Research Papers:

Are anaplastic lymphoma kinase (ALK) and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation driver biomarkers of pulmonary neuroendocrine tumors (NETs) and carcinomas (NECs)?

Birgitta Hiddinga _, Karen Zwaenepoel, Annelies Janssens, Jan Van Meerbeeck and Patrick Pauwels

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Oncotarget. 2022; 13:800-809. https://doi.org/10.18632/oncotarget.28240

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Birgitta Hiddinga1, Karen Zwaenepoel2, Annelies Janssens3, Jan Van Meerbeeck3 and Patrick Pauwels2

1 Department of Pulmonary Diseases, University Medical Center Groningen, Groningen, The Netherlands

2 Department of Pathology, Antwerp University Hospital, Edegem, Belgium

3 Department of Pulmonology and Thoracic Oncology, European Reference Network for Rare or Low Prevalence Lung Diseases: ERN-LUNG, Antwerp University Hospital, University of Antwerp, Edegem, Belgium

Correspondence to:

Birgitta Hiddinga, email: [email protected]

Keywords: MGMT promoter methylation; anaplastic lymphoma kinase; neuroendocrine tumor; neuroendocrine carcinoma; small cell lung cancer

Received: December 24, 2021     Accepted: May 07, 2022     Published: June 01, 2022

Copyright: © 2022 Hiddinga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Novel targets in neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are needed to improve outcome. The presence of O6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation in NETs and NECs may act as a predictive marker for response on treatment with temozolomide. As anaplastic lymphoma kinase (ALK) plays an important role in the nervous system we hypothesized that ALK rearrangement can act as a biomarker in patients with NETs and NECs.

Materials and Methods: We performed a retrospective analysis to establish the frequency of MGMT promoter methylation and ALK expression in tissue samples of patients with NETs and NECs.

Results: 21% (14/67) of patients tested positive for MGMT promoter methylation. MGMT promoter methylation was present in 33% (3/9) patients with typical carcinoid, in 22% (2/9) patients with atypical carcinoid, in 22% (8/37) patients with small cell lung cancer and in 8% (1/12) patient with large cell neuroendocrine carcinoma. ALK- expression was present in 14% (10 of 70 patients). In all of these patients, no ALK-rearrangement nor ALK-mutation was revealed.

Conclusions: Routine testing of NET and NEC samples for an ALK rearrangement is not recommended as ALK-expression is not associated with an ALK-rearrangement. Routine testing of NET and NEC samples for MGMT will detect a promoter hypermethylation in a sizable minority of patients who are eligible for a targeted treatment with temozolomide.

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