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

Christina Alidousty¹, Till Baar², Luciano G Martelotto³

¹University Hospital Cologne, Institute of Pathology, Cologne, Germany.

The Journal of Pathology

|June 10, 2018

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+ 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.

Insights

TP53 mutations in ALK-positive non-small cell lung cancer (NSCLC) drive chromosomal instability and gene amplifications, potentially leading to resistance to ALK inhibitors. This highlights greater tumor heterogeneity than previously understood.

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

Anaplastic lymphoma kinase (ALK) rearrangement is a key molecular subtype of non-small cell lung cancer (NSCLC).
ALK inhibitors show initial efficacy but resistance is common, with no reliable biomarkers for relapse risk.
TP53 mutations are frequently observed in various cancers but their role in ALK+ NSCLC is less understood.

Purpose of the Study:

To investigate the impact of TP53 mutations on chromosomal stability and gene alterations in ALK+ NSCLC.
To identify potential mechanisms of resistance to ALK inhibitors in TP53-mutated ALK+ NSCLC.
To explore the heterogeneity within the ALK+ NSCLC molecular subtype.

Main Methods:

NanoString nCounter technology was used to analyze 53 ALK+ NSCLC tumors and cell lines.
Comparative analysis of tumors with and without TP53 mutations.
Chromatin immunoprecipitation sequencing (ChIP-Seq) to identify MYC binding sites.

Main Results:

TP53 mutations co-occur with chromosomal instability in 24% of ALK+ NSCLC patients.
Amplifications of cancer genes including MYC, CCND1, TERT, BIRC2, ORAOV1, and YAP1 were observed in TP53-mutated tumors.
MYC overexpression in TP53-mutated cells led to increased EML4-ALK upregulation, suggesting a MYC-dependent resistance mechanism.

Conclusions:

TP53 mutations define a subset of ALK+ NSCLC with chromosomal instability and a higher burden of pathogenic aberrations.
MYC amplification and subsequent EML4-ALK upregulation represent a potential resistance mechanism to ALK inhibitors.
ALK+ NSCLC is more heterogeneous than previously recognized, with TP53 status being a key determinant.

Read full analysis

Keywords:

ALK+ adenocarcinoma TP53 chromosomal instability lung cancer

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