Mireia Menéndez

Institut Català d'Oncologia

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Conxi Lázaro

Institut d'Investigació Biomédica de Bellvitge

Gabriel Capellá

Institut Català d'Oncologia

Joan Brunet

Institut Català d'Oncologia

ÀT

Àlex Teulé

Institut Català d'Oncologia

Lídia Feliubadaló

Institut Català d'Oncologia

Eva Tornero

Centro de Investigación Biomédica en Red de Cáncer

Jesús Del Valle

Institut Català d'Oncologia

Ignacio Blanco

Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol

Sara González

Institut Català d'Oncologia

Marta Pineda

Institut Català d'Oncologia

Cooperative Institutions

Peter MacCallum Cancer Centre

112

Cancer Genetics (United States)

Institut Català d'Oncologia

University of Melbourne

Institut d'Investigació Biomédica de Bellvitge

University of Cambridge

QIMR Berghofer Medical Research Institute

University of Toronto

Centro de Investigación Biomédica en Red de Cáncer

Wellcome Sanger Institute

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ICO Amplicon NGS Data Analysis: A Web Tool for Variant Detection in Common High-Risk Hereditary Cancer Genes Analyzed by Amplicon GS Junior Next-Generation Sequencing

Human Mutation (2013)

Adriana López‐Doriga Lídia Feliubadaló Mireia Menéndez Sergio Lopez-Doriga Francisco D. Morón-Duran

Next-generation sequencing (NGS) has revolutionized genomic research and is set to have a major impact on genetic diagnostics thanks to the advent of benchtop sequencers and flexible kits for targeted libraries. Among the main hurdles in NGS are the difficulty of performing bioinformatic analysis of the huge volume of data generated and the high number of false positive calls that could be obtained, depending on the NGS technology and the analysis pipeline. Here, we present the development of a free and user-friendly Web data analysis tool that detects and filters sequence variants, provides coverage information, and allows the user to customize some basic parameters. The tool has been developed to provide accurate genetic analysis of targeted sequencing of common high-risk hereditary cancer genes using amplicon libraries run in a GS Junior System. The Web resource is linked to our own mutation database, to assist in the clinical classification of identified variants. We believe that this tool will greatly facilitate the use of the NGS approach in routine laboratories.

Amplicon

Amplicon sequencing

10.1002/humu.22484

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Citations (2)

Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points‐based ACMG/AMP approach

Human Mutation (2022)

Mads Thomassen Romy L.S. Mesman Thomas van Overeem Hansen Mireia Menéndez Maria Rossing

Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.

Exon skipping

splice

10.1002/humu.24449

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Citations (8)

High Prevalence of Somatic Oncogenic Driver Alterations in Patients With NSCLC and Li-Fraumeni Syndrome

Journal of Thoracic Oncology (2020)

Laura Mezquita Maria Jové Ernest Nadal Maria Kfoury Teresa Morán

Li–Fraumeni syndrome

10.1016/j.jtho.2020.03.005

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A Case Report and a Descriptive Retrospective Study of Cases of Inferior Vena Cava Thrombosis Diagnosed over a 10-Year Period in a Third Level Hospital

Case Reports in Clinical Medicine (2020)

Andrea Teira Mireia Menéndez Zaida Salmón Daniel Nan

Inferior vena cava thrombosis is an under-recognized entity associated with significant morbidity and mortality. This is the reason why, although the diagnosis is challenging, a high index of suspicion is required. Regarding this condition, we present the case of a 63-year-old man who had repeatedly visited the emergency room suffering from abdominal and back pain and painful lower limb edema. After several tests, including magnetic resonance imaging (MRI), he was diagnosed to have agenesis of left renal vein and inferior vena cava thrombosis, from hypercoagulable state secondary to Antiphospholipid Syndrome. He had anticoagulation treatment with low-molecular-weight heparin with good subsequent evolution. This study sets out a descriptive retrospective study of fifty cases of inferior vena cava thrombosis diagnosed in a third-level hospital in the north of Spain over a ten-year period (2010-2018). The aim of this article is to identify the epidemiology, predisposing factors and symptoms that characterize this entity, in order to be able to achieve an early diagnosis that allows us to initiate immediate treatment, minimizing acute and chronic complications of this disease.

10.4236/crcm.2020.95018

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Carboplatin (CBDCA), ifosfamide (IFX) and etoposide (VP) in advanced non small cell lung cancer (NSCLC): A phase II trial

European Journal of Cancer (1997)

Sonia Candamio Mireia Menéndez Antonio Irigoyen López F.J. Barón Francisca Vázquez

Carboplatin

10.1016/s0959-8049(97)85997-7

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Next-generation sequencing meets genetic diagnostics: development of a comprehensive workflow for the analysis of BRCA1 and BRCA2 genes

European Journal of Human Genetics (2012)

Lídia Feliubadaló Adriana López‐Doriga Ester Castellsagué Jesús Del Valle Mireia Menéndez

Identification

10.1038/ejhg.2012.270

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Citations (109)

Comparison of mRNA Splicing Assay Protocols across Multiple Laboratories: Recommendations for Best Practice in Standardized Clinical Testing

Clinical Chemistry (2013)

Phillip J Whiley Miguel de la Hoya Mads Thomassen Alexandra Becker Rita D. Brandão

Abstract BACKGROUND Accurate evaluation of unclassified sequence variants in cancer predisposition genes is essential for clinical management and depends on a multifactorial analysis of clinical, genetic, pathologic, and bioinformatic variables and assays of transcript length and abundance. The integrity of assay data in turn relies on appropriate assay design, interpretation, and reporting. METHODS We conducted a multicenter investigation to compare mRNA splicing assay protocols used by members of the ENIGMA (Evidence-Based Network for the Interpretation of Germline Mutant Alleles) consortium. We compared similarities and differences in results derived from analysis of a panel of breast cancer 1, early onset (BRCA1) and breast cancer 2, early onset (BRCA2) gene variants known to alter splicing (BRCA1: c.135-1G>T, c.591C>T, c.594-2A>C, c.671-2A>G, and c.5467+5G>C and BRCA2: c.426-12_8delGTTTT, c.7988A>T, c.8632+1G>A, and c.9501+3A>T). Differences in protocols were then assessed to determine which elements were critical in reliable assay design. RESULTS PCR primer design strategies, PCR conditions, and product detection methods, combined with a prior knowledge of expected alternative transcripts, were the key factors for accurate splicing assay results. For example, because of the position of primers and PCR extension times, several isoforms associated with BRCA1, c.594-2A>C and c.671-2A>G, were not detected by many sites. Variation was most evident for the detection of low-abundance transcripts (e.g., BRCA2 c.8632+1G>A Δ19,20 and BRCA1 c.135-1G>T Δ5q and Δ3). Detection of low-abundance transcripts was sometimes addressed by using more analytically sensitive detection methods (e.g., BRCA2 c.426-12_8delGTTTT ins18bp). CONCLUSIONS We provide recommendations for best practice and raise key issues to consider when designing mRNA assays for evaluation of unclassified sequence variants.

Primer (cosmetics)

10.1373/clinchem.2013.210658

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Citations (65)

Functional Characterization of the Novel APC N1026S Variant Associated With Attenuated Familial Adenomatous Polyposis

Gastroenterology (2007)

Mireia Menéndez Sara González Antònia Obrador‐Hevia Ana Domínguez María Jesús Pujol

Adenomatous polyposis coli

Transcription

10.1053/j.gastro.2007.10.009

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Citations (20)

Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum

JCO Precision Oncology (2024)

Cristina Fortuño Bing Feng Courtney Carroll Giovanni Innella Wendy Kohlmann

PURPOSE Establishing accurate age-related penetrance figures for the broad range of cancer types that occur in individuals harboring a pathogenic germline variant in the TP53 gene is essential to determine the most effective clinical management strategies. These figures also permit optimal use of cosegregation data for classification of TP53 variants of unknown significance. Penetrance estimation can easily be affected by bias from ascertainment criteria, an issue not commonly addressed by previous studies. MATERIALS AND METHODS We performed a maximum likelihood penetrance estimation using full pedigree data from a multicenter study of 146 TP53-positive families, incorporating adjustment for the effect of ascertainment and population-specific background cancer risks. The analysis included pedigrees from Australia, Spain, and United States, with phenotypic information for 4,028 individuals. RESULTS Core Li-Fraumeni syndrome (LFS) cancers (breast cancer, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) had the highest hazard ratios of all cancers analyzed in this study. The analysis also detected a significantly increased lifetime risk for a range of cancers not previously formally associated with TP53 pathogenic variant status, including colorectal, gastric, lung, pancreatic, and ovarian cancers. The cumulative risk of any cancer type by age 50 years was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. Females had a 63.3% (95% CI, 35.6 to 90.1) cumulative risk of developing breast cancer by age 50 years. CONCLUSION The results from maximum likelihood analysis confirm the known high lifetime risk for the core LFS-associated cancer types providing new risk estimates and indicate significantly increased lifetime risks for several additional cancer types. Accurate cancer risk estimates will help refine clinical recommendations for TP53 pathogenic variant carriers and improve TP53 variant classification.

Penetrance

Pedigree chart

10.1200/po.23.00453

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Citations (5)

TP53 germline testing and hereditary cancer: how somatic events and clinical criteria affect variant detection rate

Genome Medicine (2025)

Paula Rofes Carmen Castillo-Manzano Mireia Menéndez Àlex Teulé Sílvia Iglesias

Li–Fraumeni syndrome

Penetrance

Proband

10.1186/s13073-025-01429-5

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Citations (0)