Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• LINE-1 (L1) retrotransposons are abundant mobile elements in the human genome.
• L1 insertions can impact gene function and disease, but their role in cancer is not fully understood.

Purpose of the Study:

• To investigate the mechanisms by which L1 retrotransposons contribute to hepatocellular carcinoma (HCC) tumorigenesis.
• To identify specific L1-mediated events driving liver cancer.

Main Methods:

• Utilized enhanced retrotransposon capture sequencing (RC-seq) on 19 HCC genomes.
• Performed experimental assays to confirm functional impacts of L1 insertions.

Main Results:

• Identified germline L1 retrotransposition events in the mutated in colorectal cancers (MCC) gene in 21.1% of HCC patients, leading to MCC expression ablation and Wnt signaling activation.
• Discovered tumor-specific L1 insertions activating suppression of tumorigenicity 18 (ST18) by disrupting a negative feedback loop.
• Observed frequent ST18 amplification in mouse HCC models, supporting its role as a liver oncogene.

Conclusions:

• L1 retrotransposition is a significant etiological factor in hepatocellular carcinoma.
• Two distinct L1-mediated mechanisms contribute to HCC development: inactivation of tumor suppressors and activation of oncogenes.