Genomic characterization of co-existing neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer

Jianzhen Lin,Haitao Zhao,Kun Dong,Xu Yang,Hongyue Li,Dongxu Wang,Xinting Sang,Xin Lu,Xuejiao Guo,Han Liang,Junyu Long,Xinxin Peng,Yi Bai,Yilei Mao,Xuwo Ji

doi:10.1038/s41467-021-25012-9

Abstract

Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we perform whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients. We identify aging as a major factor contributing to accumulated mutations and a critical role of CTNNB1 mutations in these tumors. We reveal two distinct carcinoma evolutionary paths: carcinoma can either diverge earlier and evolve more independently or form through the classic adenoma/dysplasia-carcinoma sequence model. Our analysis suggests that extensive loss-of-heterozygosity and mutation events in the initial stage tend to result in a cancerous niche, leading to the subsequent BilIN-independent path. These results reframes our understanding of tumor transformation and the evolutionary trajectory of carcinogenesis in the gallbladder, laying a foundation for the early diagnosis and effective treatment of gallbladder cancer.

Highlights

Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis
After a rigorous pathological review of a large number of gallbladder tumor samples, we collected tissue samples, including normal ones, from 11 patients diagnosed with T1 tumors, in whom Gallbladder carcinoma (GBC), LG-Biliary tract intraepithelial neoplasia (BilIN), and HG-BilIN lesions geographically coexisted
To assess the relative mutation burden of GBC, we compared our GBC samples with stage-I samples of 16 other cancer types from The Cancer Genome Atlas (TCGA) and found that GBC exhibited a moderate level of tumor mutation burden (TMB), similar to that of liver hepatocellular carcinoma (LIHC) (t-test, p = 0.79) but significantly higher than that of cholangiocarcinoma (CHOL) (t-test, p = 7.3 × 10−4, Fig. 1b)

Summary

Introduction

Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. Our analysis suggests that extensive loss-of-heterozygosity and mutation events in the initial stage tend to result in a cancerous niche, leading to the subsequent BilIN-independent path. These results reframes our understanding of tumor transformation and the evolutionary trajectory of carcinogenesis in the gallbladder, laying a foundation for the early diagnosis and effective treatment of gallbladder cancer. Gallbladder carcinoma (GBC) is the most common cancer of the biliary tract[1,2]. Molecular analyses show that p53 and KRAS are commonly mutated in LG-BilIN and GBC8, and the dysregulation of p16/

Methods

Results

Conclusion