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

Clin Epigenetics. 2019 Jan 7;11(1):2. doi: 10.1186/s13148-018-0594-9.

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 O6-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 6 -methylguanine DNA methyltransferase; Succinate dehydrogenase; Wild-type GIST.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • DNA Methylation*
  • DNA Modification Methylases / genetics*
  • DNA Repair Enzymes / genetics*
  • Epigenesis, Genetic
  • Female
  • Gastrointestinal Neoplasms / genetics*
  • Gastrointestinal Stromal Tumors / genetics*
  • Humans
  • Male
  • Middle Aged
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-kit / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Succinate Dehydrogenase / deficiency
  • Tumor Suppressor Proteins / genetics*
  • Young Adult

Substances

  • Tumor Suppressor Proteins
  • Succinate Dehydrogenase
  • DNA Modification Methylases
  • MGMT protein, human
  • KIT protein, human
  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor alpha
  • DNA Repair Enzymes