Browsing by Author "Barajas, Olga"
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Publication Development and internal validation of a multifactorial riskprediction model for gallbladder cancer in a high-incidencecountry(2023) Boekstegers, Felix; Scherer, Dominique; Barahona, Carol; Marcelain, Katherine; Gárate, Valentina; Waldenberge, Melanie; Morales, Erik; Rojas, Armando; Munoz, César; Retamales, Javier; De Toro, Gonzalo; Barajas, Olga; Rivera, María; Cortés, Analía; Loader, Denisse; Saavedra, Javiera; Gutiérrez, Lorena; Ortega, Alejandro; Bertrán, Maria; Bartolotti, Leonardo; Gabler, Fernando; Campos, Monica; Alvarado, Juan; Moisán, Fabricio; Spencer, Loreto; Nervi, Bruno; Carvajal-Hausdorf, Daniel; Losada, Héctor; Almau, Mauricio; Fernández, Plinio; Olloquequi, Jordi; Fuentes, Macarena; Gonzalez, Rolando; Bortolin, Maria; Acuña, Victor; Gallo, Carla; Ruiz, Andres; Rothhamme, Francisco; Bermejo, JustoSince 2006, Chile has been implementing a gallbladder cancer (GBC) prevention program based on prophylactic cholecystectomy for gallstone patients aged 35 to 49 years. The effectiveness of this prevention program has not yet been comprehensively evaluated. We conducted a retrospective study of 473 Chilean GBC patients and 2137 population-based controls to develop and internally validate three GBC risk prediction models. The Baseline Model accounted for gallstones while adjusting for sex and birth year. Enhanced Model I also included the non-genetic risk factors: body mass index, educational level, Mapuche surnames, number of children and family history of GBC. Enhanced Model II further included Mapuche ancestry and the genotype for rs17209837. Multiple Cox regression was applied to assess the predictive performance, quantified by the area under the precision-recall curve (AUC-PRC) and the number of cholecystectomies needed (NCN) to prevent one case of GBC at age 70 years. The AUC-PRC for the Baseline Model (0.44%, 95%CI 0.42-0.46) increased by 0.22 (95%CI 0.15-0.29) when non-genetic factors were included, and by 0.25 (95%CI 0.20-0.30) when incorporating non-genetic and genetic factors. The overall NCN for Chileans with gallstones (115, 95%CI 104-131) decreased to 92 (95%CI 60-128) for Chileans with a higher risk than the median according to Enhanced Model I, and to 80 (95%CI 59-110) according to Enhanced Model II. In conclusion, age, sex and gallstones are strong risk factors for GBC, but consideration of other non-genetic factors and individual genotype data improves risk prediction and may optimize allocation of financial resources and surgical capacity.Publication Distinct Driver Pathway Enrichments and a High Prevalence of TSC2 Mutations in Right Colon Cancer in Chile: A Preliminary Comparative Analysis(2024) Tapia, Camilo; Valenzuela, Guillermo; González, Evelin; Maureira, Ignacio; Toro, Jessica; Freire, Matías; Sepúlveda, Gonzalo; Ampuero, Diego; Blanco, Alejandro; Gallegos, Iván; Morales, Fernanda; Erices, José; Barajas, Olga; Ahumada, Mónica; Contreras, Héctor; González, Jaime; Armisén, Ricardo; Marcelain, KatherineColorectal cancer (CRC) is the second leading cause of cancer deaths globally. While ethnic differences in driver gene mutations have been documented, the South American population remains understudied at the genomic level, despite facing a rising burden of CRC. We analyzed tumors of 40 Chilean CRC patients (Chp) using next-generation sequencing and compared them to data from mainly Caucasian cohorts (TCGA and MSK-IMPACT). We identified 388 mutations in 96 out of 135 genes, with TP53 (45%), KRAS (30%), PIK3CA (22.5%), ATM (20%), and POLE (20%) being the most frequently mutated. TSC2 mutations were associated with right colon cancer (44.44% in RCRC vs. 6.45% in LCRC, p-value = 0.016), and overall frequency was higher compared to TCGA (p-value = 1.847 × 10-5) and MSK-IMPACT cohorts (p-value = 3.062 × 10-2). Limited sample size restricts definitive conclusions, but our data suggest potential differences in driver mutations for Chilean patients, being that the RTK-RAS oncogenic pathway is less affected and the PI3K pathway is more altered in Chp compared to TCGA (45% vs. 25.56%, respectively). The prevalence of actionable pathways and driver mutations can guide therapeutic choices, but can also impact treatment effectiveness. Thus, these findings warrant further investigation in larger Chilean cohorts to confirm these initial observations. Understanding population-specific driver mutations can guide the development of precision medicine programs for CRC patients.Publication Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers(2023) Zollner, Linda; Boekstegers, Felix; Barahona, Carol; Scherer, Dominique; Marcelain, Katherine; Gárate, Valentina; Waldenberger, Melanie; Morales, Erik; Rojas, Armando; Munoz, César; Retamales, Javier; De Toro, Gonzalo; Vera, Allan; Barajas, Olga; Rivera, María; Cortés, Analía; Loader, Denisse; Saavedra, Javiera; Gutiérrez, Lorena; Ortega, Alejandro; Bertrán, Maria; Bartolotti, Leonardo; Gabler, Fernando; Campos, Mónica; Alvarado, Juan; Moisán, Fabricio; Spencer, Loreto; Nervi, Bruno; Carvajal-Hausdorf, Daniel; Losada, Héctor; Almau, Mauricio; Fernández, Plinio; Olloquequi, Jordi; Carter, Alice; Miquel, Juan; Bustos, Bernabe; Fuentes, Macarena; Gonzalez, Rolando; Bortolini, Maria; Acuña, Victor; Gallo, Carla; Ruiz, Andres; Rothhammer, Francisco; Bermejo, JustoA strong association between the proportion of indigenous South American Mapuche ancestry and the risk of gallbladder cancer (GBC) has been reported in observational studies. Chileans show the highest incidence of GBC worldwide, and the Mapuche are the largest indigenous people in Chile. We set out to assess the confounding-free effect of the individual proportion of Mapuche ancestry on GBC risk and to investigate the mediating effects of gallstone disease and body mass index (BMI) on this association. Genetic markers of Mapuche ancestry were selected based on the informativeness for assignment measure, and then used as instrumental variables in two-sample Mendelian randomization analyses and complementary sensitivity analyses. Results suggested a putatively causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% per 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, p = 6.7 × 10-5) and also on gallstone disease (3.6% IVW risk increase, 95% CI 3.1% to 4.0%), pointing to a mediating effect of gallstones on the association between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative effect on BMI (IVW estimate -0.006 kg/m2, 95% CI -0.009 to -0.003). The results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between the individual proportion of Mapuche ancestry and GBC risk previously noted in observational studies appears to be free of confounding, primary and secondary prevention strategies that consider genetic ancestry could be particularly efficient.Publication Identification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression(2022) Blandino, Alice; Scherer, Dominique; Rounge, Trine B.; Umu, Sinan U.; Boekstegers, Felix; Barahona Ponce, Carol; Marcelain, Katherine; Gárate-Calderón, Valentina; Waldenberger, Melanie; Morales, Erik; Rojas, Armando; Muñoz, César; Retamales, Javier; Toro, Gonzalo de; Barajas, Olga; Rivera, María Teresa; Cortés, Analía; Loader, Denisse; Saavedra, Javiera; Gutiérrez, Lorena; Ortega, Alejandro; Bertrán, María Enriqueta; Gabler, Fernando; Campos, Mónica; Alvarado, Juan; Fabrizio Moisán 18, Loreto Spencer 18, Bruno Nervi 19, Daniel E Carvajal-Hausdorf; Spencer, Loreto; Nervi, Bruno; Carvajal-Hausdorf, Daniel; Losada, Héctor; Almau, Mauricio; Fernández, Plinio; Gallegos, Iván; Olloquequi, Jordi; Fuentes-Guajardo, Macarena; González -Jose, Rolando; Bortolini, María Cátira; Gallo, Carla; Ruíz Linares, Andrés; Rothhammer, Francisco; Bermejo, Justo LorenzoLong 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.Item Validation of an NGS Panel Designed for Detection of Actionable Mutations in Tumors Common in Latin America(2021) Salvo, Mauricio; González‐Feliú, Evelin; Toro, Jessica; Gallegos, Iván; Maureira, Ignacio; Miranda‐González, Nicolás; Barajas, Olga; Bustamante, Eva; Ahumada, Mónica; Colombo, Alicia; Armisén, Ricardo; Villamán, Camilo; Ibáñez, Carolina; Bravo, María Loreto; Sanhueza, Verónica; Spencer, M. Loreto; Toro, Gonzalo de; Morales, Erik; Bizama, Carolina; García, Patricia; Carrasco, Ana María; Gutiérrez, Lorena; Bermejo, Justo Lorenzo; Verdugo, Ricardo A.; Marcelain, KatherineNext‐generation sequencing (NGS) is progressively being used in clinical practice. How‐ ever, several barriers preclude using this technology for precision oncology in most Latin American countries. To overcome some of these barriers, we have designed a 25‐gene panel that contains pre‐ dictive biomarkers for most current and near‐future available therapies in Chile and Latin America. Library preparation was optimized to account for low DNA integrity observed in formalin‐fixed paraffin‐embedded tissue. The workflow includes an automated bioinformatic pipeline that ac‐ counts for the underrepresentation of Latin Americans in genome databases. The panel detected small insertions, deletions, and single nucleotide variants down to allelic frequencies of 0.05 with high sensitivity, specificity, and reproducibility. The workflow was validated in 272 clinical samples from several solid tumor types, including gallbladder (GBC). More than 50 biomarkers were de‐ tected in these samples, mainly in BRCA1/2, KRAS, and PIK3CA genes. In GBC, biomarkers for PARP, EGFR, PIK3CA, mTOR, and Hedgehog signaling inhibitors were found. Thus, this small NGS panel is an accurate and sensitive method that may constitute a more cost‐efficient alternative to multiple non‐NGS assays and costly, large NGS panels. This kind of streamlined assay with au‐ tomated bioinformatics analysis may facilitate the implementation of precision medicine in Latin America.