Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma

Abstract

SummaryLINE-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 β-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.

Human transposon insertion profiling: Analysis, visualization and identification of somatic LINE-1 insertions in ovarian cancer

“…This conclusion is even more true for Alu insertion variants (45,46). These studies have also demonstrated that several types of epithelial cancers acquire somatic insertions of LINE-1 as they develop (15,19,24,26). Recent projects mining whole-genome sequencing data have extended our understanding of the scope of heritable LINE-1 insertions (20,21,47) and somatic retrotransposition (22,23,48) greatly.…”

“…The reference genome assembly captures fixed alleles and high-frequency alleles, but does not encompass many common variants (17). Targeted methods for recovering LINE-1 insertions for next-generation sequencing are new technologies, and include approaches developed by Rahbari and Badge (38), Devine and co-workers (15), Faulkner and coworkers (19,39,40), Kazazian and co-workers (16,41), Deininger and co-workers (42), and Gage and co-workers (43), as well as our own approaches. Collectively, their application has reinforced that LINE-1 is an important source of structural variation in humans and contributed to a growing database of LINE-1 insertion polymorphisms (44).…”

“…Because of these barriers, and assumptions that interspersed repeats are not functional, characterizations of these sequences have been incomplete. Recently, however, strategies for mapping these elements have been developed based on selective PCR amplification (15)(16)(17), hybridizationbased enrichment (18,19), and read selection from wholegenome sequencing data (20)(21)(22). These studies underscore the continued activity of LINE-1 in modern humans, and demonstrated somatic insertions in several types of human malignancy (15,19,(22)(23)(24)(25)(26)(27).…”

miR-128 represses L1 retrotransposition by binding directly to L1 RNA

“…L1 mobilizes replicatively from one location in the genome to another by a 'copy-and-paste' mechanism, and it has been proposed to be a remnant of an ancient retrovirus 12,16 . Active and inactive L1s have been implicated in the evolution of mammalian genomes and are linked to cell-based diseases, including cancer [17][18][19] . In addition, somatic L1 insertions are biased toward regions of cancer-specific DNA hypomethylation, thus suggesting that L1 insertions may provide a selective advantage during tumorigenesis 20 .…”

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

“…Accordingly, secreted cytokines and effector molecules, which are abundant in the tumor microenvironment, could constitute suitable targets for treatment and primary prevention of HCC ( 26 ). Here, we used Mdr2 -defi cient mice ( Mdr2 −/− ), which develop chronic liver infl ammation, eventually leading to infl ammationinduced liver tumors similar to human HCC ( 27,28 ), to look for candidate treatment targets modulating the tumor microenvironment that are relevant to human HCC.…”