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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.

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