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

Alice Blandino; 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; Justo Lorenzo Bermejo

doi:10.3390/cancers14030634

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

Alice Blandino
, 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, Justo Lorenzo Bermejo

Heidelberg University
Cancer Registry of Norway Institute of Population-Based Cancer Research
University of Oslo
Universidad de Chile
Helmholtz Zentrum München - German Research Center for Environmental Health
Unidad de Anatomía Patológica del Hospital Regional de Talca
Universidad Católica del Maule
Instituto Nacional Del Cáncer, Facultad de Salud y Odontología, Universidad Diego Portales
Hospital de Puerto Montt
Universidad Austral de Chile
Hospital del Salvador
Hospital Padre Hurtado
Hospital San Juan de Dios, Santiago de Chile
Hospital Regional
Hospital Base de Valdivia
Hospital San Borja Arriarán
Hospital Regional Guillermo Grant Benavente
Pontificia Universidad Católica de Chile
Universidad del Desarrollo
Hospital de Temuco
Hospital de Rancagua
University of Barcelona
Universidad Autónoma de Chile
Consejo Nacional de Investigaciones Científicas y Técnicas
Universidade Federal do Rio Grande do Sul
Universidad Peruana Cayetano Heredia
Fudan University
ADES
University College London

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candi-dates 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 lncR-NAs (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.

Original language	English
Article number	634
Journal	Cancers
Volume	14
Issue number	3
DOIs	https://doi.org/10.3390/cancers14030634
State	Published - 1 Feb 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

EQTLs
Genetic association study
LncRNAs
Molecular phenotypes
gallbladder cancer

Access to Document

10.3390/cancers14030634

Cite this

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., ... Bermejo, J. L. (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(3), Article 634. https://doi.org/10.3390/cancers14030634

@article{05348d8791e44e4da64751c52b784670,

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

abstract = "Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candi-dates 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 lncR-NAs (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.",

keywords = "EQTLs, Genetic association study, LncRNAs, Molecular phenotypes, gallbladder cancer",

author = "Alice Blandino and Dominique Scherer and Rounge, \{Trine B.\} and Umu, \{Sinan U.\} and Felix Boekstegers and \{Barahona Ponce\}, Carol and Katherine Marcelain and Valentina G{\'a}rate-Calder{\'o}n and Melanie Waldenberger and Erik Morales and Armando Rojas and C{\'e}sar Munoz and Javier Retamales and \{de Toro\}, Gonzalo and Olga Barajas and Rivera, \{Mar{\'i}a Teresa\} and Anal{\'i}a Cort{\'e}s and Denisse Loader and Javiera Saavedra and Lorena Guti{\'e}rrez and Alejandro Ortega and Bertr{\'a}n, \{Maria Enriqueta\} and Fernando Gabler and M{\'o}nica Campos and Juan Alvarado and Fabrizio Mois{\'a}n and Loreto Spencer and Bruno Nervi and Carvajal-Hausdorf, \{Daniel E.\} and H{\'e}ctor Losada and Mauricio Almau and Plinio Fern{\'a}ndez and Ivan Gallegos and Jordi Olloquequi and Macarena Fuentes-Guajardo and Rolando Gonzalez-Jose and Bortolini, \{Maria C{\'a}tira\} and Carla Gallo and \{Ruiz Linares\}, Andres and Francisco Rothhammer and Bermejo, \{Justo Lorenzo\}",

note = "Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = feb,

day = "1",

doi = "10.3390/cancers14030634",

language = "English",

volume = "14",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "3",

}

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, Ruiz Linares, A, Rothhammer, F & Bermejo, JL 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, vol. 14, no. 3, 634. https://doi.org/10.3390/cancers14030634

TY - JOUR

T1 - Identification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression

AU - Blandino, Alice

AU - Scherer, Dominique

AU - Rounge, Trine B.

AU - Umu, Sinan U.

AU - Boekstegers, Felix

AU - Barahona Ponce, Carol

AU - Marcelain, Katherine

AU - Gárate-Calderón, Valentina

AU - Waldenberger, Melanie

AU - Morales, Erik

AU - Rojas, Armando

AU - Munoz, César

AU - Retamales, Javier

AU - de Toro, Gonzalo

AU - Barajas, Olga

AU - Rivera, María Teresa

AU - Cortés, Analía

AU - Loader, Denisse

AU - Saavedra, Javiera

AU - Gutiérrez, Lorena

AU - Ortega, Alejandro

AU - Bertrán, Maria Enriqueta

AU - Gabler, Fernando

AU - Campos, Mónica

AU - Alvarado, Juan

AU - Moisán, Fabrizio

AU - Spencer, Loreto

AU - Nervi, Bruno

AU - Carvajal-Hausdorf, Daniel E.

AU - Losada, Héctor

AU - Almau, Mauricio

AU - Fernández, Plinio

AU - Gallegos, Ivan

AU - Olloquequi, Jordi

AU - Fuentes-Guajardo, Macarena

AU - Gonzalez-Jose, Rolando

AU - Bortolini, Maria Cátira

AU - Gallo, Carla

AU - Ruiz Linares, Andres

AU - Rothhammer, Francisco

AU - Bermejo, Justo Lorenzo

PY - 2022/2/1

Y1 - 2022/2/1

N2 - Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candi-dates 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 lncR-NAs (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.

AB - Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candi-dates 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 lncR-NAs (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.

KW - EQTLs

KW - Genetic association study

KW - LncRNAs

KW - Molecular phenotypes

KW - gallbladder cancer

UR - https://www.scopus.com/pages/publications/85123375413

U2 - 10.3390/cancers14030634

DO - 10.3390/cancers14030634

M3 - Article

AN - SCOPUS:85123375413

SN - 2072-6694

VL - 14

JO - Cancers

JF - Cancers

IS - 3

M1 - 634

ER -

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

Abstract

UN SDGs

Keywords

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