Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma
Menée sur des échantillons tumoraux prélevés sur 19 patients atteints d'un carcinome hépatocellulaire et à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels des rétrotransposons activent des oncogènes dans le foie de patients infectés par un virus de l'hépatite B ou C
LINE-1 (L1) retrotransposons are mobile genetic elements comprising <17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic ²-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2 / mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC. º L1 retrotransposons promote tumorigenesis in hepatocellular carcinoma (HCC) º Germline L1 and Alu insertions in MCC activate ²-catenin/Wnt signaling º L1 mobilization in tumor cells accelerates transformation of the HCC genome º A tumor-specific L1 insertion interrupts a negative feedback loop regulating ST18 L1 retrotransposons, which are widespread in the human genome, can mobilize and activate oncogenes in the livers of individuals infected with the hepatitis B or hepatitis C virus, promoting the development and growth of hepatocellular carcinoma. Genes identified by the L1 insertions present new options for cancer screening and intervention.