Abstract
Dysplastic nodules are premalignant neoplastic nodules found in explanted livers with cirrhosis. Genetic signatures of premalignant dysplastic nodules (DNs) with concurrent hepatocellular carcinoma (HCC) may provide an insight in the molecular evolution of hepatocellular carcinogenesis. We analyzed four patients with multifocal nodular lesions and cirrhotic background by whole-exome sequencing (WES). The genomic profiles of somatic single nucleotide variations (SNV) and copy number variations (CNV) in DNs were compared to those of HCCs. The number and variant allele frequency of somatic SNVs of DNs and HCCs in each patient was identical along the progression of pathological grade. The somatic SNVs in DNs showed little conservation in HCC. Additionally, CNVs showed no conservation. Phylogenetic analysis based on SNVs and copy number profiles indicated a nonlinear segregation pattern, implying independent development of DNs and HCC in each patient. Thus, somatic mutations in DNs may be developed separately from other malignant nodules in the same liver, suggesting a nonlinear model for hepatocarcinogenesis from DNs to HCC.
Highlights
Hepatocellular carcinoma (HCC) develops in patients with chronic liver diseases [1, 2]
The single nucleotide variations (SNV) detected by default filters showed no significant difference in numbers and variant types between dysplastic nodules (DNs)
We identified 132.9±98.5 somatic single nucleotide variants (SNVs) per DN, and 128.7±147.1 SNVs per nodule for hepatocellular carcinoma (HCC)
Summary
Hepatocellular carcinoma (HCC) develops in patients with chronic liver diseases [1, 2]. Chronic hepatitis and cirrhosis make up the major premalignant conditions in most HCCs [3, 4]. Premalignant lesions may be caused by viral infection, environmental chemical carcinogens, fungal toxins, as well as genetic diseases. Numerous genetic alterations initiated by chronic hepatocyte destruction and regeneration can result in neoplastic growth. Premalignant lesions of HCCs have been designated as dysplastic nodules by the International Working Party. Dysplastic nodules, which usually occur in cirrhotic livers, are further classified into low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs) depending on the degree of cytological or architectural abnormalities on histological examination [5]
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