# Genetic Aberrations in Normal Tissues Adjacent to Biliary Tract Cancers

## TL;DR

This study finds that normal tissues next to biliary tract cancers contain early genetic changes, suggesting a role in cancer development.

## Contribution

The study reveals that normal adjacent tissues in biliary tract cancer contain somatic mutations distinct from tumors and germline DNA.

## Key findings

- Normal tissues adjacent to biliary tract cancers contain early somatic variants not linked to cancer pathways.
- Genomic alterations in these tissues suggest a multistep model of carcinogenesis involving chronic inflammation.
- All extrahepatic cholangiocarcinoma patients had precursor lesions like BilIN in adjacent tissues.

## Abstract

Background: The role of normal tissues adjacent to tumors (NATs) in biliary tract cancer (BTC) remains unclear, despite their potential contributions to field cancerization. Methods: Targeted genomic profiling of tumor tissues, patient-matched NATs, and peripheral blood leukocytes from 13 patients with BTCs was performed. Clinicopathological data, including inflammatory conditions and precursor lesions (biliary intraepithelial neoplasia [BilIN] and intraductal papillary neoplasm of the bile duct), were integrated with genomic findings. Results: Tumor tissues exhibited recurrent alterations in genes regulating DNA damage response, cell cycle control, and oncogenic signaling. Importantly, rather than being genetically silent, NATs harbor early somatic variants distinct from those in both tumor and germline DNA. These alterations were not directly associated with cancer-related pathways, but rather with extracellular matrix-receptor interactions, suggesting that NATs may represent an intermediate step in carcinogenesis. All patients with extrahepatic cholangiocarcinoma presented with BilIN in adjacent tissues, providing histological evidence of field cancerization linked to chronic inflammation. Conclusions: This systematic comparison of tumors, NATs, and germline DNAs in BTCs revealed that NATs contain biologically relevant somatic mutations. The concordance between the inflammatory background, precursor lesions, and genomic alterations supports a multistep carcinogenic model and highlights opportunities for early BTC detection and risk stratification.