Genomic Sequencing Study Reveals Precancerous Changes Involved in the Development of Gallbladder Cancer

December 2021, Vol 2, No 4

The overall survival of gallbladder carcinoma (GBC), the most common cancer of the biliary tract, is poor, largely because of delayed diagnosis. Low-grade biliary tract intraepithelial neoplasia (BilIN) is a benign tumor but is thought to be precancerous and a contributing factor in gallbladder cancer. However, the genetic and evolutionary trajectories between low-grade BilIN and GBC remain unclear.

In a new study, Jianzhen Lin, PhD, Department of Liver Surgery, Peking Union Medical College Hospital, Beijing, China, and colleagues examined the connection between BilIN and GBC, and how it could improve early detection and intervention.1

“GBC is a malignancy with poor overall survival, and the molecular research on its pathogenesis and carcinogenesis is relatively rare. Like most epithelial cancer types, GBC is preceded by a series of precancerous histological and molecular changes that evolve possibly over a period of several decades,” said Dr Lin and colleagues.

Using laser microdissections, the researchers performed deep-sequencing analysis of normal gallbladder tissue, tumor samples, and BilIN isolated from 11 patients (average age, 62 years). They separated GBC, low-grade BilIN, high-grade BilIN, and normal gallbladder tissue and conducted whole-exome sequencing on 44 samples.

The mutations in stage I tumors were mainly caused by age; in the GBC samples, age-related signature 1 contributed to more than 75% of the mutations, and APOBEC-related signature 2 contributed to approximately 10%. Dr Lin and colleagues noted that all low-grade or high-grade BilIN and GBC “are an inevitable consequence of aging and mutation accumulation.”

“These results indicate the importance of mutations accumulated by the aging process for GBC development and provide the first view of mutational characteristics of GBC coexisting with LG/HG-BilIN,” they added.

They further observed several recurrent driver mutations in GBC, noting that CTNNB1 mutations are critical for cancer development. In the cohort, 5 of 11 patients harbored CTNNB1 mutations; in 4 of these 5 cases, GBC and its adjacent low-grade BilIN shared the same mutations in CTNNB1, suggesting that CTNNB1 mutations play a more active role in the formation of carcinoma of adenoma or dysplasia than GBC alone.

Further analysis identified 2 distinct carcinoma evolutionary paths, showing that some GBCs do arise from BilIN, but others follow an independent path. Extensive loss of heterozygosity and mutation events in the initial stage tend to form a cancerous niche, leading to the subsequent BilIN-independent path.

The researchers suggest that proactive intervention needs to focus on identifying patients with high levels of loss of heterozygosity, so that earlier or more aggressive cholecystectomy may be adopted as a primary prevention approach for GBC.


  1. 1. Lin J, Peng X, Dong K, et al. Genomic characterization of co-existing neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer. Nat Commun. 2021;12:4753. doi: 10.1038/s41467-021-25012-9.

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