Pathognomonic genetic signatures of gallbladder cancer: Results of ongoing prospective study.

Abstract

e16236 Background: Gene polymorphisms play a pivotal role in gallbladder cancer (GBC) susceptibility and progression, underscoring the need to pinpoint key variants for enhanced diagnostic and therapeutic strategies. Methods: We performed germline and somatic whole exome sequencing (WES) of gallbladder cancer patients. WES was done by TarGT Absolute (4BASECARE) under armed forces medical research project. Patient recruitment was done after ethics committee approval. Results: 26 patients were enrolled from Jan 2021 till Dec 2023. Table depicts the baseline demographics. A total of 10 single nucleotide polymorphisms (SNPs) spanning nine candidate genes— XRCC1, CR1, APOB, CYP1B1, NAT2, ERCC2, OGG1, GSTP1 , and XPC —were prioritized based on their established or putative roles in DNA repair, xenobiotic metabolism, lipid regulation, and immune complex clearance. Notable findings include significant associations of GSTP1 (rs1138272) and CR1 (rs17259045) variants with elevated GBC risk, implicating impaired detoxification pathways and reduced immune complex clearance as contributors to tumorigenesis. Additionally, 9% of the patient cohort presented with pathogenic mutations in ATM, BRCA1, FANCC genes indicating elevated risk of cancer in these patients as compared to the normal population. We also observed deleterious mutations in six genes FREM1, MYO3A, ZFHX3, RAX2, ASPM, and NANOS1 in the cohort. Conclusions: By integrating germline whole-exome sequencing we have identified potential genetic variants and implicated genes that may contribute to GBC tumor formation. These findings provide a foundation for future research and explore their clinical utility in improving early detection and therapeutic approaches for GBC. Baseline demographic characteristics of study participants (n=26). Variables Frequency n (%) Age years Median Range 31-77  <=50 years 6 (23)  >50 years 20 (77) Gender  Female 17 (65)  Male 9 (35) Cholelithiasis  No 14 (54)  Yes 12 (46) Cholecystectomy  Not done 18 (70)  Done 8 (30) Gangetic Belt Residence  Yes 14 (54)  No 12 (46) Jaundice on presentation  Absent 14 (54)  Present 12 (46) Bilirubin  <=4 mg/dl 19 (73)  >4 mg/dl 7 (23)