CARVAJAL HAUSDORF, DANIEL EDUARDO
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CARVAJAL HAUSDORF, DANIEL EDUARDO
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dcarvajal@udd.cl
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56274228900

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Gallbladder Cancer Risk and Indigenous South American Mapuche Ancestry: Instrumental Variable Analysis Using Ancestry-Informative Markers

2023 , Linda Zollner , Felix Boekstegers , Carol Barahona Ponce , Dominique Scherer , Katherine Marcelain , Valentina Gárate-Calderón , Melanie Waldenberger , Erik Morales , Armando Rojas , César Munoz , Javier Retamales , Gonzalo De Toro , Allan Vera Kortmann , Olga Barajas , María Teresa Rivera , Analía Cortés , Denisse Loader , Javiera Saavedra , Lorena Gutiérrez , Alejandro Ortega , Maria Enriqueta Bertrán , Leonardo Bartolotti , Fernando Gabler , Mónica Campos , Juan Alvarado , Fabricio Moisán , Loreto Spencer , Bruno Nervi , CARVAJAL HAUSDORF, DANIEL EDUARDO , Héctor Losada , Mauricio Almau , Plinio Fernández , Jordi Olloquequi , Alice R. Carter , Juan Francisco Miquel Poblete , Bernabe Ignacio Bustos , Macarena Fuentes Guajardo , Rolando Gonzalez-Jose , Maria Cátira Bortolini , Victor Acuña-Alonzo , Carla Gallo , Andres Ruiz Linares , Francisco Rothhammer , Justo Lorenzo Bermejo

A 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.

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Development and internal validation of a multifactorial risk prediction model for gallbladder cancer in a high‐incidence country

2023 , Felix Boekstegers , Dominique Scherer , 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 , Leonardo Bartolotti , Fernando Gabler , Mónica Campos , Juan Alvarado , Fabricio Moisán , Loreto Spencer , Bruno Nervi , CARVAJAL HAUSDORF, DANIEL EDUARDO , Héctor Losada , Mauricio Almau , Plinio Fernández , Jordi Olloquequi , Macarena Fuentes‐Guajardo , Rolando Gonzalez‐Jose , Maria Cátira Bortolini , Victor Acuña‐Alonzo , Carla Gallo , Andres Ruiz Linares , Francisco Rothhammer , Justo Lorenzo Bermejo

AbstractSince 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.

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NTRK genomic alterations in Latin-American cancer patients.

2021 , CARVAJAL HAUSDORF, DANIEL EDUARDO , Claudio Salas , Katherine Marcelain , Francisco Perez , Evelin Feliu , Kurt Schalper , Solange Rivas , ARMISEN YAÑEZ, RICARDO AMADO

e15088 Background: The neurotrophic receptor tyrosine kinase genes NTRK1-3 encode the tropomyosin receptor kinase proteins TRKA, TRKB, and TRKC, respectively. TRK fusions lead to overexpression of the chimeric protein, resulting in constitutively active, ligand-independent downstream signaling. NTRKs act as oncogenes, they can be targeted, and it is estimated that they are present in up to 0.3% of tumors. The incidence of actionable alterations in these genes is currently unknown in Latin-American patients. We investigated the presence of NTRK1-3 mutations/rearrangements in 3 independent patient series from several tertiary hospitals from Chile, Brazil and Peru. Methods: 1795 FFPE tumor samples from multiple institutions divided in 3 series were analyzed using 2 NGS panels: Oncomine Focus Assay (OFA; 52 genes) and Oncomine Comprehensive Assay (OCA; 161 genes. Data on NTRK1-3 SNVs, indels, CNVs and fusions was obtained. Bioinformatic workflows were used to study the biologic significance of these alterations. Results: Using OCA (series 1-2), 31 somatic variants were found in gastric, CRC, gallbladder, lung and pancreatic cases out of 300 patients. From these, 13 were located in the tyrosine kinase domain. Using OFA, no NTRK alteration were detected (series 3, 1495 NSCLC cases). Conclusions: NTRK alterations are rare events in Latin-American cancer patients. In 3 series including 1,795 patients, 31 somatic variants were detected. No NTRK fusions or CNVs were identified. The presence of NTRK mutations in the tyrosine kinase domain warrants further research into their potential to benefit from FDA/EMA-approved targeted therapies. [Table: see text]

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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

2022 , 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 , CARVAJAL HAUSDORF, DANIEL EDUARDO , 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

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.

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