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Genetic instability and recurrent MYC amplification in ALK‐ translocated NSCLC: a central role of TP53 mutations
Author(s) -
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,
MerkelbachBruse Sabine,
Ihle Michaela A,
Wolf Jürgen,
Buettner Reinhard,
Schultheis Anne Maria
Publication year - 2018
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5110
Subject(s) - anaplastic lymphoma kinase , cancer research , chromosome instability , biology , lung cancer , cancer , mutation , fluorescence in situ hybridization , targeted therapy , genome instability , gene , microbiology and biotechnology , medicine , genetics , pathology , dna damage , malignant pleural effusion , chromosome , dna
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+ tumours 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 tumours than initially thought, and that TP53 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. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.