Evidence for L1-associated DNA rearrangements and negligible L1 retrotransposition in glioblastoma multiforme

Patricia Carreira, Adam D Ewing, Guibo Li, Stephanie N. Schauer, Kyle R Upton, Allister C. Fagg, Santiago Morell, Michaela Kindlova, Patricia Gerdes, Sandra R Richardson, Bo Li, Daniel J Gerhardt, Wang Jun, Paul Brennan, Geoffrey J. Faulkner

Research output: Contribution to journalArticlepeer-review

Abstract

Background
LINE-1 (L1) retrotransposons are a notable endogenous source of mutagenesis in mammals. Notably, cancer cells can support unusual L1 retrotransposition and L1-associated sequence rearrangement mechanisms following DNA damage. Recent reports suggest that L1 is mobile in epithelial tumours and neural cells but, paradoxically, not in brain cancers.
Results
Here, using retrotransposon capture sequencing (RC-seq), we surveyed L1 mutations in 14 tumours classified as glioblastoma multiforme (GBM) or as a lower grade glioma. In four GBM tumours, we characterised one probable endonuclease-independent L1 insertion, two L1-associated rearrangements and one likely Alu-Alu recombination event adjacent to an L1. These mutations included PCR validated intronic events in MeCP2 and EGFR. Despite sequencing L1 integration sites at up to 250x depth by RC-seq, we found no tumour-specific, endonuclease-dependent L1 insertions. Whole genome sequencing analysis of the tumours carrying the MeCP2 and EGFR L1 mutations also revealed no endonuclease-dependent L1 insertions. In a complementary in vitro assay, wild-type and endonuclease mutant L1 reporter constructs each mobilised very inefficiently in four cultured GBM cell lines.
Conclusions
These experiments altogether highlight the consistent absence of canonical L1 retrotransposition in GBM tumours and cultured cell lines, as well as atypical L1-associated sequence rearrangements following DNA damage in vivo.
Original languageEnglish
JournalMobile DNA
Early online date11 Nov 2016
DOIs
Publication statusE-pub ahead of print - 11 Nov 2016

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