The expression of LINE1-MET chimeric transcript identifies a subgroup of aggressive breast cancers

Umberto Miglio, Enrico Berrino, Mara Panero, Giulio Ferrero, Lucia Coscujuela Tarrero, Valentina Miano, Carmine Dell'Aglio, Ivana Sarotto, Laura Annaratone, Caterina Marchiò, Paolo M. Comoglio, Michele De Bortoli, Barbara Pasini, Tiziana Venesio, Anna Sapino

Research output: Contribution to journalArticle

Abstract

Demethylation of the long interspersed nuclear element (LINE-1; L1) antisense promoter can result in transcription of neighboring 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 tumors 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.

Original languageEnglish
Pages (from-to)2838-2848
Number of pages11
JournalInternational Journal of Cancer
Volume143
Issue number11
DOIs
Publication statusPublished - Dec 1 2018

Keywords

  • breast cancer
  • chimeric transcript
  • L1-MET
  • LINE-1
  • triple negative breast cancer (TNBC)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Miglio, U., Berrino, E., Panero, M., Ferrero, G., Coscujuela Tarrero, L., Miano, V., Dell'Aglio, C., Sarotto, I., Annaratone, L., Marchiò, C., Comoglio, P. M., De Bortoli, M., Pasini, B., Venesio, T., & Sapino, A. (2018). The expression of LINE1-MET chimeric transcript identifies a subgroup of aggressive breast cancers. International Journal of Cancer, 143(11), 2838-2848. https://doi.org/10.1002/ijc.31831