Mutational landscape of a chemically-induced mouse model of liver cancer

Abstract

Carcinogen-induced mouse models of liver cancer are used extensively to study the pathogenesis of the disease and have a critical role in validating candidate therapeutics. These models can recapitulate molecular and histological features of human disease. However, it is not known if the spectra of genomic alterations driving these mouse tumour genomes are comparable to those found in humans. Here, we provide a detailed characterisation of the exome-wide pattern of mutations in tumours from mice exposed to diethylnitrosamine (DEN), a commonly used model of hepatocellular carcinoma (HCC). DEN-initiated tumours had a high, uniform number of somatic single nucleotide variants (SNVs), with very few insertions, deletions or copy number alterations, consistent with the known genotoxic action of DEN. Exposure of hepatocytes to DEN left a reproducible mutational imprint in resulting tumour exomes which we could computationally reconstruct using six known COSMIC mutational signatures. The tumours carried a high diversity of low-incidence, non-synonymous point mutations in many oncogenes and tumour suppressors, reflecting the stochastic introduction of SNVs into the hepatocyte genome by the carcinogen. We identified four recurrently mutated genes that were putative oncogenic drivers of HCC in this model. Every neoplasm carried activating hotspot mutations either in codon 61 of Hras, in codon 584 of Braf or in codon 254 of Egfr. Truncating mutations of Apc occurred in 21% of neoplasms, which were exclusively carcinomas supporting a role for deregulation of Wnt/β-catenin signalling in cancer progression. Conclusion: Our study provides detailed insight into the mutational landscape of tumours arising in a commonly-used carcinogen model of hepatocellular carcinoma, facilitating the future use of this model to understand the human disease.

Pervasive lesion segregation shapes cancer genome evolution

“…Known driver mutations were identified in the EGFR/RAS/RAF pathway 10,16,17 (Fig. 1d) 70 validating this well controlled model system of liver tumourigenesis.…”

“…We chemically induced liver tumours in fifteen-day-old (P15) male C3H/HeOuJ inbred mice 45 (subsequently C3H, n=104) using a single dose of diethylnitrosamine (DEN), thus greatly extending our previous study 10 . To provide a genetic comparison and a validation dataset in a divergent mouse strain 11 , we treated a cohort of CAST/EiJ mice with DEN (subsequently CAST, n=84).…”

“…We further validated the multi-allelic variant calls from whole genome sequencing within independently performed deep exome sequencing of the same tumours 10 . The second and 280…”

The Mutational Features of Aristolochic Acid–Induced Mouse and Human Liver Cancers

“…Zhai et al (15) Singapore 9 4 (44) 2 (22) 1 (11) Ahn et al (16) Korea 231 16 (7) 12 (5) 8 (3) Worldwide HCC total 1,957 186 (10) 144 (7) 95 (5) ICC Zou et al (21) China (mainland) 103 11 (11) 8 (8) 3 (3) cHCC-ICC Xue et al (22) Asia ‡ 121 29 (24) 20 (17) 17 (14) *Indicates the estimated lower boundary of the 95% confidence interval of AA signature exposure > 0 (P < 0.05). † Indicates the estimated lower boundary of the 95% confidence interval of AA signature exposure no less than 20% (P < 0.05).…”

Impact factors that modulate gastric cancer risk in Helicobacter pylori‐infected rodent models

“…Chemical carcinogens are widely used to establish cancer-associated animal models. [61][62][63][64][65] MNNG and MNU, which belong to the family of N-nitroso compounds, are the two common carcinogens for constructing animal models of GC. Administration of these carcinogens can lead to a transition mutation between GC and AT base pairs and ultimately promote gastric carcinogenesis.…”