Investigation of the involvement of chromosomal rearrangements in the hepatocarcinogenic process of acetamide in rats

Abstract

Aim:

Acetamide (AA) found in various foods is a potent carcinogen in rat liver. We have shown that AA induces characteristic large micronuclei in rat hepatocytes which show chromothripsis-like molecular pathological features. To clarify the involvement of chromothripsis in AA hepatocarcinogenesis, we performed mutation analysis using a next-generation sequencing (NGS) and optical genome mapping (OGM) on AA-induced rat liver tumors.

Method:

6-week-old male F344 rats were given a diet containing 2.5% AA for 26～30 weeks. Normal livers in the control group, hepatocellular adenoma and carcinoma in the AA-treated group were subjected to NGS and OGM analysis.

Results:

In NGS analysis, large and random copy number gains were observed in AA-induced liver tumors on various chromosomes, and copy number gains of Chr7 including the oncogenes c-Myc and MDM2 were commonly observed. In OGS analysis, drastic interchromosomal translocations were observed in AA-induced liver tumors.

Discussion:

Chromothripsis is known to cause complex copy number and structural alterations through chromosome shattering and rearrangement. The large and random copy number gains and drastic interchromosomal translocations observed in AA-induced liver tumors supported the involvement of chromothripsis in the hepatocarcinogenesis of AA. The detailed locus of chromosomal translocations and their relationship with copy number gains of oncogenes is currently under investigation.