Preferential MGMT methylation could predispose a subset of KIT/PDGFRA-WT GISTs, including SDH-deficient ones, to respond to alkylating agents

Riccardo Ricci, Maurizio Martini, Gloria Ravegnini, Tonia Cenci, Massimo Milione, Paola Lanza, Francesco Pierconti, Donatella Santini, Sabrina Angelini, Alberto Biondi, Fausto Rosa, Sergio Alfieri, Gennaro Clemente, Roberto Persiani, Alessandra Cassano, Maria A. Pantaleo, Luigi M. Larocca

Research output: Contribution to journalArticle

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Abstract

Background: Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) constitute a small KIT/PDGFRA-WT GIST subgroup featuring DNA methylation which, although pervasive, appears nevertheless not randomly distributed. Although often indolent, these tumors are mostly chemorefractory in aggressive cases. Promoter methylation-induced O 6 -methylguanine DNA methyltransferase (MGMT) inactivation improves the efficacy of alkylating agents in gliomas, colorectal cancer and diffuse large B cell lymphoma. MGMT methylation has been found in some GISTs, without determining SDH status. Thirty-six GISTs were enrolled in past sarcoma trials testing alkylating agents, with negative results. Nevertheless, a possible effect on MGMT-methylated GISTs could have escaped detection, since tested GISTs were neither selected by genotype nor investigated for SDH; MGMT was studied in two cases only, revealing baseline activity; these trials were performed prior to the adoption of Choi criteria, the most sensitive for detecting GIST responses to therapy. Under these circumstances, we investigated whether MGMT methylation is preferentially found in SDH-deficient cases (identified by SDHB immunohistochemistry) by analyzing 48 pathogenetically heterogeneous GISTs by methylation-specific PCR, as a premise for possible investigations on the use of alkylating drugs in these tumors. Results: Nine GISTs of our series were SDH-deficient, revealing significantly enriched in MGMT-methylated cases (6/9-67%-, vs. 6/39-15%- of SDH-proficient GISTs; p = 0.004). The pathogenetically heterogeneous KIT/PDGFRA-WT GISTs were also significantly MGMT-methylated (11/24-46%-, vs. 1/24-4%- of KIT/PDGFRA-mutant cases, p = 0.002). Conclusions: A subset of KIT/PDGFRA-WT GISTs, including their largest pathogenetically characterized subgroup (i.e., SDH-deficient ones), is preferentially MGMT-methylated. This finding could foster a reappraisal of alkylating agents for treating malignant cases occurring among these overall chemorefractory tumors.

Original languageEnglish
Article number2
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 7 2019

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Gastrointestinal Stromal Tumors
Succinate Dehydrogenase
Alkylating Agents
Methyltransferases
DNA Methylation
DNA
Methylation
O(6)-Methylguanine-DNA Methyltransferase
Neoplasms
Lymphoma, Large B-Cell, Diffuse
Glioma
Sarcoma
Colorectal Neoplasms
Immunohistochemistry
Genotype

Keywords

  • DNA methylation
  • Gastrointestinal stromal tumors
  • Molecular diagnosis
  • O -methylguanine DNA methyltransferase
  • Succinate dehydrogenase
  • Wild-type GIST

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

Cite this

Preferential MGMT methylation could predispose a subset of KIT/PDGFRA-WT GISTs, including SDH-deficient ones, to respond to alkylating agents. / Ricci, Riccardo; Martini, Maurizio; Ravegnini, Gloria; Cenci, Tonia; Milione, Massimo; Lanza, Paola; Pierconti, Francesco; Santini, Donatella; Angelini, Sabrina; Biondi, Alberto; Rosa, Fausto; Alfieri, Sergio; Clemente, Gennaro; Persiani, Roberto; Cassano, Alessandra; Pantaleo, Maria A.; Larocca, Luigi M.

In: Clinical Epigenetics, Vol. 11, No. 1, 2, 07.01.2019.

Research output: Contribution to journalArticle

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title = "Preferential MGMT methylation could predispose a subset of KIT/PDGFRA-WT GISTs, including SDH-deficient ones, to respond to alkylating agents",
abstract = "Background: Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) constitute a small KIT/PDGFRA-WT GIST subgroup featuring DNA methylation which, although pervasive, appears nevertheless not randomly distributed. Although often indolent, these tumors are mostly chemorefractory in aggressive cases. Promoter methylation-induced O 6 -methylguanine DNA methyltransferase (MGMT) inactivation improves the efficacy of alkylating agents in gliomas, colorectal cancer and diffuse large B cell lymphoma. MGMT methylation has been found in some GISTs, without determining SDH status. Thirty-six GISTs were enrolled in past sarcoma trials testing alkylating agents, with negative results. Nevertheless, a possible effect on MGMT-methylated GISTs could have escaped detection, since tested GISTs were neither selected by genotype nor investigated for SDH; MGMT was studied in two cases only, revealing baseline activity; these trials were performed prior to the adoption of Choi criteria, the most sensitive for detecting GIST responses to therapy. Under these circumstances, we investigated whether MGMT methylation is preferentially found in SDH-deficient cases (identified by SDHB immunohistochemistry) by analyzing 48 pathogenetically heterogeneous GISTs by methylation-specific PCR, as a premise for possible investigations on the use of alkylating drugs in these tumors. Results: Nine GISTs of our series were SDH-deficient, revealing significantly enriched in MGMT-methylated cases (6/9-67{\%}-, vs. 6/39-15{\%}- of SDH-proficient GISTs; p = 0.004). The pathogenetically heterogeneous KIT/PDGFRA-WT GISTs were also significantly MGMT-methylated (11/24-46{\%}-, vs. 1/24-4{\%}- of KIT/PDGFRA-mutant cases, p = 0.002). Conclusions: A subset of KIT/PDGFRA-WT GISTs, including their largest pathogenetically characterized subgroup (i.e., SDH-deficient ones), is preferentially MGMT-methylated. This finding could foster a reappraisal of alkylating agents for treating malignant cases occurring among these overall chemorefractory tumors.",
keywords = "DNA methylation, Gastrointestinal stromal tumors, Molecular diagnosis, O -methylguanine DNA methyltransferase, Succinate dehydrogenase, Wild-type GIST",
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T1 - Preferential MGMT methylation could predispose a subset of KIT/PDGFRA-WT GISTs, including SDH-deficient ones, to respond to alkylating agents

AU - Ricci, Riccardo

AU - Martini, Maurizio

AU - Ravegnini, Gloria

AU - Cenci, Tonia

AU - Milione, Massimo

AU - Lanza, Paola

AU - Pierconti, Francesco

AU - Santini, Donatella

AU - Angelini, Sabrina

AU - Biondi, Alberto

AU - Rosa, Fausto

AU - Alfieri, Sergio

AU - Clemente, Gennaro

AU - Persiani, Roberto

AU - Cassano, Alessandra

AU - Pantaleo, Maria A.

AU - Larocca, Luigi M.

PY - 2019/1/7

Y1 - 2019/1/7

N2 - Background: Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) constitute a small KIT/PDGFRA-WT GIST subgroup featuring DNA methylation which, although pervasive, appears nevertheless not randomly distributed. Although often indolent, these tumors are mostly chemorefractory in aggressive cases. Promoter methylation-induced O 6 -methylguanine DNA methyltransferase (MGMT) inactivation improves the efficacy of alkylating agents in gliomas, colorectal cancer and diffuse large B cell lymphoma. MGMT methylation has been found in some GISTs, without determining SDH status. Thirty-six GISTs were enrolled in past sarcoma trials testing alkylating agents, with negative results. Nevertheless, a possible effect on MGMT-methylated GISTs could have escaped detection, since tested GISTs were neither selected by genotype nor investigated for SDH; MGMT was studied in two cases only, revealing baseline activity; these trials were performed prior to the adoption of Choi criteria, the most sensitive for detecting GIST responses to therapy. Under these circumstances, we investigated whether MGMT methylation is preferentially found in SDH-deficient cases (identified by SDHB immunohistochemistry) by analyzing 48 pathogenetically heterogeneous GISTs by methylation-specific PCR, as a premise for possible investigations on the use of alkylating drugs in these tumors. Results: Nine GISTs of our series were SDH-deficient, revealing significantly enriched in MGMT-methylated cases (6/9-67%-, vs. 6/39-15%- of SDH-proficient GISTs; p = 0.004). The pathogenetically heterogeneous KIT/PDGFRA-WT GISTs were also significantly MGMT-methylated (11/24-46%-, vs. 1/24-4%- of KIT/PDGFRA-mutant cases, p = 0.002). Conclusions: A subset of KIT/PDGFRA-WT GISTs, including their largest pathogenetically characterized subgroup (i.e., SDH-deficient ones), is preferentially MGMT-methylated. This finding could foster a reappraisal of alkylating agents for treating malignant cases occurring among these overall chemorefractory tumors.

AB - Background: Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) constitute a small KIT/PDGFRA-WT GIST subgroup featuring DNA methylation which, although pervasive, appears nevertheless not randomly distributed. Although often indolent, these tumors are mostly chemorefractory in aggressive cases. Promoter methylation-induced O 6 -methylguanine DNA methyltransferase (MGMT) inactivation improves the efficacy of alkylating agents in gliomas, colorectal cancer and diffuse large B cell lymphoma. MGMT methylation has been found in some GISTs, without determining SDH status. Thirty-six GISTs were enrolled in past sarcoma trials testing alkylating agents, with negative results. Nevertheless, a possible effect on MGMT-methylated GISTs could have escaped detection, since tested GISTs were neither selected by genotype nor investigated for SDH; MGMT was studied in two cases only, revealing baseline activity; these trials were performed prior to the adoption of Choi criteria, the most sensitive for detecting GIST responses to therapy. Under these circumstances, we investigated whether MGMT methylation is preferentially found in SDH-deficient cases (identified by SDHB immunohistochemistry) by analyzing 48 pathogenetically heterogeneous GISTs by methylation-specific PCR, as a premise for possible investigations on the use of alkylating drugs in these tumors. Results: Nine GISTs of our series were SDH-deficient, revealing significantly enriched in MGMT-methylated cases (6/9-67%-, vs. 6/39-15%- of SDH-proficient GISTs; p = 0.004). The pathogenetically heterogeneous KIT/PDGFRA-WT GISTs were also significantly MGMT-methylated (11/24-46%-, vs. 1/24-4%- of KIT/PDGFRA-mutant cases, p = 0.002). Conclusions: A subset of KIT/PDGFRA-WT GISTs, including their largest pathogenetically characterized subgroup (i.e., SDH-deficient ones), is preferentially MGMT-methylated. This finding could foster a reappraisal of alkylating agents for treating malignant cases occurring among these overall chemorefractory tumors.

KW - DNA methylation

KW - Gastrointestinal stromal tumors

KW - Molecular diagnosis

KW - O -methylguanine DNA methyltransferase

KW - Succinate dehydrogenase

KW - Wild-type GIST

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