THE EXPRESSION OF LINE1-MET CHIMERIC TRANSCRIPT IDENTIFIES A SUBGROUP OF AGGRESSIVE BREAST CANCERS

Demethylation of the long interspersed nuclear element (LINE-1; L1) antisense promoter can result in transcription of neighbouring sequences as for the L1-MET transcript produced by the L1 placed in the second intron of MET. To define the role of L1-MET, we investigated the sequence and the transcription of L1-MET in vitro models and heterogeneous breast cancers, previously reported to show other L1-derived transcripts. L1-MET expressing cell lines were initially identified in silico and investigated for L1-MET promoter methylation, cDNA sequence and cell fraction mRNA. The transcriptional level of L1-MET and MET were then evaluated in breast specimens, including 9 cancer cell lines, 41 carcinomas of different subtypes, and 11 normal tissues. In addition to a L1-MET transcript ending at MET exon 21, six novel L1-MET splice variants were identified. Normal breast tissues were negative for the L1-MET expression, whereas the triple-negative breast cancer (TNBC) and the high-grade carcinomas were enriched with the L1-MET mRNA (P =0.005 and P=0.018, respectively). In cancer cells and tissues the L1-MET expression was associated with its promoter hypomethylation (ρ= -0.8 and -0.9, respectively). No correlation was found between L1-MET and MET mRNA although L1-MET expressing tumours with higher L1-MET/MET ratio were negative for the MET protein expression (P=0.006). Besides providing the first identification and detailed description of L1-MET in breast cancer, we clearly demonstrate that higher levels of this transcript specifically recognize a subset of more aggressive carcinomas, mainly TNBC. We suggest the possible evaluation of L1-MET in the challenging diagnosis of early TNBCs This article is protected by copyright. All rights reserved.