Open Access

ARTICLE

Evaluation of MGMT Gene Methylation in Neuroendocrine Neoplasms

Rosa Della Monica^*1, Mariella Cuomo^*†1, Roberta Visconti^‡, Annabella di Mauro^§, Michela Buonaiuto^*, Davide Costabile^*†, Giulia De Riso^†, Teodolinda Di Risi^*, Elia Guadagno^¶, Roberto Tafuto^#, Sabrina Lamia^**, Alessandro Ottaiano^††, Paolo Cappabianca^#, Maria Laura Del Basso de Caro^¶, Fabiana Tatangelo^§, Juergen Hench^‡‡, Stephan Frank^‡‡, Salvatore Tafuto^**, Lorenzo Chiariotti^*†

* CEINGE Biotecnologie Avanzate, Naples, Italy
† Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II,” Naples, Italy
‡ Institute of Experimental Endocrinology and Oncology, Italian National Council of Research, Naples, Italy
§ Department of Pathology, National Cancer Institute, IRCCS-Foundation “G. Pascale,” Naples, Italy
¶ Department of Advanced Biomedical Sciences, Section of Pathology, University of Naples “Federico II,” Naples, Italy
# Division of Neurosurgery, University of Naples “Federico II,” Naples, Italy
** S.C. Sarcomas and Rare Tumors, National Cancer Institute, IRCCS-Foundation “G. Pascale,” Naples, Italy
†† Department of Abdominal Oncology, National Cancer Institute, IRCCS-Foundation “G. Pascale,” Naples, Italy
‡‡ Institute for Medical Genetics and Pathology, Division of Neuropathology, University Hospital Basel, Basel, Switzerland

Oncology Research 2020, 28(9), 837-845. https://doi.org/10.3727/096504021X16214197880808

Abstract

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O6 -methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high-resolution, next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in welldifferentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs.

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