TY - JOUR
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 Maria
PY - 2019
Y1 - 2019
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 - Developmental Biology
KW - Gastrointestinal stromal tumors
KW - Genetics
KW - Genetics (clinical)
KW - Molecular Biology
KW - Molecular diagnosis
KW - O 6 -methylguanine DNA methyltransferase
KW - Succinate dehydrogenase
KW - Wild-type GIST
KW - DNA methylation
KW - Developmental Biology
KW - Gastrointestinal stromal tumors
KW - Genetics
KW - Genetics (clinical)
KW - Molecular Biology
KW - Molecular diagnosis
KW - O 6 -methylguanine DNA methyltransferase
KW - Succinate dehydrogenase
KW - Wild-type GIST
UR - http://hdl.handle.net/10807/129422
UR - http://www.springer.com/biomed/human+genetics/journal/13148
U2 - 10.1186/s13148-018-0594-9
DO - 10.1186/s13148-018-0594-9
M3 - Article
SN - 1868-7083
VL - 11
SP - N/A-N/A
JO - Clinical Epigenetics
JF - Clinical Epigenetics
ER -