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

Source: https://onco.cc/key-papers/paper-lin-gallbladder-neoplasia-carcinoma-evolution-nat-commun-2021/  
OnCo record `paper-lin-gallbladder-neoplasia-carcinoma-evolution-nat-commun-2021` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Sequencing benign, precancerous and cancerous patches from the same gallbladders showed two ways cancer arises: the textbook stepwise route through adenoma and dysplasia, and an early split in which the cancer evolves on its own after heavy chromosome loss.

## Summary

Whole-exome sequencing was performed on co-existing low-grade biliary intraepithelial neoplasia (adenoma), high-grade BilIN and carcinoma lesions, and normal tissues, from the same patients. Ageing was identified as a major factor contributing to accumulated mutations, and CTNNB1 mutations played a critical role in these tumours.

Two distinct carcinoma evolutionary paths were revealed: carcinoma can either diverge earlier and evolve more independently, or form through the classic adenoma or dysplasia to carcinoma sequence. Extensive loss of heterozygosity and mutation events in the initial stage tended to result in a cancerous niche, leading to the subsequent BilIN-independent path.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature Communications
- Year: 2021
- DOI: 10.1038/s41467-021-25012-9
- Authors: Lin J, Peng X, Dong K, et al.
- Findings: CTNNB1 mutation was a critical event in co-existing neoplasia and carcinoma; ageing drove mutation accumulation.; Two evolutionary paths: the classic adenoma or dysplasia to carcinoma sequence, and early divergence with independent evolution.; Extensive early loss of heterozygosity created a cancerous niche for the BilIN-independent path.
- What it means: Molecular confirmation that the visible precursor is not always the parent of the cancer beside it, which tempers hopes that finding and removing dysplasia catches every tumour, and puts Wnt signalling through CTNNB1 at the start of the raised route.
- Caveats: Small number of patients with multi-region sampling; the abstract does not state n.; Chinese cohort.

## Sources

- Lin et al., Nat Commun 2021: co-existing neoplasia and carcinoma lesions of the gallbladder: https://doi.org/10.1038/s41467-021-25012-9
- PubMed: https://pubmed.ncbi.nlm.nih.gov/34362903/

## Connected records

- cancers: [Gallbladder cancer](https://onco.cc/cancers/gallbladder/)
- targets: [CTNNB1](https://onco.cc/targets/ctnnb1/)
- pathways: [Wnt / β-catenin](https://onco.cc/pathways/wnt/)
- terms: [Dysplasia (pre-cancerous change)](https://onco.cc/terms/dysplasia/), [Metaplasia, dysplasia, carcinoma in situ: the flat route to gallbladder cancer](https://onco.cc/terms/metaplasia-dysplasia-carcinoma-sequence/)
- journals: [Nature Communications](https://onco.cc/journals/nature-communications/)

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