Identification and validation of circulating sncRNAs causally associated with gallbladder cancer and development of a multifactorial risk prediction score

• Applicants: Professor Dr. Justo Lorenzo Bermejo; Dr. Melanie Waldenberger
• Subject Area: Medical Informatics and Medical Bioinformatics
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424112940

Around 57,000 persons die every year due to gallbladder cancer (GBC). Early symptoms are vague and only 5% of GBC patients are alive five years after diagnosis. Surgical removal of the gallbladder(cholecystectomy) offers the potential for cure of GBC confined to the mucosa. Unfortunately, a reliable test to predict or detect early GBC is not available yet. This research proposal aims at 1) unravelling the causal mechanisms underlying GBC development, and 2) developing and validating a risk score for GBC prediction before clinical manifestation, eventually revolutionizing the prevention of this neglected disease. Specific objectives for the first three years of the project are: 1) to pre-select candidate sncRNAs based on expression changes in gallbladder tissue along the multistage model of carcinogenesis represented by the sequence “Gallstones and Inflammation – Dysplasia – GBC”, 2) to identify and validate circulating sncRNAs associated to GBC risk, 3) to test the causality, and to estimate the causal effects of associated sncRNAs by Mendelian randomization, and 4) to build a risk score which combines established GBC risk factors and newly identified sncRNAsassociated with GBC risk. Comprehensive clinical and environmental exposure information, and sncRNA sequence data from 90 formalin-fixed paraffin-embedded (FFPE) tissue samples (30 from gallstone, 30 from dysplasia and 30 from GBC Chilean patients) are available. This dataset will be complemented with clinical and environmental data, and with • 180 additional FFPE samples from Peruvian and Argentinian patients (60 with gallstones, 60 withdysplasia and 60 affected by GBC), and • independent serum/DNA samples from 375 gallstone and 375 GBC patients (250 from Chile, 250 from Peru and 250 from Argentina). GBC is relatively rare – it causes around 1500 deaths in Germany every year (krebsdaten.de). The tumor is very aggressive but there is ample opportunity for GBC prevention: 10-20 years are needed for tumour development and prophylactic cholecystectomy can be offered to individuals at high GBC risk. New insights into the causal mechanisms that underlie GBC development will improve current understanding of the biological links between established risk factors and GBC, eventually translating into relevant findings to public health policies in general, and to GBC prevention in particular. Individual estimates of GBC risk based on the developed risk score would guide surveillance and personal decisions on the possible benefit of prophylactic cholecystectomy for persons at high risk (e.g., first-degree relatives of GBC patients and severely obese women). This would significantly improve GBC prevention in both industrialized and less developed countries. The access to unique datasets and sample collections from regions with a high GBC incidence, and the use of innovative laboratory techniques and advanced statistical methods strongly endorse the present proposal.

• DFG Programme: Research Grants