ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans

Boekstegers, Felix; Marcelain, Katherine; Ponce, Carol Barahona; Benavides, Pablo F. Baez; Müller, Bettina; Toro, Gonzalo de; Retamales, Javier; Barajas, Olga; Ahumada, Miguel; Morales, Erik; Rojas, Armando; Sanhueza, Verónica; Loader, Denisse; Rivera, Maria; Gutiérrez, Lorena; Bernal, Giuliano; Ortega, Alejandro; Montalvo, Domingo; Portiño, Sergio; Bertrán, Maria Enriqueta; Gabler, Fernando; Spencer, Loreto; Olloquequi, Jordi; Silos, Rosa González; Fischer, Christine; Scherer, Dominique; Jenab, Mazda; Aleksandrova, Krasimira; Katzke, Verena; Weiderpass, Elisabete; Moradi, Tahereh; Fischer, Krista; Bossers, Willem; Brenner, Hermann; Hveem, Kristian; Eklund, Niina; Völker, Uwe; Waldenberger, Mélanie; Guajardo, Macarena Fuentes; González‐José, Rolando; Bedoya, Gabriel; Bortolini, María Cátira; Canizales, Samuel; Gallo, Carla; Ruiz-Linares, Andrés; Rothhammer, Francisco; Bermejo, Justo Lorenzo

doi:10.1016/j.canep.2019.101643

Cited by 10 publications

(6 citation statements)

References 14 publications

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“…The most notable SNPs after replication and meta-analysis were rs1558375 (GWAS p = 3.8 × 10 −9 ; replication p = 0.01; combined p = 2.3 × 10 −10 ), rs17209837 (GWAS p = 2.0 × 10 −8 ; replication p = 0.02; combined p = 2.3 × 10 −9 ), and rs4148808 (GWAS p = 2.4 × 10 −8 ; replication p = 0.008; combined p = 2.7 × 10 −9 ) [35]. Interestingly, these ABCB1/4 GBC risk variants also showed similar risk effects in Chileans, according to a recent multicenter population-based candidate variant association study that included 255 GBC cases and 2042 controls from a Chilean retrospective study [36].…”

Section: Genetic Susceptibility Biomarkersmentioning

confidence: 95%

Current and New Biomarkers for Early Detection, Prognostic Stratification, and Management of Gallbladder Cancer Patients

García

Lamarca

Díaz

et al. 2020

Cancers

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Gallbladder cancer (GBC) is an aggressive disease that shows evident geographic variation and is characterized by a poor prognosis, mainly due to the late diagnosis and ineffective treatment. Genetic variants associated with GBC susceptibility, including polymorphisms within the toll-like receptors TLR2 and TLR4, the cytochrome P450 1A1 (CYP1A1), and the ATP-binding cassette (ABC) transporter ABCG8 genes, represent promising biomarkers for the stratification of patients at higher risk of GBC; thus, showing potential to prioritize cholecystectomy, particularly considering that early diagnosis is difficult due to the absence of specific signs and symptoms. Similarly, our better understanding of the gallbladder carcinogenic processes has led to identify several cellular and molecular events that may influence patient management, including HER2 aberrations, high tumor mutational burden, microsatellite instability, among others. Despite these reports on interesting and promising markers for risk assessment, diagnosis, and prognosis; there is an unmet need for reliable and validated biomarkers that can improve the management of GBC patients and support clinical decision-making. This review article examines the most potentially significant biomarkers of susceptibility, diagnosis, prognosis, and therapy selection for GBC patients, highlighting the need to find and validate existing and new molecular biomarkers to improve patient outcomes.

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Section: Genetic Susceptibility Biomarkersmentioning

confidence: 95%

Current and New Biomarkers for Early Detection, Prognostic Stratification, and Management of Gallbladder Cancer Patients

García

Lamarca

Díaz

et al. 2020

Cancers

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“…(4,5) Previous studies investigated Indian patients, who show lower rates of GSD (86% for Chilean compared with 33% for Indian patients with GBC), (42) and applied a different study design (fresh-frozen tumor, adjacent nontumor, and gallstone samples). (10,43) An enhanced understanding of the molecular alterations occurring during GBC development in regions with a high incidence of both GSD and GBC, such as southern Chile, is crucial to improve GBC prevention and treatment in order to ultimately reduce the GBC burden.…”

Section: Discussionmentioning

confidence: 99%

Epigenome‐Wide Analysis of Methylation Changes in the Sequence of Gallstone Disease, Dysplasia, and Gallbladder Cancer

et al. 2021

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Background & aims: Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract. Most cases of GBC are diagnosed in low-and middle-income countries and research into this disease has long been limited. In this study we therefore investigate the epigenetic changes along the model of GBC carcinogenesis represented by the sequence gallstone disease → dysplasia → GBC in Chile, the country with the highest incidence of GBC worldwide.Approach: To perform epigenome-wide methylation profiling, genomic DNA extracted from sections of FFPE gallbladder tissue was analyzed using Illumina Infinium MethylationEPIC BeadChips. Pre-processed, quality-controlled data from 82 samples (gallstones n=32, lowgrade dysplasia n=13, high-grade dysplasia n=9, GBC n=28) were available to identify differentially methylated markers, regions, and pathways as well as changes in copy number variations (CNVs). Main results:The number and magnitude of epigenetic changes increased with disease development and predominantly involved the hypermethylation of CpG islands and gene promoter regions. The methylation of genes implicated in Wnt signaling, Hedgehog signaling, and tumor suppression increased with tumor grade. CNVs also increased with GBC development and affected CDKN2A, MDM2, TP53, and CCND1. Gains in the targetable ERBB2 were detected in 14% of the GBC samples. Conclusions:Our results indicate that GBC carcinogenesis comprises three main methylation stages: early (gallstone disease and low-grade dysplasia), intermediate (highgrade dysplasia), and late (GBC). The identified gradual changes in methylation and CNVs may help to enhance our understanding of the mechanisms underlying this aggressive disease and eventually lead to improved treatment and early diagnosis of GBC.

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“…Enhanced Model I additionally considered the non‐genetic risk factors BMI, education, Mapuche surnames, number of children in women (0‐2 vs 3+), and family history of GBC. The genetic variant rs17209837 (A > T) is associated with GBC risk in the Chilean population, especially among individuals with a high proportion of Mapuche ancestry, 10 and Enhanced Model II further included the individual proportion of Mapuche ancestry and the rs17209837 genotype as genetic risk factors.…”

Section: Methodsmentioning

confidence: 99%

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

Boekstegers

Scherer

Ponce

et al. 2023

Intl Journal of Cancer

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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.

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ABCB1/4 gallbladder cancer risk variants identified in India also show strong effects in Chileans

Cited by 10 publications

References 14 publications

Current and New Biomarkers for Early Detection, Prognostic Stratification, and Management of Gallbladder Cancer Patients

Current and New Biomarkers for Early Detection, Prognostic Stratification, and Management of Gallbladder Cancer Patients

Epigenome‐Wide Analysis of Methylation Changes in the Sequence of Gallstone Disease, Dysplasia, and Gallbladder Cancer

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

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