46 results on '"Alkorta-Aranburu G"'
Search Results
2. Familial primary cutaneous amyloidosis: Caspase activation may be involved in amyloid formation
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Antoñanzas, J. (Javier), Pelacho-Samper, B. (Beatriz), Alkorta-Aranburu, G. (Gorka), Echeveste, J.I. (José I.), and España, A. (Agustín)
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Caspases ,Apoptosis ,Amyloidosis - Abstract
Primary localized cutaneous amyloidosis (PLCA) is a rare form of cutaneous amyloidosis, characterized by the presence of flat-topped papules and macules with amyloid deposits in the superficial dermis. It is a purely cutaneous disease with no association with systemic forms of amyloidosis.1 Although most cases are sporadic, familial cases (FPLCA) represent about 10% of total reports and show an autosomal dominant inheritance, with mutations described in the genes for the oncostatin M receptor (OSMR) and the interleukin-31 receptor A (IL31RA).2 Herein, we present a family affected by FPLCA and underline the role of caspase activation in amyloid formation.
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- 2022
3. 232P Identification of ‘secondary’ germline cancer predisposition variants from somatic tumour testing: Should we evolve towards universal screening?
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Gallego Martinez, A., Imizcoz, T., Sánchez-Lorenzo, L., Mora, M., Domínguez, D., Gurpide, A., Espinos Jimenez, J., Aramendia, J.M., Chopitea Ortega, A., Santisteban Eslava, M., Ponz-Sarvise, M., González, J.L., Landa Magdalena, A., Sanmamed, M.F., Alkorta-Aranburu, G., Rodriguez Rodriguez, J., Herráiz Bayod, T., Gonzalez Martin, A., and Patiño-García, A.
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- 2023
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4. Epitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants
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Conde-Gallastegi, E. (Enrique), Vercher-Herráez, E. (Enric), Soria-Castellano, M. (Marta), Suarez-Olmos, J. (Jesús), Mancheño, U. (Uxua), Elizalde, E. (Edurne), Rodríguez, M.L. (M. Luis), González-Vaz, J. (Javier), Casares, N. (Noelia), Rodríguez-García, E. (Estefanía), Hommel, M. (Mirja), González-Aseguinolaza, G. (Gloria), Uranga-Murillo, I. (Iratxe), Pardo, J. (Julián), Alkorta-Aranburu, G. (Gorka), Melero, I. (Ignacio), Lasarte, J.J. (Juan José), and Hervas-Stubbs, S. (Sandra)
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Chimeric antigen ,Adaptive immunity ,Adoptive ,Receptors ,Tumor escape ,Combined modality therapy ,Immunotherapy - Abstract
Background Target antigen (Ag) loss has emerged as a major cause of relapse after chimeric antigen receptor T (CART)-cell therapy. We reasoned that the combination of CART cells, with the consequent tumor debulking and release of Ags, together with an immunomodulatory agent, such as the stimulator of interferon gene ligand (STING-L) 2 ' 3 '-cyclic GMP-AMP (2 ' 3 '-cGAMP), may facilitate the activation of an endogenous response to secondary tumor Ags able to counteract this tumor escape mechanism. Methods Mice bearing B16-derived tumors expressing prostate-specific membrane Ag or gp75 were treated systemically with cognate CART cells followed by intratumoral injections of 2 ' 3 '-cGAMP. We studied the target Ag inmunoediting by CART cells and the effect of the CART/STING-L combination on the control of STING-L-treated and STING-L-non-treated tumors and on the endogenous antitumor T-cell response. The role of Batf3-dependent dendritic cells (DCs), stimulator of interferon gene (STING) signaling and perforin (Perf)-mediated killing in the efficacy of the combination were analyzed. Results Using an immune-competent solid tumor model, we showed that CART cells led to the emergence of tumor cells that lose the target Ag, recreating the cancer immunoediting effect of CART-cell therapy.
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- 2021
5. Biological and clinical significance of dysplastic hematopoiesis in patients with newly-diagnosed multiple myeloma
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Maia C, Puig N, Cedena M, Goicoechea I, Valdes-Mas R, Vazquez I, Chillon M, Aguirre P, Sarvide S, Gracia-Aznarez F, Alkorta-Aranburu G, Calasanz M, Garcia-Sanz R, Gonzalez M, Gutierrez N, Martinez-Lopez J, Perez J, Merino J, Moreno C, Burgos L, Alignani D, Botta C, Prosper F, Matarraz S, Orfao A, Oriol A, Teruel A, de Paz R, de Arriba F, Hernandez Garcia M, Palomera L, Martinez R, Rosinol L, Mateos M, Lahuerta J, Blade J, San Miguel J, and Paiva B
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hemic and lymphatic diseases - Abstract
Risk of developing myelodysplastic syndromes (MDS) is significantly increased in both multiple myeloma (MM) and MGUS, suggesting that is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 MM patients enrolled in the PETHEMA/GEM2012MENOS65 trial (NCT01916252), and investigated the clinical significance of monocytic MDS-PA in a larger series of 1,252 patients enrolled in four PETHEMA/GEM protocols. At diagnosis, 33/285 (11.6%) cases displayed MDS-PA. Bulk- and single-cell targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients unveiled clonal hematopoiesis in 13/26 (50%) cases with MDS-PA versus 9/41 (22%) without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86/285 patients, and showed that in most cases (69/86, 80%) MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations unfrequently emerged after high-dose therapy. Based on MFC profiling, we found that patients with MDS-PA have altered hematopoiesis and Treg distribution in the tumor microenvironment. Importantly, presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematological toxicity and was independently associated with inferior progression-free (HR:1.5, P=.02) and overall survival (HR:1.7, P=.01). This study unveils the biological and clinical significance of dysplastic hematopoiesis in newly-diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC. Copyright © 2020 American Society of Hematology.
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- 2020
6. ASSOCIATION BETWEEN HUNTINGTONʼS DISEASE AGE OF ONSET (AOO) AND GENETIC FACTORS, OTHER THAN THE CAG REPEAT LENGTH, IN THE BASQUE POPULATION: I01
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Valcárcel, L, García, M, Manuel Fernández, J, Lezcano, E, Losada, J, Ruiz, J, Alkorta-Aranburu, G, Iriondo Orensanz, M, Fullaondo, A, and Aguirre, A
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- 2009
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7. Replication of twelve association studies for Huntington’s disease residual age of onset in large Venezuelan kindreds
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Andresen, J M, Gayán, J, Cherny, S S, Brocklebank, D, Alkorta-Aranburu, G, Addis, E A, Cardon, L R, Housman, D E, and Wexler, N S
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- 2007
8. Genomewide linkage analysis of age of onset of Huntington's disease
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Gayan, J, Brocklebank, D, Andresen, J, Alkorta-Aranburu, G, Cader, M, Roberts, SA, Cherny, S, Wexler, N, Cardon, L, Housman, D, and USVCRG
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- 2016
9. Clinical utility of gene panel-based testing for hereditary myelodysplastic syndrome/acute leukemia predisposition syndromes
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Guidugli, L, primary, Johnson, A K, additional, Alkorta-Aranburu, G, additional, Nelakuditi, V, additional, Arndt, K, additional, Churpek, J E, additional, Godley, L A, additional, Townsley, D, additional, Young, N S, additional, Fitzpatrick, C, additional, del Gaudio, D, additional, Das, S, additional, and Li, Z, additional
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- 2017
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10. Reconstructing Native American population history
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Reich, D., Patterson, N., Campbell, D., Tandon, A., Mazieres, S., Ray, N., Parra, M.V., Rojas, W., Duque, C., Mesa, N., García, L.F., Triana, O., Blair, S., Maestre, A., Dib, J.C., Bravi, C.M., Bailliet, G., Corach, D., Hünemeier, T., Bortolini, M.C., Salzano, F.M., Petzl-Erler, M.L., Acuña-Alonzo, V., Aguilar-Salinas, C., Canizales-Quinteros, S., Tusié-Luna, T., Riba, L., Rodríguez-Cruz, M., Lopez-Alarcón, M., Coral-Vazquez, R., Canto-Cetina, T., Silva-Zolezzi, I., Fernandez-Lopez, J.C., Contreras, A.V., Jimenez-Sanchez, G., Gómez-Vázquez, M.J., Molina, J., Carracedo, A., Salas, A., Gallo López-Aliaga, Carla Maria, Poletti, G., Witonsky, D.B., Alkorta-Aranburu, G., Sukernik, R.I., Osipova, L., Fedorova, S.A., Vasquez, R., Villena, M., Moreau, C., Barrantes, R., Pauls, D., Excoffier, L., Bedoya, G., Rothhammer, F., Dugoujon, J.-M., Larrouy, G., Klitz, W., Labuda, D., Kidd, J., Kidd, K., Di Rienzo, A., Freimer, N.B., Price, A.L., and Ruiz-Linares, A.
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Gene Flow ,Canada ,Genotype ,Life History ,Population Dynamics ,Review ,Eskimo ,Divergence ,Arctic ,Progeny ,Isthmus Of Panama ,Polymorphism ,Migration ,Language ,Ancestry ,Inheritance ,Asian ,Data Set ,Population Dispersion ,Dispersal ,South America ,Siberia ,Panama [Central America] ,Genetic Variability ,Archaeology ,American Indian ,Single Nucleotide Polymorphism ,purl.org/pe-repo/ocde/ford#3.01.00 [https] ,Demographic History ,Reconstruction ,Indigenous Population - Abstract
The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call First American. However, speakers of Eskimog-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.
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- 2012
11. Continued lessons from theINSgene: an intronic mutation causing diabetes through a novel mechanism
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Carmody, David, primary, Park, Soo-Young, additional, Ye, Honggang, additional, Perrone, Marie E, additional, Alkorta-Aranburu, G, additional, Highland, Heather M, additional, Hanis, Craig L, additional, Philipson, Louis H, additional, Bell, Graeme I, additional, and Greeley, Siri Atma W, additional
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- 2015
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12. Phenotypic heterogeneity in monogenic diabetes: The clinical and diagnostic utility of a gene panel-based next-generation sequencing approach
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Alkorta-Aranburu, G., primary, Carmody, D., additional, Cheng, Y.W., additional, Nelakuditi, V., additional, Ma, L., additional, Dickens, Jazzmyne T., additional, Das, S., additional, Greeley, S.A.W., additional, and del Gaudio, D., additional
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- 2014
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13. Genomewide linkage analysis of age of onset of Huntington's disease
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Gayan, J, Brocklebank, D, Andresen, JM, Alkorta-Aranburu, G, Cader, MZ, Roberts, SA, Cherny, SS, Wexler, NS, Cardon, LR, and Housman, DE
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- 2007
14. Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.
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Carmody, David, Soo-Young Park, Honggang Ye, Perrone, Marie E., Alkorta-Aranburu, G., Highland, Heather M., Hanis, Craig L., Philipson, Louis H., Bell, Graeme I., and Greeley, Siri Atma W.
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INSULIN genetics ,GENETIC polymorphisms ,DIABETES risk factors ,GENETIC mutation ,NEONATAL diseases ,ULTRASONIC imaging - Abstract
Background Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus. Methods Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (http://monogenicdiabetes. uchicago.edu). Results The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional β cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site. Conclusions Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without β cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life. [ABSTRACT FROM AUTHOR]
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- 2015
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15. Laboratory Cross-Comparison and Ring Test Trial for Tumor BRCA Testing in a Multicenter Epithelial Ovarian Cancer Series: The BORNEO GEICO 60-0 Study
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Zaida Garcia-Casado, Ana Oaknin, Marta Mendiola, Gorka Alkorta-Aranburu, Jose Ramon Antunez-Lopez, Gema Moreno-Bueno, Jose Palacios, Alfonso Yubero, Raul Marquez, Alejandro Gallego, Ana Beatriz Sanchez-Heras, Jose Antonio Lopez-Guerrero, Cristina Perez-Segura, Pilar Barretina-Ginesta, Jesus Alarcon, Lydia Gaba, Antonia Marquez, Judit Matito, Juan Cueva, Isabel Palacio, Maria Iglesias, Angels Arcusa, Luisa Sanchez-Lorenzo, Eva Guerra-Alia, Ignacio Romero, Ana Vivancos, Institut Català de la Salut, [Garcia-Casado Z] Molecular Biology Department, Fundacion Instituto Valenciano de Oncologia, Valencia, Spain. [Oaknin A] Medical Oncology Department, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Mendiola M] Instituto de Investigacion Biomedica del Hospital La Paz (IdiPAZ), Madrid, Spain. Centro de Investigacion Biomedica en Red de Cáncer (CIBERONC) Instituto de Salud Carlos III, Madrid, Spain. [Alkorta-Aranburu G] CIMA LAB Diagnostics/Universidad de Navarra, Pamplona, Spain. [Antunez-Lopez JR] Molecular Biology Department, Hospital Clinico Universitario Santiago, Santiago, Spain. [Moreno-Bueno G] Centro de Investigacion Biomedica en Red de Cáncer (CIBERONC) Instituto de Salud Carlos III, Madrid, Spain. Fundacion MD Anderson, Madrid, Spain. Departamento de Bioquímica, Instituto de Investigaciones Biomedicas ‘Alberto Sols. Conexion Cancer (UAM-CSIC), Universidad Autonoma de Madrid (UAM), IdiPAZ, Madrid, Spain, Vall d'Hebron Barcelona Hospital Campus, AstraZeneca, [Garcia-Casado, Zaida] Fdn Inst Valenciano Oncol, Mol Biol Dept, Valencia 46009, Spain, [Antonio Lopez-Guerrero, Jose] Fdn Inst Valenciano Oncol, Mol Biol Dept, Valencia 46009, Spain, [Oaknin, Ana] Vall dHebron Inst Oncol, Med Oncol Dept, Barcelona 08035, Spain, [Mendiola, Marta] Inst Invest Biomed Hosp La Paz IdiPAZ, Madrid 28029, Spain, [Mendiola, Marta] Inst Salud Carlos III, Ctr Invest Biomed Red Canc CIBERONC, Madrid 28029, Spain, [Moreno-Bueno, Gema] Inst Salud Carlos III, Ctr Invest Biomed Red Canc CIBERONC, Madrid 28029, Spain, [Palacios, Jose] Inst Salud Carlos III, Ctr Invest Biomed Red Canc CIBERONC, Madrid 28029, Spain, [Alkorta-Aranburu, Gorka] Univ Navarra, CIMA LAB Diagnost, Pamplona 31008, Spain, [Ramon Antunez-Lopez, Jose] Hosp Clin Univ Santiago, Mol Biol Dept, Santiago 15706, Spain, [Moreno-Bueno, Gema] Fdn MD Anderson, Madrid 28033, Spain, [Marquez, Raul] Fdn MD Anderson, Madrid 28033, Spain, [Moreno-Bueno, Gema] Univ Autonoma Madrid UAM, Inst Invest Biomed Alberto Sols Conex Canc UAM CS, Dept Bioquim, IdiPAZ, Madrid 28029, Spain, [Palacios, Jose] Hosp Univ Ramon Y Cajal, Pathol Dept, Madrid 28034, Spain, [Palacios, Jose] Alcala Univ, Fac Med, Madrid 28801, Spain, [Palacios, Jose] Inst Ramon Y Cajal Hlth Res IRYCIS, Madrid 28034, Spain, [Yubero, Alfonso] Hosp Clin Univ Lozano Blesa, Med Oncol Dept, Zaragoza 50009, Spain, [Gallego, Alejandro] Hosp Univ La Paz, Med Oncol Dept, Madrid 28029, Spain, [Beatriz Sanchez-Heras, Ana] Hosp Gen Univ Elche, Med Oncol Dept, Elche 03203, Spain, [Antonio Lopez-Guerrero, Jose] Univ Catolica Valencia, Valencia 46001, Spain, [Antonio Lopez-Guerrero, Jose] Unidad Mixta Invest Canc IVO CIPF, Valencia 46009, Spain, [Perez-Segura, Cristina] Hosp St Pau & Santa Tecla, Med Oncol Dept, Tarragona 43003, Spain, [Barretina-Ginesta, Pilar] Inst Catala dOncol Girona, Med Oncol Dept, Girona 17007, Spain, [Alarcon, Jesus] Hosp Univ Son Espases, Med Oncol Dept, Palma De Mallorca 07120, Spain, [Gaba, Lydia] Hosp Clin Barcelona, Med Oncol Dept, Barcelona 08036, Spain, [Marquez, Antonia] Reg & Virgen Victoria Univ Hosp, Med Oncol Interctr Unit, IBIMA, Malaga 29010, Spain, [Matito, Judit] Vall dHebron Inst Oncol VHIO, Canc Genom Lab, Barcelona 08035, Spain, [Vivancos, Ana] Vall dHebron Inst Oncol VHIO, Canc Genom Lab, Barcelona 08035, Spain, [Cueva, Juan] Hosp Clin Univ Santiago, Med Oncol Dept, Santiago 15706, Spain, [Palacio, Isabel] Hosp Univ Cent Asturias, Med Oncol Dept, Oviedo 33011, Spain, [Iglesias, Maria] Hosp Univ Son LLatzer, Med Oncol Dept, Palma De Mallorca 07198, Spain, [Arcusa, Angels] Hosp Terrassa, Med Oncol Dept, Terrassa 08227, Spain, [Sanchez-Lorenzo, Luisa] Clin Univ Navarra, Med Oncol Dept, Pamplona 31008, Spain, [Guerra-Alia, Eva] Hosp Univ Ramon Y Cajal, Med Oncol Dept, Madrid 28034, Spain, [Romero, Ignacio] Inst Valenciano Oncol, Med Oncol Dept, Valencia 46009, Spain, and Astra Zeneca Farmaceutica Spain SA
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Standards ,Germline ,Survival ,Medicine (miscellaneous) ,Ovaris - Càncer - Aspectes genètics ,Guidelines ,neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas [ENFERMEDADES] ,Sequence variants ,Association ,Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Genetic Testing [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Somatic mutations ,Ovarian cancer ,Other subheadings::Other subheadings::/genetics [Other subheadings] ,Chemotherapy ,Joint-consensus-recommendation ,Ring Test Trial ,Otros calificadores::Otros calificadores::/genética [Otros calificadores] ,Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms [DISEASES] ,Cromosomes humans - Anomalies - Diagnòstic ,diagnóstico::técnicas y procedimientos diagnósticos::técnicas de laboratorio clínico::pruebas genéticas [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,College ,BRCA mutations ,BRCA testing ,ovarian cancer ,NGS - Abstract
Germline and tumor BRCA testing constitutes a valuable tool for clinical decision-making in the management of epithelial ovarian cancer (EOC) patients. Tissue testing is able to identify both germline (g) and somatic (s) BRCA variants, but tissue preservation methods and the widespread implementation of NGS represent pre-analytical and analytical challenges that need to be managed. This study was carried out on a multicenter prospective GEICO cohort of EOC patients with known gBRCA status in order to determine the inter-laboratory reproducibility of tissue sBRCA testing. The study consisted of two independent experimental approaches, a bilateral comparison between two reference laboratories (RLs) testing 82 formalin-paraffin-embedded (FFPE) EOC samples each, and a Ring Test Trial (RTT) with five participating clinical laboratories (CLs) evaluating the performance of tissue BRCA testing in a total of nine samples. Importantly, labs employed their own locally adopted next-generation sequencing (NGS) analytical approach. BRCA mutation frequency in the RL sub-study cohort was 23.17%: 12 (63.1%) germline and 6 (31.6%) somatic. Concordance between the two RLs with respect to BRCA status was 84.2% (gBRCA 100%). The RTT study distributed a total of nine samples (three commercial synthetic human FFPE references, three FFPE, and three OC DNA) among five CLs. The median concordance detection rate among them was 64.7% (range: 35.3–70.6%). Analytical discrepancies were mainly due to the minimum variant allele frequency thresholds, bioinformatic pipeline filters, and downstream variant interpretation, some of them with consequences of clinical relevance. Our study demonstrates a wide range of concordance in the identification and interpretation of BRCA sequencing data, highlighting the relevance of establishing standard criteria for detecting, interpreting, and reporting BRCA variants., This research was funded by Astra Zéneca Farmacéutica Spain SA (Grant Number GEICO60-0).
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- 2022
16. Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma.
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Labiano I, Huerta AE, Alsina M, Arasanz H, Castro N, Mendaza S, Lecumberri A, Gonzalez-Borja I, Guerrero-Setas D, Patiño-Garcia A, Alkorta-Aranburu G, Hernández-Garcia I, Arrazubi V, Mata E, Gomez D, Viudez A, and Vera R
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- Humans, Male, Female, Aged, Middle Aged, Prognosis, Biomarkers, Tumor genetics, Biomarkers, Tumor blood, High-Throughput Nucleotide Sequencing methods, Gene Frequency, Proto-Oncogene Proteins p21(ras) genetics, Aged, 80 and over, Tumor Suppressor Protein p53 genetics, Mutation, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal blood, Circulating Tumor DNA genetics, Circulating Tumor DNA blood, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms blood
- Abstract
Pancreatic ductal adenocarcinoma represents one of the solid tumors showing the worst prognosis worldwide, with a high recurrence rate after adjuvant or neoadjuvant therapy. Circulating tumor DNA analysis raised as a promising non-invasive tool to characterize tumor genomics and to assess treatment response. In this study, surgical tumor tissue and sequential blood samples were analyzed by next-generation sequencing and were correlated with clinical and pathological characteristics. Thirty resectable/borderline pancreatic ductal adenocarcinoma patients treated at the Hospital Universitario de Navarra were included. Circulating tumoral DNA sequencing identified pathogenic variants in KRAS and TP53, and in other cancer-associated genes. Pathogenic variants at diagnosis were detected in patients with a poorer outcome, and were correlated with response to neoadjuvant therapy in borderline pancreatic ductal adneocarcinoma patients. Higher variant allele frequency at diagnosis was associated with worse prognosis, and thesum of variant allele frequency was greater in samples at progression. Our results build on the potential value of circulating tumor DNA for non-metastatic pancreatic ductal adenocarcinoma patients, by complementing tissue genetic information and as a non-invasive tool for treatment decision. Confirmatory studies are needed to corroborate these findings., (© 2024. The Author(s).)
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- 2024
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17. Gut microbiota produces biofilm-associated amyloids with potential for neurodegeneration.
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Fernández-Calvet A, Matilla-Cuenca L, Izco M, Navarro S, Serrano M, Ventura S, Blesa J, Herráiz M, Alkorta-Aranburu G, Galera S, Ruiz de Los Mozos I, Mansego ML, Toledo-Arana A, Alvarez-Erviti L, and Valle J
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- Animals, Humans, Mice, Autophagy, Neurodegenerative Diseases metabolism, Mice, Inbred C57BL, Bacterial Proteins metabolism, Bacterial Proteins genetics, Brain metabolism, Brain pathology, Synucleinopathies metabolism, Synucleinopathies pathology, Gastrointestinal Microbiome, Caenorhabditis elegans metabolism, Caenorhabditis elegans microbiology, Biofilms growth & development, Amyloid metabolism, alpha-Synuclein metabolism, alpha-Synuclein genetics, Parkinson Disease metabolism, Parkinson Disease microbiology, Parkinson Disease pathology, Dopaminergic Neurons metabolism
- Abstract
Age-related neurodegenerative diseases involving amyloid aggregation remain one of the biggest challenges of modern medicine. Alterations in the gastrointestinal microbiome play an active role in the aetiology of neurological disorders. Here, we dissect the amyloidogenic properties of biofilm-associated proteins (BAPs) of the gut microbiota and their implications for synucleinopathies. We demonstrate that BAPs are naturally assembled as amyloid-like fibrils in insoluble fractions isolated from the human gut microbiota. We show that BAP genes are part of the accessory genomes, revealing microbiome variability. Remarkably, the abundance of certain BAP genes in the gut microbiome is correlated with Parkinson's disease (PD) incidence. Using cultured dopaminergic neurons and Caenorhabditis elegans models, we report that BAP-derived amyloids induce α-synuclein aggregation. Our results show that the chaperone-mediated autophagy is compromised by BAP amyloids. Indeed, inoculation of BAP fibrils into the brains of wild-type mice promote key pathological features of PD. Therefore, our findings establish the use of BAP amyloids as potential targets and biomarkers of α-synucleinopathies., (© 2024. The Author(s).)
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- 2024
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18. Whole exome sequencing and machine learning germline analysis of individuals presenting with extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma.
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Patiño-García A, Guruceaga E, Andueza MP, Ocón M, Fodop Sokoudjou JJ, de Villalonga Zornoza N, Alkorta-Aranburu G, Uria IT, Gurpide A, Camps C, Jantus-Lewintre E, Navamuel-Andueza M, Sanmamed MF, Melero I, Elgendy M, Fusco JP, Zulueta JJ, de-Torres JP, Bastarrika G, Seijo L, Pio R, Montuenga LM, Hernáez M, Ochoa I, and Perez-Gracia JL
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- Humans, Middle Aged, Aged, Exome Sequencing, Genetic Predisposition to Disease, Phenotype, Germ Cells pathology, Adenocarcinoma of Lung genetics, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
Background: Tobacco is the main risk factor for developing lung cancer. Yet, while some heavy smokers develop lung cancer at a young age, other heavy smokers never develop it, even at an advanced age, suggesting a remarkable variability in the individual susceptibility to the carcinogenic effects of tobacco. We characterized the germline profile of subjects presenting these extreme phenotypes with Whole Exome Sequencing (WES) and Machine Learning (ML)., Methods: We sequenced germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age (extreme cases) or who did not develop lung cancer at an advanced age (extreme controls), selected from databases including over 6600 subjects. We selected individual coding genetic variants and variant-rich genes showing a significantly different distribution between extreme cases and controls. We validated the results from our discovery cohort, in which we analysed by WES extreme cases and controls presenting similar phenotypes. We developed ML models using both cohorts., Findings: Mean age for extreme cases and controls was 50.7 and 79.1 years respectively, and mean tobacco consumption was 34.6 and 62.3 pack-years. We validated 16 individual variants and 33 variant-rich genes. The gene harbouring the most validated variants was HLA-A in extreme controls (4 variants in the discovery cohort, p = 3.46E-07; and 4 in the validation cohort, p = 1.67E-06). We trained ML models using as input the 16 individual variants in the discovery cohort and tested them on the validation cohort, obtaining an accuracy of 76.5% and an AUC-ROC of 83.6%. Functions of validated genes included candidate oncogenes, tumour-suppressors, DNA repair, HLA-mediated antigen presentation and regulation of proliferation, apoptosis, inflammation and immune response., Interpretation: Individuals presenting extreme phenotypes of high and low risk of developing tobacco-associated lung adenocarcinoma show different germline profiles. Our strategy may allow the identification of high-risk subjects and the development of new therapeutic approaches., Funding: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript., Competing Interests: Declaration of interests MFS reports grants from Bristol Myers Squibb and Roche, as well as honoraria from lectures and advisory from MSD, BMS and Numab; and travel support from Roche, Astra-Zeneca and BMS. IM reports receiving commercial research grants from AstraZeneca, BMS, Highlight Therapeutics, Alligator, Pfizer Genmab and Roche; has received speakers bureau honoraria from MSD; and is a consultant or advisory board member for BMS, Roche, AstraZeneca, Genmab, Pharmamar, F-Star, Bioncotech, Bayer, Numab, Pieris, Gossamer, Alligator and Merck Serono. JJZ declares consultancy and advisory Board from American Heart Technologies and Median Technologies. GB declares honoraria from lectures and advisory from General Electric, Siemens Healthineers; educational activities for General Electric, Siemens Healthineers, Bayer; and institutional research grants from Siemens Healthineers, Guerbet. LMS reports a role as scientific advisor for Sabartech, Serum, Astra Zeneca, Roche, MSD, and Median technologies, and has received honoraria as a speaker from Astra Zeneca, GSK, Roche, Menarini, and Chiesi. LMM declares research grants from Astra-Zeneca, BMS, Serum Detect Inc. and Pharmamar; speaker fee from Astra Zeneca; participation in advisory boards from Serum Detect Inc; and has a Licenced patent co-holder from AMADIX. JLPG declares research grants and support from Astellas, Amgen, BMS, MSD, Novartis, Roche, Seattle Genetics; participates in advisory boards for Astellas, BMS, Ipsen, MSD, Roche, Seattle Genetics; and travel support from BMS, MSD, Roche., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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19. Primary trimethylaminuria syndrome: more than an unpleasant odor.
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Antoñanzas J, Querol-Cisneros E, Alkorta-Aranburu G, Patiño-García A, and España A
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- Humans, Syndrome, Methylamines, Odorants, Metabolism, Inborn Errors
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- 2023
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20. Laboratory Cross-Comparison and Ring Test Trial for Tumor BRCA Testing in a Multicenter Epithelial Ovarian Cancer Series: The BORNEO GEICO 60-0 Study.
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Garcia-Casado Z, Oaknin A, Mendiola M, Alkorta-Aranburu G, Antunez-Lopez JR, Moreno-Bueno G, Palacios J, Yubero A, Marquez R, Gallego A, Sanchez-Heras AB, Lopez-Guerrero JA, Perez-Segura C, Barretina-Ginesta P, Alarcon J, Gaba L, Marquez A, Matito J, Cueva J, Palacio I, Iglesias M, Arcusa A, Sanchez-Lorenzo L, Guerra-Alia E, Romero I, and Vivancos A
- Abstract
Germline and tumor BRCA testing constitutes a valuable tool for clinical decision-making in the management of epithelial ovarian cancer (EOC) patients. Tissue testing is able to identify both germline (g) and somatic (s) BRCA variants, but tissue preservation methods and the widespread implementation of NGS represent pre-analytical and analytical challenges that need to be managed. This study was carried out on a multicenter prospective GEICO cohort of EOC patients with known gBRCA status in order to determine the inter-laboratory reproducibility of tissue sBRCA testing. The study consisted of two independent experimental approaches, a bilateral comparison between two reference laboratories (RLs) testing 82 formalin-paraffin-embedded (FFPE) EOC samples each, and a Ring Test Trial (RTT) with five participating clinical laboratories (CLs) evaluating the performance of tissue BRCA testing in a total of nine samples. Importantly, labs employed their own locally adopted next-generation sequencing (NGS) analytical approach. BRCA mutation frequency in the RL sub-study cohort was 23.17%: 12 (63.1%) germline and 6 (31.6%) somatic. Concordance between the two RLs with respect to BRCA status was 84.2% (g BRCA 100%). The RTT study distributed a total of nine samples (three commercial synthetic human FFPE references, three FFPE, and three OC DNA) among five CLs. The median concordance detection rate among them was 64.7% (range: 35.3-70.6%). Analytical discrepancies were mainly due to the minimum variant allele frequency thresholds, bioinformatic pipeline filters, and downstream variant interpretation, some of them with consequences of clinical relevance. Our study demonstrates a wide range of concordance in the identification and interpretation of BRCA sequencing data, highlighting the relevance of establishing standard criteria for detecting, interpreting, and reporting BRCA variants.
- Published
- 2022
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21. NGS-Based Molecular Karyotyping of Multiple Myeloma: Results from the GEM12 Clinical Trial.
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Rosa-Rosa JM, Cuenca I, Medina A, Vázquez I, Sánchez-delaCruz A, Buenache N, Sánchez R, Jiménez C, Rosiñol L, Gutiérrez NC, Ruiz-Heredia Y, Barrio S, Oriol A, Martin-Ramos ML, Blanchard MJ, Ayala R, Ríos-Tamayo R, Sureda A, Hernández MT, de la Rubia J, Alkorta-Aranburu G, Agirre X, Bladé J, Mateos MV, Lahuerta JJ, San-Miguel JF, Calasanz MJ, Garcia-Sanz R, and Martínez-Lopez J
- Abstract
Next-generation sequencing (NGS) has greatly improved our ability to detect the genomic aberrations occurring in multiple myeloma (MM); however, its transfer to routine clinical labs and its validation in clinical trials remains to be established. We designed a capture-based NGS targeted panel to identify, in a single assay, known genetic alterations for the prognostic stratification of MM. The NGS panel was designed for the simultaneous study of single nucleotide and copy number variations, insertions and deletions, chromosomal translocations and V(D)J rearrangements. The panel was validated using a cohort of 149 MM patients enrolled in the GEM2012MENOS65 clinical trial. The results showed great global accuracy, with positive and negative predictive values close to 90% when compared with available data from fluorescence in situ hybridization and whole-exome sequencing. While the treatments used in the clinical trial showed high efficacy, patients defined as high-risk by the panel had shorter progression-free survival ( p = 0.0015). As expected, the mutational status of TP53 was significant in predicting patient outcomes ( p = 0.021). The NGS panel also efficiently detected clonal IGH rearrangements in 81% of patients. In conclusion, molecular karyotyping using a targeted NGS panel can identify relevant prognostic chromosomal abnormalities and translocations for the clinical management of MM patients.
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- 2022
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22. Familial primary cutaneous amyloidosis: Caspase activation may be involved in amyloid formation.
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Antoñanzas J, Pelacho-Samper B, Alkorta-Aranburu G, Echeveste JI, and Alonso AE
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- Amyloid physiology, Caspases, Humans, Skin Diseases, Genetic, Amyloidosis, Amyloidosis, Familial genetics
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- 2022
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23. Oncolytic DNX-2401 Virus for Pediatric Diffuse Intrinsic Pontine Glioma.
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Gállego Pérez-Larraya J, Garcia-Moure M, Labiano S, Patiño-García A, Dobbs J, Gonzalez-Huarriz M, Zalacain M, Marrodan L, Martinez-Velez N, Puigdelloses M, Laspidea V, Astigarraga I, Lopez-Ibor B, Cruz O, Oscoz Lizarbe M, Hervas-Stubbs S, Alkorta-Aranburu G, Tamayo I, Tavira B, Hernandez-Alcoceba R, Jones C, Dharmadhikari G, Ruiz-Moreno C, Stunnenberg H, Hulleman E, van der Lugt J, Idoate MÁ, Diez-Valle R, Esparragosa Vázquez I, Villalba M, de Andrea C, Núñez-Córdoba JM, Ewald B, Robbins J, Fueyo J, Gomez-Manzano C, Lang FF, Tejada S, and Alonso MM
- Subjects
- Adenoviridae, Adolescent, Astrocytoma radiotherapy, Astrocytoma therapy, Child, Child, Preschool, Glioma radiotherapy, Glioma therapy, Humans, Infusions, Intralesional, Quality of Life, Tumor Microenvironment, Brain Stem Neoplasms mortality, Brain Stem Neoplasms pathology, Brain Stem Neoplasms radiotherapy, Brain Stem Neoplasms therapy, Diffuse Intrinsic Pontine Glioma mortality, Diffuse Intrinsic Pontine Glioma radiotherapy, Diffuse Intrinsic Pontine Glioma therapy, Oncolytic Virotherapy adverse effects, Oncolytic Virotherapy methods, Oncolytic Viruses
- Abstract
Background: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking., Methods: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses., Results: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×10
10 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire., Conclusions: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.)., (Copyright © 2022 Massachusetts Medical Society.)- Published
- 2022
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24. Next-generation sequencing of bile cell-free DNA for the early detection of patients with malignant biliary strictures.
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Arechederra M, Rullán M, Amat I, Oyon D, Zabalza L, Elizalde M, Latasa MU, Mercado MR, Ruiz-Clavijo D, Saldaña C, Fernández-Urién I, Carrascosa J, Jusué V, Guerrero-Setas D, Zazpe C, González-Borja I, Sangro B, Herranz JM, Purroy A, Gil I, Nelson LJ, Vila JJ, Krawczyk M, Zieniewicz K, Patkowski W, Milkiewicz P, Cubero FJ, Alkorta-Aranburu G, G Fernandez-Barrena M, Urman JM, Berasain C, and Avila MA
- Subjects
- Bile, Cholangiopancreatography, Endoscopic Retrograde, Constriction, Pathologic diagnosis, Early Detection of Cancer, High-Throughput Nucleotide Sequencing, Humans, Prospective Studies, Sensitivity and Specificity, Bile Duct Neoplasms diagnosis, Bile Duct Neoplasms genetics, Bile Duct Neoplasms pathology, Cell-Free Nucleic Acids, Cholestasis etiology, Cholestasis genetics
- Abstract
Objective: Despite significant progresses in imaging and pathological evaluation, early differentiation between benign and malignant biliary strictures remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP) is used to investigate biliary strictures, enabling the collection of bile. We tested the diagnostic potential of next-generation sequencing (NGS) mutational analysis of bile cell-free DNA (cfDNA)., Design: A prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay., Results: An initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut., Conclusion: Implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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25. Machine Learning-Based Approach Highlights the Use of a Genomic Variant Profile for Precision Medicine in Ovarian Failure.
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Henarejos-Castillo I, Aleman A, Martinez-Montoro B, Gracia-Aznárez FJ, Sebastian-Leon P, Romeu M, Remohi J, Patiño-Garcia A, Royo P, Alkorta-Aranburu G, and Diaz-Gimeno P
- Abstract
Ovarian failure (OF) is a common cause of infertility usually diagnosed as idiopathic, with genetic causes accounting for 10-25% of cases. Whole-exome sequencing (WES) may enable identifying contributing genes and variant profiles to stratify the population into subtypes of OF. This study sought to identify a blood-based gene variant profile using accumulation of rare variants to promote precision medicine in fertility preservation programs. A case-control ( n = 118, n = 32, respectively) WES study was performed in which only non-synonymous rare variants <5% minor allele frequency (MAF; in the IGSR) and coverage ≥ 100× were considered. A profile of 66 variants of uncertain significance was used for training an unsupervised machine learning model to separate cases from controls (97.2% sensitivity, 99.2% specificity) and stratify the population into two subtypes of OF (A and B) (93.31% sensitivity, 96.67% specificity). Model testing within the IGSR female population predicted 0.5% of women as subtype A and 2.4% as subtype B. This is the first study linking OF to the accumulation of rare variants and generates a new potential taxonomy supporting application of this approach for precision medicine in fertility preservation.
- Published
- 2021
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26. Performance comparison of two next-generation sequencing panels to detect actionable mutations in cell-free DNA in cancer patients.
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Macías M, Cañada-Higueras E, Alegre E, Bielsa A, Gracia J, Patiño-García A, Ferrer-Costa R, Sendino T, Andueza MP, Mateos B, Rodríguez J, Corral J, Gúrpide A, Lopez-Picazo JM, Perez-Gracia JL, Gil-Bazo I, Alkorta-Aranburu G, and González Á
- Subjects
- Humans, Cell-Free Nucleic Acids genetics, High-Throughput Nucleotide Sequencing methods, Mutation, Neoplasms genetics
- Abstract
Background Genomic alterations studies in cell-free DNA (cfDNA) have increasing clinical use in oncology. Next-generation sequencing (NGS) technology provides the most complete mutational analysis, but nowadays limited data are available related to the comparison of results reported by different platforms. Here we compare two NGS panels for cfDNA: Oncomine™ Pan-Cancer Cell-Free Assay (Thermo Fisher Scientific), suitable for clinical laboratories, and Guardant360® (GuardantHealth), with more genes targeted but only available in an outsourcing laboratory. Methods Peripheral blood was obtained from 16 advanced cancer patients in which Guardant360® (G360) was requested as part of their clinical assistance. Blood samples were sent to be analyzed with G360 panel, and an additional blood sample was drawn to obtain and analyze cfDNA with Oncomine™ Pan-Cancer (OM) panel in an Ion GeneStudio S5™ System. Results cfDNA analysis globally rendered 101 mutations. Regarding the 55/101 mutations claimed to be included by manufacturers in both panels, 17 mutations were reported only by G360, 10 only by OM and 28 by both. In those coincident cases, there was a high correlation between the variant allele fractions (VAFs) calculated with each panel (r = 0.979, p < 0.01). Regarding the six actionable mutations with an FDA-approved therapy reported by G360, one was missed with OM. Also, 12 mutations with clinical trials available were reported by G360 but not by OM. Conclusions In summary, G360 and OM can produce different mutational profile in the same sample, even in genes included in both panels, which is especially important if these mutations are potentially druggable.
- Published
- 2020
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27. The Dynamic Use of EGFR Mutation Analysis in Cell-Free DNA as a Follow-Up Biomarker during Different Treatment Lines in Non-Small-Cell Lung Cancer Patients.
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Macías M, Alegre E, Alkorta-Aranburu G, Patiño-García A, Mateos B, Andueza MP, Gúrpide A, Lopez-Picazo JM, Gil-Bazo I, Perez-Gracia JL, and González Á
- Subjects
- Aged, Antineoplastic Agents therapeutic use, Biomarkers, Tumor blood, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung drug therapy, Cell-Free Nucleic Acids blood, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Female, Humans, Lung Neoplasms blood, Lung Neoplasms drug therapy, Male, Middle Aged, Protein Kinase Inhibitors therapeutic use, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung genetics, Cell-Free Nucleic Acids genetics, Lung Neoplasms genetics, Mutation
- Abstract
Epidermal growth factor receptor ( EGFR ) mutational testing in advanced non-small-cell lung cancer (NSCLC) is usually performed in tumor tissue, although cfDNA (cell-free DNA) could be an alternative. We evaluated EGFR mutations in cfDNA as a complementary tool in patients, who had already known EGFR mutations in tumor tissue and were treated with either EGFR-tyrosine kinase inhibitors (TKIs) or chemotherapy. We obtained plasma samples from 21 advanced NSCLC patients with known EGFR tumor mutations, before and during therapy with EGFR-TKIs and/or chemotherapy. cfDNA was isolated and EGFR mutations were analyzed with the multiple targeted cobas EGFR Mutation Test v2. EGFR mutations were detected at baseline in cfDNA from 57% of patients. The semiquantitative index (SQI) significantly decreased from the baseline (median = 11, IQR = 9.5-13) to the best response (median = 0, IQR = 0-0, p < 0.01), followed by a significant increase at progression (median = 11, IQR = 11-15, p < 0.01) in patients treated with either EGFR-TKIs or chemotherapy. The SQI obtained with the cobas EGFR Mutation Test v2 did not correlate with the concentration in copies/mL determined by droplet digital PCR. Resistance mutation p.T790M was observed at progression in patients with either type of treatment. In conclusion, cfDNA multiple targeted EGFR mutation analysis is useful for treatment monitoring in tissue of EGFR -positive NSCLC patients independently of the drug received.
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- 2019
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28. Reprogramming human T cell function and specificity with non-viral genome targeting.
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Roth TL, Puig-Saus C, Yu R, Shifrut E, Carnevale J, Li PJ, Hiatt J, Saco J, Krystofinski P, Li H, Tobin V, Nguyen DN, Lee MR, Putnam AL, Ferris AL, Chen JW, Schickel JN, Pellerin L, Carmody D, Alkorta-Aranburu G, Del Gaudio D, Matsumoto H, Morell M, Mao Y, Cho M, Quadros RM, Gurumurthy CB, Smith B, Haugwitz M, Hughes SH, Weissman JS, Schumann K, Esensten JH, May AP, Ashworth A, Kupfer GM, Greeley SAW, Bacchetta R, Meffre E, Roncarolo MG, Romberg N, Herold KC, Ribas A, Leonetti MD, and Marson A
- Subjects
- Animals, Autoimmunity genetics, CRISPR-Cas Systems genetics, Cells, Cultured, Humans, Interleukin-2 Receptor alpha Subunit genetics, Male, Mice, Neoplasm Transplantation, Protein Engineering, Receptors, Antigen, T-Cell genetics, T-Lymphocytes cytology, Cellular Reprogramming genetics, Gene Editing, Genome, Human genetics, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
Decades of work have aimed to genetically reprogram T cells for therapeutic purposes
1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4 . The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6 . Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.- Published
- 2018
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29. Does arterial hypertension influence the onset of Huntington's disease?
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Valcárcel-Ocete L, Fullaondo A, Alkorta-Aranburu G, García-Barcina M, Roos RAC, Hjermind LE, Saft C, Frontali M, Reilmann R, Rickards H, Zubiaga AM, and Aguirre A
- Subjects
- Age of Onset, Alleles, Female, Humans, Huntington Disease epidemiology, Huntington Disease genetics, Male, Middle Aged, Huntington Disease complications, Hypertension complications
- Abstract
Huntington's disease (HD) age of onset (AO) is mainly determined by the length of the CAG repeat expansion in the huntingtin gene. The remaining AO variability has been attributed to other little-known factors. A factor that has been associated with other neurodegenerative diseases is arterial hypertension (AHT). The aim of this study is to evaluate the contribution of AHT to the AO of HD. We used data from a cohort of 630 European HD patients with adult onset collected by the REGISTRY project of the European Huntington's Disease Network. Multiple linear regression and ANOVA, controlling for the CAG repeat number of the expanded allele (CAGexp) of each patient, were performed to assess the association between the AHT condition and the AO of the motor symptoms (mAO). The results showed a significant association between AHT and mAO, especially when we only considered the patients diagnosed with AHT prior to manifesting any HD signs (pre-HD AHT). Remarkably, despite the low number of cases, those patients developed motor symptoms 5-8 years later than normotensive patients in the most frequent CAGexp range (40-44). AHT is an age-related condition and consequently, the age of the patient at the time of data collection could be a confounder variable. However, given that most pre-HD AHT patients included in our study had started treatment with antihypertensive drugs prior to the onset of HD, and that antihypertensive drugs have been suggested to confer a neuroprotective effect in other neurodegenerative diseases, raises the interest in elucidating the impact of AHT and/or AHT treatment in HD age of onset in further studies. A confirmation of our results in a larger sample set would open the possibility to significantly improve HD management., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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30. Pancreatic Histopathology of Human Monogenic Diabetes Due to Causal Variants in KCNJ11, HNF1A, GATA6, and LMNA.
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Sanyoura M, Jacobsen L, Carmody D, Del Gaudio D, Alkorta-Aranburu G, Arndt K, Hu Y, Kobiernicki F, Kusmartseva I, Atkinson MA, Philipson LH, Schatz D, Campbell-Thompson M, and Greeley SAW
- Subjects
- Adolescent, Adult, Child, Diabetes Mellitus genetics, Female, Genetic Testing, Humans, Male, Pancreas metabolism, Prognosis, Retrospective Studies, Diabetes Mellitus pathology, GATA6 Transcription Factor genetics, Genetic Variation, Hepatocyte Nuclear Factor 1-alpha genetics, Lamin Type A genetics, Pancreas pathology, Potassium Channels, Inwardly Rectifying genetics
- Abstract
Context: Monogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes., Objective: Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology., Methods: We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed., Results: Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant β cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates., Conclusions: Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes., (Copyright © 2017 Endocrine Society)
- Published
- 2018
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31. Rare form of autosomal dominant familial Cornelia de Lange syndrome due to a novel duplication in SMC3.
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Infante E, Alkorta-Aranburu G, and El-Gharbawy A
- Abstract
Clinical features are variable in patients with Cornelia de Lange syndrome (CdLS). Milder forms exist with structural maintenance of chromosomes 3 (SMC3) mutations. Inherited milder forms of CdLS are uncommon and may be missed if genetic testing is limited to Nipped-B-like protein (NIPBL) and SMC1A. Parental studies should be pursued if there is a history of learning disabilities and/or dysmorphic features.
- Published
- 2017
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32. Olfactory Dysfunction in Older Adults is Associated with Feelings of Depression and Loneliness.
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Sivam A, Wroblewski KE, Alkorta-Aranburu G, Barnes LL, Wilson RS, Bennett DA, and Pinto JM
- Subjects
- Aged, Aged, 80 and over, Cognition physiology, Demography, Female, Humans, Linear Models, Logistic Models, Longitudinal Studies, Male, Mental Health, Middle Aged, Odds Ratio, Risk Factors, Depression complications, Loneliness psychology, Olfaction Disorders complications, Olfaction Disorders pathology
- Abstract
Olfactory dysfunction is a common complaint among physician visits. Olfactory loss affects quality of life and impairs function and activities of daily living. The purpose of our study was to assess the degree of odor identification associated with mental health. Olfactory function was measured using the brief smell identification test. Depressive symptoms were measured by the Center for Epidemiologic Studies Depression scale. Loneliness was assessed by the de Jong-Gierveld Loneliness Scale. Cognition was measured by a battery of 19 cognitive tests. The frequency of olfactory dysfunction in our study was ~40%. Older subjects had worse olfactory performance, as previously found. More loneliness was associated with worse odor identification. Similarly, symptoms of depression were associated with worse olfaction (among men). Although better global cognitive function was strongly associated with better odor identification, after controlling for multiple factors, the associations with depression and loneliness were unchanged. Clinicians should assess these mental health conditions when treating older patients who present with olfactory deficits., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2016
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33. Improved molecular diagnosis of patients with neonatal diabetes using a combined next-generation sequencing and MS-MLPA approach.
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Alkorta-Aranburu G, Sukhanova M, Carmody D, Hoffman T, Wysinger L, Keller-Ramey J, Li Z, Johnson AK, Kobiernicki F, Botes S, Fitzpatrick C, Das S, and Del Gaudio D
- Subjects
- Case-Control Studies, Diabetes Mellitus genetics, Follow-Up Studies, Humans, Infant, Newborn, Infant, Newborn, Diseases genetics, Polymerase Chain Reaction, Prognosis, Prospective Studies, Retrospective Studies, Biomarkers metabolism, DNA Methylation, Diabetes Mellitus diagnosis, High-Throughput Nucleotide Sequencing methods, Infant, Newborn, Diseases diagnosis, Molecular Diagnostic Techniques methods, Multiplex Polymerase Chain Reaction methods
- Abstract
Background: We evaluated a methylation-specific multiplex-ligation-dependent probe amplification (MS-MLPA) assay for the molecular diagnosis of transient neonatal diabetes mellitus (TNDM) caused by 6q24 abnormalities and assessed the clinical utility of using this assay in combination with next generation sequencing (NGS) analysis for diagnosing patients with neonatal diabetes (NDM)., Methods: We performed MS-MLPA in 18 control samples and 42 retrospective NDM cases with normal bi-parental inheritance of chromosome 6. Next, we evaluated 22 prospective patients by combining NGS analysis of 11 NDM genes and the MS-MLPA assay., Results: 6q24 aberrations were identified in all controls and in 19% of patients with normal bi-parental inheritance of chromosome 6. The MS-MLPA/NGS combined approach identified a genetic cause in ~64% of patients with NDM of unknown etiology., Conclusions: MS-MLPA is a reliable method to identify all known 6q24 abnormalities and comprehensive testing of all causes reveals a causal mutation in ~64% of patients.
- Published
- 2016
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34. Estimating the Ages of Selection Signals from Different Epochs in Human History.
- Author
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Nakagome S, Alkorta-Aranburu G, Amato R, Howie B, Peter BM, Hudson RR, and Di Rienzo A
- Subjects
- Alleles, Bayes Theorem, Computational Biology methods, Computer Simulation, Evolution, Molecular, Gene Frequency, Genetic Variation, Humans, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Genetics, Population, Models, Genetic, Selection, Genetic
- Abstract
Genetic variation harbors signatures of natural selection driven by selective pressures that are often unknown. Estimating the ages of selection signals may allow reconstructing the history of environmental changes that shaped human phenotypes and diseases. We have developed an approximate Bayesian computation (ABC) approach to estimate allele ages under a model of selection on new mutations and under demographic models appropriate for human populations. We have applied it to two resequencing data sets: An ultra-high depth data set from a relatively small sample of unrelated individuals and a lower depth data set in a larger sample with transmission information. In addition to evaluating the accuracy of our method based on simulations, for each SNP, we assessed the consistency between the posterior probabilities estimated by the ABC approach and the ancient DNA record, finding good agreement between the two types of data and methods. Applying this ABC approach to data for eight single nucleotide polymorphisms (SNPs), we were able to rule out an onset of selection prior to the dispersal out-of-Africa for three of them and more recent than the spread of agriculture for an additional three SNPs., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2016
- Full Text
- View/download PDF
35. Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults.
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Dong J, Yang J, Tranah G, Franceschini N, Parimi N, Alkorta-Aranburu G, Xu Z, Alonso A, Cummings SR, Fornage M, Huang X, Kritchevsky S, Liu Y, London S, Niu L, Wilson RS, De Jager PL, Yu L, Singleton AB, Harris T, Mosley TH Jr, Pinto JM, Bennett DA, and Chen H
- Subjects
- Adult, Aged, Female, Genome-Wide Association Study, Genotype, Humans, Longitudinal Studies, Male, Polymorphism, Single Nucleotide, Prospective Studies, United States, White People, Smell genetics
- Abstract
Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (Pmeta < 1 × 10). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P = 3.02 × 10; and rs2732614 in KIAA1267-LRRC37A, P = 6.65 × 10) exhibited cis effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P < 1 × 10). Gene-based and pathway-enrichment analyses further implicated MAPT in regulating the sense of smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases., Competing Interests: XH received research grants and consultation fees from NIEHS, NIH, and GE. Other authors declare no competing financial interests.
- Published
- 2015
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36. Exploring Genetic Factors Involved in Huntington Disease Age of Onset: E2F2 as a New Potential Modifier Gene.
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Valcárcel-Ocete L, Alkorta-Aranburu G, Iriondo M, Fullaondo A, García-Barcina M, Fernández-García JM, Lezcano-García E, Losada-Domingo JM, Ruiz-Ojeda J, Álvarez de Arcaya A, Pérez-Ramos JM, Roos RA, Nielsen JE, Saft C, Zubiaga AM, and Aguirre A
- Subjects
- Adult, Age of Onset, Aged, Alleles, Exons genetics, Female, Genotype, Humans, Male, Middle Aged, Trinucleotide Repeats genetics, Young Adult, Genes, Modifier genetics, Huntington Disease genetics, Polymorphism, Single Nucleotide genetics
- Abstract
Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim of this study is to explore the contribution of candidate genetic factors to HD AO in order to gain insight into the pathogenic mechanisms underlying this disorder. For that purpose, two AO definitions were used: the earliest age with unequivocal signs of HD (earliest AO or eAO), and the first motor symptoms age (motor AO or mAO). Multiple linear regression analyses were performed between genetic variation within 20 candidate genes and eAO or mAO, using DNA and clinical information of 253 HD patients from REGISTRY project. Gene expression analyses were carried out by RT-qPCR with an independent sample of 35 HD patients from Basque Country Hospitals. We found suggestive association signals between HD eAO and/or mAO and genetic variation within the E2F2, ATF7IP, GRIN2A, GRIN2B, LINC01559, HIP1 and GRIK2 genes. Among them, the most significant was the association between eAO and rs2742976, mapping to the promoter region of E2F2 transcription factor. Furthermore, rs2742976 T allele patient carriers exhibited significantly lower lymphocyte E2F2 gene expression, suggesting a possible implication of E2F2-dependent transcriptional activity in HD pathogenesis. Thus, E2F2 emerges as a new potential HD AO modifier factor.
- Published
- 2015
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37. PRIMAL: Fast and accurate pedigree-based imputation from sequence data in a founder population.
- Author
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Livne OE, Han L, Alkorta-Aranburu G, Wentworth-Sheilds W, Abney M, Ober C, and Nicolae DL
- Subjects
- Female, Genome, Human, Genomics, Humans, Male, Polymorphism, Single Nucleotide genetics, Sequence Analysis, DNA, South Dakota, White People genetics, Algorithms, Founder Effect, Models, Genetic, Pedigree, Software
- Abstract
Founder populations and large pedigrees offer many well-known advantages for genetic mapping studies, including cost-efficient study designs. Here, we describe PRIMAL (PedigRee IMputation ALgorithm), a fast and accurate pedigree-based phasing and imputation algorithm for founder populations. PRIMAL incorporates both existing and original ideas, such as a novel indexing strategy of Identity-By-Descent (IBD) segments based on clique graphs. We were able to impute the genomes of 1,317 South Dakota Hutterites, who had genome-wide genotypes for ~300,000 common single nucleotide variants (SNVs), from 98 whole genome sequences. Using a combination of pedigree-based and LD-based imputation, we were able to assign 87% of genotypes with >99% accuracy over the full range of allele frequencies. Using the IBD cliques we were also able to infer the parental origin of 83% of alleles, and genotypes of deceased recent ancestors for whom no genotype information was available. This imputed data set will enable us to better study the relative contribution of rare and common variants on human phenotypes, as well as parental origin effect of disease risk alleles in >1,000 individuals at minimal cost.
- Published
- 2015
- Full Text
- View/download PDF
38. Strong artificial selection in domestic mammals did not result in an increased recombination rate.
- Author
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Muñoz-Fuentes V, Marcet-Ortega M, Alkorta-Aranburu G, Linde Forsberg C, Morrell JM, Manzano-Piedras E, Söderberg A, Daniel K, Villalba A, Toth A, Di Rienzo A, Roig I, and Vilà C
- Subjects
- Animals, Canidae genetics, Dogs, Female, Genomics, Goats genetics, Male, Mammals, Sheep genetics, Spermatocytes metabolism, Genetic Variation genetics, Recombination, Genetic genetics
- Abstract
Recombination rates vary in intensity and location at the species, individual, sex and chromosome levels. Despite the fundamental biological importance of this process, the selective forces that operate to shape recombination rate and patterns are unclear. Domestication offers a unique opportunity to study the interplay between recombination and selection. In domesticates, intense selection for particular traits is imposed on small populations over many generations, resulting in organisms that differ, sometimes dramatically, in morphology and physiology from their wild ancestor. Although earlier studies suggested increased recombination rate in domesticates, a formal comparison of recombination rates between domestic mammals and their wild congeners was missing. In order to determine broad-scale recombination rate, we used immunolabeling detection of MLH1 foci as crossover markers in spermatocytes in three pairs of closely related wild and domestic species (dog and wolf, goat and ibex, and sheep and mouflon). In the three pairs, and contrary to previous suggestions, our data show that contemporary recombination rate is higher in the wild species. Subsequently, we inferred recombination breakpoints in sequence data for 16 genomic regions in dogs and wolves, each containing a locus associated with a dog phenotype potentially under selection during domestication. No difference in the number and distribution of recombination breakpoints was found between dogs and wolves. We conclude that our data indicate that strong directional selection did not result in changes in recombination in domestic mammals, and that both upper and lower bounds for crossover rates may be tightly regulated., (© The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
- Full Text
- View/download PDF
39. Admixture facilitates genetic adaptations to high altitude in Tibet.
- Author
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Jeong C, Alkorta-Aranburu G, Basnyat B, Neupane M, Witonsky DB, Pritchard JK, Beall CM, and Di Rienzo A
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Tibet, Young Adult, Adaptation, Biological, Altitude, Asian People genetics, Basic Helix-Loop-Helix Transcription Factors genetics, Gene Flow, Hypoxia-Inducible Factor-Proline Dioxygenases genetics
- Abstract
Admixture is recognized as a widespread feature of human populations, renewing interest in the possibility that genetic exchange can facilitate adaptations to new environments. Studies of Tibetans revealed candidates for high-altitude adaptations in the EGLN1 and EPAS1 genes, associated with lower haemoglobin concentration. However, the history of these variants or that of Tibetans remains poorly understood. Here we analyse genotype data for the Nepalese Sherpa, and find that Tibetans are a mixture of ancestral populations related to the Sherpa and Han Chinese. EGLN1 and EPAS1 genes show a striking enrichment of high-altitude ancestry in the Tibetan genome, indicating that migrants from low altitude acquired adaptive alleles from the highlanders. Accordingly, the Sherpa and Tibetans share adaptive haemoglobin traits. This admixture-mediated adaptation shares important features with adaptive introgression. Therefore, we identify a novel mechanism, beyond selection on new mutations or on standing variation, through which populations can adapt to local environments.
- Published
- 2014
- Full Text
- View/download PDF
40. Plasma hepcidin of Ethiopian highlanders with steady-state hypoxia.
- Author
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Lundgrin EL, Janocha AJ, Koch CD, Gebremedhin A, Di Rienzo A, Alkorta-Aranburu G, Brittenham GM, Erzurum SC, and Beall CM
- Subjects
- Adult, Enzyme-Linked Immunosorbent Assay, Erythropoietin metabolism, Ethiopia, Female, Ferritins blood, Hemoglobins metabolism, Hepcidins, Humans, Male, Oxyhemoglobins metabolism, Young Adult, Altitude, Antimicrobial Cationic Peptides blood, Hypoxia blood
- Published
- 2013
- Full Text
- View/download PDF
41. Reconstructing Native American population history.
- Author
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Reich D, Patterson N, Campbell D, Tandon A, Mazieres S, Ray N, Parra MV, Rojas W, Duque C, Mesa N, García LF, Triana O, Blair S, Maestre A, Dib JC, Bravi CM, Bailliet G, Corach D, Hünemeier T, Bortolini MC, Salzano FM, Petzl-Erler ML, Acuña-Alonzo V, Aguilar-Salinas C, Canizales-Quinteros S, Tusié-Luna T, Riba L, Rodríguez-Cruz M, Lopez-Alarcón M, Coral-Vazquez R, Canto-Cetina T, Silva-Zolezzi I, Fernandez-Lopez JC, Contreras AV, Jimenez-Sanchez G, Gómez-Vázquez MJ, Molina J, Carracedo A, Salas A, Gallo C, Poletti G, Witonsky DB, Alkorta-Aranburu G, Sukernik RI, Osipova L, Fedorova SA, Vasquez R, Villena M, Moreau C, Barrantes R, Pauls D, Excoffier L, Bedoya G, Rothhammer F, Dugoujon JM, Larrouy G, Klitz W, Labuda D, Kidd J, Kidd K, Di Rienzo A, Freimer NB, Price AL, and Ruiz-Linares A
- Subjects
- Americas, Asia, Cluster Analysis, Emigration and Immigration statistics & numerical data, Gene Flow, Genetics, Population, History, Ancient, Humans, Models, Genetic, Polymorphism, Single Nucleotide genetics, Siberia, Emigration and Immigration history, Indians, North American genetics, Indians, North American history, Phylogeny
- Abstract
The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.
- Published
- 2012
- Full Text
- View/download PDF
42. The genetic architecture of adaptations to high altitude in Ethiopia.
- Author
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Alkorta-Aranburu G, Beall CM, Witonsky DB, Gebremedhin A, Pritchard JK, and Di Rienzo A
- Subjects
- Acclimatization genetics, Altitude, Altitude Sickness genetics, CpG Islands genetics, DNA Methylation genetics, Ethiopia, Ethnicity genetics, Gene Frequency, Humans, Polymorphism, Single Nucleotide, Selection, Genetic, Adaptation, Physiological, Genome-Wide Association Study, Hemoglobins genetics, Hypoxia genetics, Hypoxia physiopathology
- Abstract
Although hypoxia is a major stress on physiological processes, several human populations have survived for millennia at high altitudes, suggesting that they have adapted to hypoxic conditions. This hypothesis was recently corroborated by studies of Tibetan highlanders, which showed that polymorphisms in candidate genes show signatures of natural selection as well as well-replicated association signals for variation in hemoglobin levels. We extended genomic analysis to two Ethiopian ethnic groups: Amhara and Oromo. For each ethnic group, we sampled low and high altitude residents, thus allowing genetic and phenotypic comparisons across altitudes and across ethnic groups. Genome-wide SNP genotype data were collected in these samples by using Illumina arrays. We find that variants associated with hemoglobin variation among Tibetans or other variants at the same loci do not influence the trait in Ethiopians. However, in the Amhara, SNP rs10803083 is associated with hemoglobin levels at genome-wide levels of significance. No significant genotype association was observed for oxygen saturation levels in either ethnic group. Approaches based on allele frequency divergence did not detect outliers in candidate hypoxia genes, but the most differentiated variants between high- and lowlanders have a clear role in pathogen defense. Interestingly, a significant excess of allele frequency divergence was consistently detected for genes involved in cell cycle control and DNA damage and repair, thus pointing to new pathways for high altitude adaptations. Finally, a comparison of CpG methylation levels between high- and lowlanders found several significant signals at individual genes in the Oromo., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2012
- Full Text
- View/download PDF
43. Adaptations to climate-mediated selective pressures in humans.
- Author
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Hancock AM, Witonsky DB, Alkorta-Aranburu G, Beall CM, Gebremedhin A, Sukernik R, Utermann G, Pritchard JK, Coop G, and Di Rienzo A
- Subjects
- Acclimatization, Gene Frequency, Humans, Temperature, Ultraviolet Rays, Climate, Genetics, Population, Genome, Human, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Selection, Genetic
- Abstract
Humans inhabit a remarkably diverse range of environments, and adaptation through natural selection has likely played a central role in the capacity to survive and thrive in extreme climates. Unlike numerous studies that used only population genetic data to search for evidence of selection, here we scan the human genome for selection signals by identifying the SNPs with the strongest correlations between allele frequencies and climate across 61 worldwide populations. We find a striking enrichment of genic and nonsynonymous SNPs relative to non-genic SNPs among those that are strongly correlated with these climate variables. Among the most extreme signals, several overlap with those from GWAS, including SNPs associated with pigmentation and autoimmune diseases. Further, we find an enrichment of strong signals in gene sets related to UV radiation, infection and immunity, and cancer. Our results imply that adaptations to climate shaped the spatial distribution of variation in humans., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2011
- Full Text
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44. Adaptations to new environments in humans: the role of subtle allele frequency shifts.
- Author
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Hancock AM, Alkorta-Aranburu G, Witonsky DB, and Di Rienzo A
- Subjects
- Climate, Energy Metabolism genetics, Gene Frequency, Haplotypes genetics, Humans, Pigmentation genetics, Polymorphism, Single Nucleotide genetics, Adaptation, Biological genetics, Environment, Evolution, Molecular, Genetic Variation, Phenotype, Selection, Genetic
- Abstract
Humans show tremendous phenotypic diversity across geographically distributed populations, and much of this diversity undoubtedly results from genetic adaptations to different environmental pressures. The availability of genome-wide genetic variation data from densely sampled populations offers unprecedented opportunities for identifying the loci responsible for these adaptations and for elucidating the genetic architecture of human adaptive traits. Several approaches have been used to detect signals of selection in human populations, and these approaches differ in the assumptions they make about the underlying mode of selection. We contrast the results of approaches based on haplotype structure and differentiation of allele frequencies to those from a method for identifying single nucleotide polymorphisms strongly correlated with environmental variables. Although the first group of approaches tends to detect new beneficial alleles that were driven to high frequencies by selection, the environmental correlation approach has power to identify alleles that experienced small shifts in frequency owing to selection. We suggest that the first group of approaches tends to identify only variants with relatively strong phenotypic effects, whereas the environmental correlation methods can detect variants that make smaller contributions to an adaptive trait.
- Published
- 2010
- Full Text
- View/download PDF
45. Colloquium paper: human adaptations to diet, subsistence, and ecoregion are due to subtle shifts in allele frequency.
- Author
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Hancock AM, Witonsky DB, Ehler E, Alkorta-Aranburu G, Beall C, Gebremedhin A, Sukernik R, Utermann G, Pritchard J, Coop G, and Di Rienzo A
- Subjects
- Animals, Biological Evolution, Ecology, Genetics, Population, Haplotypes, Homozygote, Humans, Models, Biological, Models, Genetic, Selection, Genetic, Adaptation, Physiological, Diet, Gene Frequency
- Abstract
Human populations use a variety of subsistence strategies to exploit an exceptionally broad range of ecoregions and dietary components. These aspects of human environments have changed dramatically during human evolution, giving rise to new selective pressures. To understand the genetic basis of human adaptations, we combine population genetics data with ecological information to detect variants that increased in frequency in response to new selective pressures. Our approach detects SNPs that show concordant differences in allele frequencies across populations with respect to specific aspects of the environment. Genic and especially nonsynonymous SNPs are overrepresented among those most strongly correlated with environmental variables. This provides genome-wide evidence for selection due to changes in ecoregion, diet, and subsistence. We find particularly strong signals associated with polar ecoregions, with foraging, and with a diet rich in roots and tubers. Interestingly, several of the strongest signals overlap with those implicated in energy metabolism phenotypes from genome-wide association studies, including SNPs influencing glucose levels and susceptibility to type 2 diabetes. Furthermore, several pathways, including those of starch and sucrose metabolism, are enriched for strong signals of adaptations to a diet rich in roots and tubers, whereas signals associated with polar ecoregions are overrepresented in genes associated with energy metabolism pathways.
- Published
- 2010
- Full Text
- View/download PDF
46. Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds.
- Author
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Gayán J, Brocklebank D, Andresen JM, Alkorta-Aranburu G, Zameel Cader M, Roberts SA, Cherny SS, Wexler NS, Cardon LR, and Housman DE
- Subjects
- Adult, Age of Onset, Chromosome Mapping, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 6, Genome, Human, Humans, Middle Aged, Pedigree, Venezuela epidemiology, Genetic Linkage, Huntington Disease genetics
- Abstract
The age of onset of Huntington's disease (HD) is inversely correlated with the CAG length in the HD gene. The CAG repeat length accounts for 70% of the variability in HD age of onset. However, 90% of individuals worldwide with expanded alleles possess between 40 and 50 CAG repeat lengths in their HD gene. For these people, the size of their repeat only determines 44% of the variability in their age of onset. Once the effect of the CAG repeat has been accounted for, the residual variance in age of onset is a heritable trait. Targeted candidate gene studies and a genome scan have suggested some loci as potential modifiers of the age of onset of HD. We analyzed the large Venezuelan kindreds in which the HD gene was originally identified. These kindreds offer greater analytic power than standard sib-pair designs. We developed novel pedigree-member selection procedures to maximize power. Using a 5,858-single-nucleotide-polymorphism marker panel, we performed a genomewide linkage analysis. We discovered two novel loci on chromosome 2. Chromosome 2p25 (logarithm of the odds ratio (LOD)=4.29) and 2q35 (LOD=3.39) may contain genes that modify age of onset. A third linkage peak on chromosome 6q22 (LOD=2.48) may confirm the most promising locus from a previous genome scan. Two other candidate loci are suggestive on chromosome 5 (LOD=3.31 at 5p14 and LOD=3.14 at 5q32). All these regions harbor candidate genes that are potential HD modifier genes. Finding these modifier genes can reveal accessible and promising new therapeutic pathways and targets to ameliorate and cure HD., ((c) 2008 Wiley-Liss, Inc.)
- Published
- 2008
- Full Text
- View/download PDF
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