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Identification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression

Statistical Genetics Research Group, Institute of Medical Biometry, Heidelberg University, 69120 Heidelberg, Germany
Department of Research, Cancer Registry of Norway, 0379 Oslo, Norway
Department of Informatics, University of Oslo, 0304 Oslo, Norway
Department of Basic and Clinical Oncology, Medical Faculty, University of Chile, Santiago 8380000, Chile
Research Unit Molecular Epidemiology and Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
Hospital Regional de Talca, Talca 3460000, Chile
Facultad de Medicina, Universidad Católica del Maule, Talca 3460000, Chile
Instituto Nacional del Cáncer, Santiago 7500650, Chile
Hospital de Puerto Montt, Puerto Montt 5480000, Chile
Escuela de Tecnología Médica, Universidad Austral de Chile sede Puerto Montt, Puerto Montt 5480000, Chile
Hospital Clínico Universidad de Chile, Santiago 8380456, Chile
Hospital del Salvador, Santiago 7500922, Chile
Hospital Padre Hurtado, Santiago 8880456, Chile
Hospital San Juan de Dios, Santiago, 8320000, Chile
Hospital Regional, Arica 1000000, Chile
Unidad Registro hospitalario de Cáncer, Hospital Base Valdivia, Valdivia 5090146, Chile
Hospital San Borja Arriarán, Santiago 8320000, Chile
Hospital Regional Guillermo Grant Benavente, Concepcion 4070386, Chile
Departamento de Hematología y Oncología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330077, Chile
Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago 7650568, Chile
Hospital de Temuco, Temuco 4780000, Chile
Hospital de Rancagua, Rancagua 2820000, Chile
Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain
Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca 3460000, Chile
Departamento de Tecnología Médica, Facultad de Ciencias de la Salud, Tarapacá University, Arica 1000815, Chile
Instituto Patagónico de Ciencias Sociales y Humanas, Centro Nacional Patagónico, CONICET, Puerto Madryn U9120ACD, Argentina
Instituto de Biociências, Universidad Federal do Rio Grande do Sul, Puerto Alegre 15053, Brazil
Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 15102, Peru
Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai 200434, China
ADES (Anthropologie Bio-Culturelle, Droit, Éthique et Santé), UFR de Médecine, Aix-Marseille University, 13007 Marseille, France
Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, London WC1E 6BT, UK
Instituto de Alta Investigación, Tarapacá University, Arica 1000000, Chile
Author to whom correspondence should be addressed.
Academic Editor: Lyndsay Rhodes
Cancers 2022, 14(3), 634;
Received: 19 November 2021 / Revised: 18 January 2022 / Accepted: 21 January 2022 / Published: 27 January 2022
(This article belongs to the Collection The Role of Non-coding RNA in Cancer)
Gallbladder cancer (GBC) is an aggressive disease with poor prognosis that urgently needs risk biomarkers for prevention. Long noncoding RNAs (lncRNAs) have been linked to various types of cancer and have good potential as circulating biomarkers. Prediction of lncRNA expression based on genotype data may contribute to quantify individual GBC risk even without direct lncRNA expression measurement. In this study, we investigate the relationship between GBC risk and genotype-based expression of circulating lncRNAs.
Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candidates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both lncRNA expression and genotype, and genotype information only to identify circulating lncRNAs associated with the risk of gallbladder cancer (GBC) using robust linear and logistic regression techniques. In the first dataset, we preselect lncRNAs based on expression changes along the sequence “gallstones → dysplasia → GBC”. In the second dataset, we validate associations between genetic variants and serum expression levels of the preselected lncRNAs (cis-lncRNA-eQTLs) and build lncRNA expression prediction models. In the third dataset, we predict serum lncRNA expression based on individual genotypes and assess the association between genotype-based expression and GBC risk. AC084082.3 and LINC00662 showed increasing expression levels (p-value = 0.009), while C22orf34 expression decreased in the sequence from gallstones to GBC (p-value = 0.04). We identified and validated two cis-LINC00662-eQTLs (r2 = 0.26) and three cis-C22orf34-eQTLs (r2 = 0.24). Only LINC00662 showed a genotyped-based serum expression associated with GBC risk (OR = 1.25 per log2 expression unit, 95% CI 1.04–1.52, p-value = 0.02). Our results suggest that preselection of lncRNAs based on tissue samples and exploitation of cis-lncRNA-eQTLs may facilitate the identification of circulating noncoding RNAs linked to cancer risk. View Full-Text
Keywords: gallbladder cancer; lncRNAs; eQTLs; genetic association study; molecular phenotypes gallbladder cancer; lncRNAs; eQTLs; genetic association study; molecular phenotypes
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MDPI and ACS Style

Blandino, A.; Scherer, D.; Rounge, T.B.; Umu, S.U.; Boekstegers, F.; Barahona Ponce, C.; Marcelain, K.; Gárate-Calderón, V.; Waldenberger, M.; Morales, E.; Rojas, A.; Munoz, C.; Retamales, J.; de Toro, G.; Barajas, O.; Rivera, M.T.; Cortés, A.; Loader, D.; Saavedra, J.; Gutiérrez, L.; Ortega, A.; Bertrán, M.E.; Gabler, F.; Campos, M.; Alvarado, J.; Moisán, F.; Spencer, L.; Nervi, B.; Carvajal-Hausdorf, D.E.; Losada, H.; Almau, M.; Fernández, P.; Gallegos, I.; Olloquequi, J.; Fuentes-Guajardo, M.; Gonzalez-Jose, R.; Bortolini, M.C.; Gallo, C.; Linares, A.R.; Rothhammer, F.; Lorenzo Bermejo, J. Identification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression. Cancers 2022, 14, 634.

AMA Style

Blandino A, Scherer D, Rounge TB, Umu SU, Boekstegers F, Barahona Ponce C, Marcelain K, Gárate-Calderón V, Waldenberger M, Morales E, Rojas A, Munoz C, Retamales J, de Toro G, Barajas O, Rivera MT, Cortés A, Loader D, Saavedra J, Gutiérrez L, Ortega A, Bertrán ME, Gabler F, Campos M, Alvarado J, Moisán F, Spencer L, Nervi B, Carvajal-Hausdorf DE, Losada H, Almau M, Fernández P, Gallegos I, Olloquequi J, Fuentes-Guajardo M, Gonzalez-Jose R, Bortolini MC, Gallo C, Linares AR, Rothhammer F, Lorenzo Bermejo J. Identification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression. Cancers. 2022; 14(3):634.

Chicago/Turabian Style

Blandino, Alice, Dominique Scherer, Trine B. Rounge, Sinan U. Umu, Felix Boekstegers, Carol Barahona Ponce, Katherine Marcelain, Valentina Gárate-Calderón, Melanie Waldenberger, Erik Morales, Armando Rojas, César Munoz, Javier Retamales, Gonzalo de Toro, Olga Barajas, María Teresa Rivera, Analía Cortés, Denisse Loader, Javiera Saavedra, Lorena Gutiérrez, Alejandro Ortega, Maria Enriqueta Bertrán, Fernando Gabler, Mónica Campos, Juan Alvarado, Fabrizio Moisán, Loreto Spencer, Bruno Nervi, Daniel E. Carvajal-Hausdorf, Héctor Losada, Mauricio Almau, Plinio Fernández, Ivan Gallegos, Jordi Olloquequi, Macarena Fuentes-Guajardo, Rolando Gonzalez-Jose, Maria Cátira Bortolini, Carla Gallo, Andres Ruiz Linares, Francisco Rothhammer, and Justo Lorenzo Bermejo. 2022. "Identification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression" Cancers 14, no. 3: 634.

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