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

Since 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.Fil: Boekstegers, Felix. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Scherer, Dominique. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Barahona Ponce, Carol. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Marcelain, Katherine. Universidad de Chile; ChileFil: Gárate Calderón, Valentina. Universidad de Chile; ChileFil: Waldenberger, Melanie. No especifíca;Fil: Morales, Erik. Universidad Católica de Maule; ChileFil: Rojas, Armando. Universidad Católica de Maule; ChileFil: Munoz, César. Universidad Católica de Maule; ChileFil: Retamales, Javier. Instituto Nacional del Cáncer; ChileFil: de Toro, Gonzalo. Universidad Austral de Chile; ChileFil: Barajas, Olga. Universidad de Chile; ChileFil: Rivera, María Teresa. Hospital del Salvador; ChileFil: Cortés, Analía. Hospital del Salvador; ChileFil: Loader, Denisse. Hospital Padre Hurtado; ChileFil: Saavedra, Javiera. Hospital Padre Hurtado; ChileFil: Gutiérrez, Lorena. Hospital San Juan de Dios; ChileFil: Ortega, Alejandro. Hospital Regional; ChileFil: Bertrán, Maria Enriqueta. Hospital Base de Valdivia; ChileFil: Bartolotti, Leonardo. Hospital Base de Valdivia; ChileFil: Gabler, Fernando. Hospital Clínico San Borja Arriarán; ChileFil: Campos, Mónica. Hospital Clínico San Borja Arriarán; ChileFil: Alvarado, Juan. Hospital Regional de Concepción - Dr. Guillermo Grant Benavente; ChileFil: Moisán, Fabricio. Hospital Regional de Concepción - Dr. Guillermo Grant Benavente; ChileFil: Spencer, Loreto. Hospital Regional de Concepción - Dr. Guillermo Grant Benavente; ChileFil: Nervi, Bruno. No especifíca;Fil: Carvajal Hausdorf, Daniel. Universidad del Desarrollo; ChileFil: Losada, Héctor. Universidad de La Frontera; ChileFil: Almau, Mauricio. Hospital de Rancagua; ChileFil: Fernández, Plinio. Hospital de Rancagua; ChileFil: Olloquequi, Jordi. Universidad de Barcelona; EspañaFil: Fuentes Guajardo, Macarena. Universidad de Tarapacá; ChileFil: Gonzalez-Jose, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; ArgentinaFil: Bortolini, Maria Cátira. Universidade Federal do Rio Grande do Sul; BrasilFil: Acuña Alonzo, Victor. No especifíca;Fil: Gallo, Carla. Universidad Peruana Cayetano Heredia; PerúFil: Ruiz-Linares, Andres. Colegio Universitario de Londres; Reino UnidoFil: Rothhammer, Francisco. Universidad de Tarapacá; ChileFil: Lorenzo Bermejo, Justo. Ruprecht Karls Universitat Heidelberg; Alemani

Mendelian Randomization Analysis of the Relationship Between Native American Ancestry and Gallbladder Cancer Risk

Background A strong association between the proportion of Native American 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 Native American people in Chile. We set out to investigate the causal association between Native American Mapuche ancestry and GBC risk, and the possible mediating effects of gallstone disease and body mass index (BMI) on this association. Methods Markers of Mapuche ancestry were selected based on the informativeness for assignment measure and then used as instrumental variables in two-sample mendelian randomization (MR) analyses and complementary sensitivity analyses. Result We found evidence of a causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% for every 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, p = 6.6×10-5). Mapuche ancestry was also causally linked to gallstone disease (IVW risk increase of 3.6% per 1% increase in Mapuche proportion, 95% CI 3.1% to 4.0%, p = 1.0×10-59), suggesting a mediating effect of gallstones in the relationship between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative causal effect on BMI (IVW estimate -0.006 kg/m2 per 1% increase in Mapuche proportion, 95% CI -0.009 to -0.003, p = 4.4×10-5). Conclusions The results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between Mapuche ancestry and GBC risk previously noted in observational studies appears to be causal, primary and secondary prevention strategies that take into account the individual proportion of Mapuche ancestry could be particularly efficient