> Details

Alidousty, Christina; Baar, Till; Martelotto, Luciano G; Heydt, Carina; Wagener, Svenja; Fassunke, Jana; Duerbaum, Nicolai; Scheel, Andreas H; Frank, Sandra; Holz, Barbara; Binot, Elke; Kron, Anna; Merkelbach‐Bruse, Sabine; Ihle, Michaela A; Wolf, Jürgen; Buettner, Reinhard; Schultheis, Anne Maria

Genetic instability and recurrent MYC amplification in ALK‐translocated NSCLC: a central role of TP53 mutations

Reference
management

Bookmarks

Remove from
bookmarks

Share this on Whatsapp

Close

Bookmarks



You can manage bookmarks using lists, please log in to your user account for this.
  • Media type: E-Article
  • Title: Genetic instability and recurrent MYC amplification in ALK‐translocated NSCLC: a central role of TP53 mutations
  • Contributor: Alidousty, Christina; Baar, Till; Martelotto, Luciano G; Heydt, Carina; Wagener, Svenja; Fassunke, Jana; Duerbaum, Nicolai; Scheel, Andreas H; Frank, Sandra; Holz, Barbara; Binot, Elke; Kron, Anna; Merkelbach‐Bruse, Sabine; Ihle, Michaela A; Wolf, Jürgen; Buettner, Reinhard; Schultheis, Anne Maria
  • imprint: Wiley, 2018
  • Published in: The Journal of Pathology
  • Language: English
  • DOI: 10.1002/path.5110
  • ISSN: 1096-9896; 0022-3417
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>The anaplastic lymphoma kinase (<jats:italic>ALK</jats:italic>) rearrangement defines a distinct molecular subtype of non‐small cell lung cancer (NSCLC). Despite the excellent initial efficacy of ALK inhibitors in patients with <jats:italic>ALK+</jats:italic> lung cancer, resistance occurs almost inevitably. To date, there is no reliable biomarker allowing the identification of patients at higher risk of relapse. Here, we analysed a subset of 53 <jats:italic>ALK+</jats:italic> tumours with and without <jats:italic>TP53</jats:italic> mutation and <jats:italic>ALK+</jats:italic> NSCLC cell lines by NanoString nCounter technology. We found that the co‐occurrence of early <jats:italic>TP53</jats:italic> mutations in <jats:italic>ALK+</jats:italic> NSCLC can lead to chromosomal instability: 24% of <jats:italic>TP53</jats:italic>‐mutated patients showed amplifications of known cancer genes such as <jats:italic>MYC</jats:italic> (14%), <jats:italic>CCND1</jats:italic> (10%), <jats:italic>TERT</jats:italic> (5%), <jats:italic>BIRC2</jats:italic> (5%), <jats:italic>ORAOV1</jats:italic> (5%), and <jats:italic>YAP1</jats:italic> (5%). MYC‐overexpressing <jats:italic>ALK+ TP53</jats:italic>‐mutated cells had a proliferative advantage compared to wild‐type cells. ChIP‐Seq data revealed MYC‐binding sites within the promoter region of <jats:italic>EML4</jats:italic>, and MYC overexpression in <jats:italic>ALK</jats:italic>+ <jats:italic>TP53</jats:italic>‐mutated cells resulted in an upregulation of EML4–ALK, indicating a potential MYC‐dependent resistance mechanism in patients with increased <jats:italic>MYC</jats:italic> copy number. Our study reveals that <jats:italic>ALK+</jats:italic> NSCLC represents a more heterogeneous subgroup of tumours than initially thought, and that <jats:italic>TP53</jats:italic> mutations in that particular cancer type define a subset of tumours that harbour chromosomal instability, leading to the co‐occurrence of pathogenic aberrations. © 2018 The Authors. <jats:italic>The Journal of Pathology</jats:italic> published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</jats:p>