Alidousty, Christina, Baar, Till ORCID: 0000-0002-6744-1463, 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, Juergen, Buettner, Reinhard and Schultheis, Anne Maria (2018). Genetic instability and recurrent MYC amplification in ALK-translocated NSCLC: a central role of TP53 mutations. J. Pathol., 246 (1). S. 67 - 77. HOBOKEN: WILEY. ISSN 1096-9896

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Abstract

The anaplastic lymphoma kinase (ALK) rearrangement defines a distinct molecular subtype of non-small cell lung cancer (NSCLC). Despite the excellent initial efficacy of ALK inhibitors in patients with ALK+ 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 ALK+ tumors with and without TP53 mutation and ALK+ NSCLC cell lines by NanoString nCounter technology. We found that the co-occurrence of early TP53 mutations in ALK+ NSCLC can lead to chromosomal instability: 24% of TP53-mutated patients showed amplifications of known cancer genes such as MYC (14%), CCND1 (10%), TERT (5%), BIRC2 (5%), ORAOV1 (5%), and YAP1 (5%). MYC-overexpressing ALK+ TP53-mutated cells had a proliferative advantage compared to wild-type cells. ChIP-Seq data revealed MYC-binding sites within the promoter region of EML4, and MYC overexpression in ALK+ TP53-mutated cells resulted in an upregulation of EML4-ALK, indicating a potential MYC-dependent resistance mechanism in patients with increased MYC copy number. Our study reveals that ALK+ NSCLC represents a more heterogeneous subgroup of tumors than initially thought, and that TP53 mutations in that particular cancer type define a subset of tumors that harbour chromosomal instability, leading to the co-occurrence of pathogenic aberrations. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Alidousty, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baar, TillUNSPECIFIEDorcid.org/0000-0002-6744-1463UNSPECIFIED
Martelotto, Luciano G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heydt, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagener, SvenjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fassunke, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duerbaum, NicolaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheel, Andreas H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frank, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holz, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Binot, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kron, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ihle, Michaela A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schultheis, Anne MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-173722
DOI: 10.1002/path.5110
Journal or Publication Title: J. Pathol.
Volume: 246
Number: 1
Page Range: S. 67 - 77
Date: 2018
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1096-9896
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
C-MYC; CRIZOTINIB RESISTANCE; LUNG; P53; REARRANGEMENTS; EXPRESSION; LANDSCAPE; PROTEIN; CELLS; EGFRMultiple languages
Oncology; PathologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17372

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