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Sequential Occurrence of Preneoplastic Lesions and Accumulation of Loss of Heterozygosity in Patients With Gallbladder Stones Suggest Causal Association With Gallbladder Cancer

Jain, Kajal MSc, PhD*; Mohapatra, Trilochan MSc, PhD; Das, Prasenjit MD; Misra, Mahesh Chandra MS§; Gupta, Siddhartha Datta MD; Ghosh, Manju PhD; Kabra, Madhulika MD; Bansal, Virinder Kumar MS§; Kumar, Subodh MS§; Sreenivas, Vishnubhatla MSc, PhD; Garg, Pramod Kumar MD, DM*

doi: 10.1097/SLA.0000000000000495
Original Articles

Background: Causal association of gallbladder stones with gallbladder cancer (GBC) is not yet well established.

Objective: To study the frequency of occurrence of preneoplastic histological lesions and loss of heterozygosity (LOH) of tumor suppressor genes in patients with gallstones.

Methods: All consecutive patients with gallstones undergoing cholecystectomy from 2007–2011 were included prospectively. Histological examination of the gallbladder specimens was done for preneoplastic lesions. LOH at 8 loci, that is 3p12, 3p14.2, 5q21, 9p21, 9q, 13q, 17p13, and 18q for tumor suppressor genes (DUTT1, FHIT, APC, p16, FCMD, RB1, p53, and DCC genes) that are associated with GBC was tested from microdissected preneoplastic lesions using microsatellite markers. These LOH were also tested in 30 GBC specimens.

Results: Of the 350 gallbladder specimens from gallstone patients, hyperplasia was found in 32%, metaplasia in 47.8%, dysplasia in 15.7%, and carcinoma in situ in 0.6%. Hyperplasia, metaplasia, and dysplasia alone were found in 11.7%, 24.6%, and 1.4% of patients, respectively. A combination of hyperplasia and dysplasia, metaplasia and dysplasia, and hyperplasia, metaplasia, and dysplasia was found in 3.4%, 6.3%, and 4.3% of patients, respectively. LOH was present in 2.1% to 47.8% of all the preneoplastic lesions at different loci. Fractional allelic loss was significantly higher in those with dysplasia compared with other preneoplastic lesions (0.31 vs 0.22; P = 0.042). No preneoplastic lesion or LOH was found in normal gallbladders.

Conclusions: Patients with gallstones had a high frequency of preneoplastic lesions and accumulation of LOH at various tumor suppressor genes, suggesting a possible causal association of gallstones with GBC.

Supplemental Digital Content is Available in the Text.Gallbladder specimens of patients with gallstones were examined for preneoplastic lesions and loss of heterozygosity for various microsatellite markers in the preneoplastic lesions. Gallstone patients had a high frequency of preneoplastic lesions and accumulation of loss of heterozygosity at various tumor suppressor genes, suggesting a possible causal association of gallstones with gallbladder cancer.

*Departments of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India

Indian Agricultural Research Institute, New Delhi, India;

Departments of Pathology


Pediatrics (Genetics unit), and

Biostatistics, All India Institute of Medical Sciences, New Delhi, India.

Reprints: Pramod Kumar Garg, MD, Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110 029, India. E-mail:

Disclosure: Supported by research grant from the Department of Biotechnology, Government of India. The funding agencies had no role in study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.

The authors declare no conflicts of interest.

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