Characterisation of dysplastic liver nodules using low-pass DNA sequencing and detection of chromosome arm-level abnormalities in blood-derived cell-free DNA

Fateen, Waleed, Johnson, Philip J ORCID: 0000-0003-1404-0209, Wood, Henry M, Zhang, Han, He, Shan, El-Meteini, Mahmoud, Wyatt, Judy I, Aithal, Guruprasad P and Quirke, Philip (2021) Characterisation of dysplastic liver nodules using low-pass DNA sequencing and detection of chromosome arm-level abnormalities in blood-derived cell-free DNA. JOURNAL OF PATHOLOGY, 255 (1). pp. 30-40.

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Abstract

High-grade dysplasia carries significant risk of transformation to hepatocellular carcinoma (HCC). Despite this, at the current standard of care, all non-malignant hepatic nodules including high-grade dysplastic nodules are managed similarly. This is partly related to difficulties in distinguishing high-risk pathology in the liver. We aimed to identify chromosome arm-level somatic copy number alterations (SCNAs) that characterise the transition of liver nodules along the cirrhosis-dysplasia-carcinoma axis. We validated our findings on an independent cohort using blood-derived cell-free DNA. A repository of non-cancer DNA sequences obtained from patients with HCC (n = 389) was analysed to generate cut-off thresholds aiming to minimise false-positive SCNAs. Tissue samples representing stages from the multistep process of hepatocarcinogenesis (n = 184) were subjected to low-pass whole genome sequencing. Chromosome arm-level SCNAs were identified in liver cirrhosis, dysplastic nodules, and HCC to assess their discriminative capacity. Samples positive for 1q+ or 8q+ arm-level duplications were likely to be either HCC or high-grade dysplastic nodules as opposed to low-grade dysplastic nodules or cirrhotic tissue with an odds ratio (OR) of 35.5 (95% CI 11.5-110) and 16 (95% CI 6.4-40.2), respectively (p < 0.0001). In an independent cohort of patients recruited from Nottingham, UK, at least two out of four alterations (1q+, 4q-, 8p-, and 8q+) were detectable in blood-derived cell-free DNA of patients with HCC (n = 22) but none of the control patients with liver cirrhosis (n = 9). Arm-level SCNAs on 1q+ or 8q+ are associated with high-risk liver pathology. These can be detected using low-pass sequencing of cell-free DNA isolated from blood, which may be a future early cancer screening tool for patients with liver cirrhosis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Item Type:	Article
Uncontrolled Keywords:	hepatocellular carcinoma, copy number, premalignant lesions, tumour pathology, cell-free DNA, early cancer
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	27 May 2021 08:00
Last Modified:	04 Sep 2023 02:42
DOI:	10.1002/path.5734
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3124134