplatin

Univariate analysis

10.1158/1538-7445.am10-379

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High‐Throughput Phosphoproteomics from Formalin‐Fixed, Paraffin‐Embedded Tissues

Current Protocols in Chemical Biology (2012)

Angelo Gámez‐Pozo Iker Sánchez‐Navarro Nuria Ibarz Ferrer Fernando Garcı́a Keith Ashman

Abstract Liquid chromatography coupled with tandem mass spectrometry–based high‐throughput proteomics allows detection and characterization of thousands of peptides and their post‐translational modifications in a single sample. Protein phosphorylation affects most eukaryotic cellular processes, and its deregulation is considered a hallmark of cancer and other diseases. High‐throughput phosphoproteomics may enable monitoring of altered signaling pathways as a means of stratifying tumors and facilitating the discovery of new drugs. Unfortunately, the development of molecular tests for clinical use is constrained by the limited availability of fresh frozen, clinically annotated samples, and protocols that allow the use of human archival formalin‐fixed, paraffin‐embedded samples are required. The protocols in this article describe a global procedure for evaluating hundreds of protein phosphorylation sites in protein extracts obtained from formalin‐fixed, paraffin‐embedded tissues. Curr. Protoc. Chem. Biol . 4:161‐175 © 2012 by John Wiley & Sons, Inc.

Phosphoproteomics

10.1002/9780470559277.ch110242

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TREATMENT OF PROXIMAL HUMERAL FRACTURES USING BIARTICULAR ARTHROPLASTY

Orthopaedic Proceedings (2004)

Agustí Bartra Francesc Angles-Crespo J Galí-López C Puig-Rosell Iker Sánchez‐Navarro

Introduction and Objectives: Fractures of the proximal third of the humerus represent 4–5% of all fractures in our area. About 80–85% can be treated conservatively, though there is controversy over the best method treatment for complex fractures. The aim of our study is to analyse the results of treatment of these fractures by means of biarticular arthroplasty. Materials and Methods: This is a retrospective study of 29 patients: 17 females and 12 males, with a mean age of 73.5 years, all of whom suffered complex fractures of the head of the humerus and were treated between the years 1995 and 2002. Minimum clinical follow-up time was 1 year. Patients were evaluated radiographically and clinically using the test of Constant, Swanson, and UCLA. Results: One case developed a deep infection, which required removal of the arthroplasty and one case require replacement due to recurrent dislocation. Mean pain values measured on the RVA scale were 1.7 out of 10. Range of motion was limited compared to the contra-lateral shoulder. Mean Constant function index was 61.6 points, with a mean weighted Constant value of 90.8%. Discussion and Conclusions: Biarticular prosthetic replacement offers good results in treatment of complex fractures of the proximal humerus, resulting in a shoulder that is non-painful though somewhat limited in strength and mobility. Best results are achieved in younger patients.

Shoulder Fracture

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Exome sequencing identifies PEX6 mutations in three cases diagnosed with Retinitis Pigmentosa and hearing impairment

Molecular vision (2020)

Gema García‐García Iker Sánchez‐Navarro Elena Aller Teresa Jaijo Carla Fuster‐García

Purpose The aim of the present work is the molecular diagnosis of three patients with deafness and retinal degeneration. Methods Three patients from two unrelated families were initially analyzed with custom gene panels for Usher genes, non-syndromic hearing loss, or inherited syndromic retinopathies and further investigated by means of clinical or whole exome sequencing. Results The study allowed us to detect likely pathogenic variants in PEX6, a gene typically involved in peroxisomal biogenesis disorders (PBDs). Beside deaf-blindness, both families showed additional features: Siblings from Family 1 showed enamel alteration and abnormal peroxisome. In addition, the brother had mild neurodevelopmental delay and nephrolithiasis. The case II:1 from Family 2 showed intellectual disability, enamel alteration, and dysmorphism. Conclusions We have reported three new cases with pathogenic variants in PEX6 presenting with milder forms of the Zellweger spectrum disorders (ZSD). The three cases showed distinct clinical features. Thus, expanding the phenotypic spectrum of PBDs and ascertaining exome sequencing is an effective strategy for an accurate diagnosis of clinically overlapping and genetically heterogeneous disorders such as deafness-blindness association.

Usher syndrome

Exome

10.13039/100006458

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Citations (7)