Abnormal MGMT Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical Outcome
Liping Lou,1,* Wendi Zhang,2,* Jun Li,1 Yu Wang1 1Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Sc...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2020-10-01
|
| Series: | Cancer Management and Research |
| Subjects: | |
| Online Access: | https://www.dovepress.com/abnormal-mgmt-promoter-methylation-in-gastrointestinal-stromal-tumors--peer-reviewed-article-CMAR |
| _version_ | 1828777317795627008 |
|---|---|
| author | Lou L Zhang W Li J Wang Y |
| author_facet | Lou L Zhang W Li J Wang Y |
| author_sort | Lou L |
| collection | DOAJ |
| description | Liping Lou,1,* Wendi Zhang,2,* Jun Li,1 Yu Wang1 1Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu WangInstitute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei Province, People’s Republic of ChinaEmail tongjisiyu@163.comPurpose: KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GISTs) represent a heterogeneous subgroup of GISTs that lack KIT or PDGFRA mutations and possess distinct genetic alterations and primary resistance to imatinib. Succinate dehydrogenase (SDH)-deficient GISTs comprise the largest subpopulation of WT GISTs that are characterized by loss-of-function of SDH. O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA repair enzyme that has been identified as a predictor of positive treatment response to alkylating agents in a variety of cancers. The aim of this study was to evaluate the expression of MGMT and the prevalence of MGMT promoter methylation in GISTs and to determine the association between MGMT promoter methylation and clinicopathological characteristics and clinical outcomes.Patients and Methods: A heterogeneous cohort of 137 primary GISTs that confirmed by immunohistochemistry and KIT/PDGFRA mutation analysis were retrospectively selected and analyzed for MGMT expression and MGMT promoter methylation using immunohistochemical staining and methylation-specific PCR (MSP). A concordance analysis between MGMT promoter methylation and clinicopathological characteristics and prognosis was also performed.Results: A total of 44.5% (65/137) of GIST patients displayed loss of MGMT protein expression, and 10.9% (15/137) of these patients exhibited MGMT promoter methylation. However, no significant correlation was observed between the loss of MGMT protein expression and MGMT promoter methylation. WT GISTs possessing an epithelioid or mixed phenotype, particularly those that were SDH-deficient, displayed a markedly higher prevalence of MGMT promoter methylation compared to that in KIT/PDGFRA mutated GISTs. Moreover, MGMT promoter methylation was identified as a potential independent prognostic factor for OS and DFS in patients with GIST.Conclusion: MGMT promoter methylation is particularly frequent in SDH-deficient GISTs and in WT GISTs possessing an epithelioid/mixed phenotype, and knowledge of this methylation status may offer a novel potential therapeutic option for WT GISTs.Keywords: gastrointestinal stromal tumor, O6-methylguanine-DNA methyltransferase, wild-type, succinate dehydrogenase deficiency |
| first_indexed | 2024-12-11T16:18:06Z |
| format | Article |
| id | doaj.art-6b7934a6cd5044129fc80bd28c5057e4 |
| institution | Directory Open Access Journal |
| issn | 1179-1322 |
| language | English |
| last_indexed | 2024-12-11T16:18:06Z |
| publishDate | 2020-10-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Cancer Management and Research |
| spelling | doaj.art-6b7934a6cd5044129fc80bd28c5057e42022-12-22T00:58:54ZengDove Medical PressCancer Management and Research1179-13222020-10-01Volume 129941995257989Abnormal MGMT Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical OutcomeLou LZhang WLi JWang YLiping Lou,1,* Wendi Zhang,2,* Jun Li,1 Yu Wang1 1Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu WangInstitute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei Province, People’s Republic of ChinaEmail tongjisiyu@163.comPurpose: KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GISTs) represent a heterogeneous subgroup of GISTs that lack KIT or PDGFRA mutations and possess distinct genetic alterations and primary resistance to imatinib. Succinate dehydrogenase (SDH)-deficient GISTs comprise the largest subpopulation of WT GISTs that are characterized by loss-of-function of SDH. O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA repair enzyme that has been identified as a predictor of positive treatment response to alkylating agents in a variety of cancers. The aim of this study was to evaluate the expression of MGMT and the prevalence of MGMT promoter methylation in GISTs and to determine the association between MGMT promoter methylation and clinicopathological characteristics and clinical outcomes.Patients and Methods: A heterogeneous cohort of 137 primary GISTs that confirmed by immunohistochemistry and KIT/PDGFRA mutation analysis were retrospectively selected and analyzed for MGMT expression and MGMT promoter methylation using immunohistochemical staining and methylation-specific PCR (MSP). A concordance analysis between MGMT promoter methylation and clinicopathological characteristics and prognosis was also performed.Results: A total of 44.5% (65/137) of GIST patients displayed loss of MGMT protein expression, and 10.9% (15/137) of these patients exhibited MGMT promoter methylation. However, no significant correlation was observed between the loss of MGMT protein expression and MGMT promoter methylation. WT GISTs possessing an epithelioid or mixed phenotype, particularly those that were SDH-deficient, displayed a markedly higher prevalence of MGMT promoter methylation compared to that in KIT/PDGFRA mutated GISTs. Moreover, MGMT promoter methylation was identified as a potential independent prognostic factor for OS and DFS in patients with GIST.Conclusion: MGMT promoter methylation is particularly frequent in SDH-deficient GISTs and in WT GISTs possessing an epithelioid/mixed phenotype, and knowledge of this methylation status may offer a novel potential therapeutic option for WT GISTs.Keywords: gastrointestinal stromal tumor, O6-methylguanine-DNA methyltransferase, wild-type, succinate dehydrogenase deficiencyhttps://www.dovepress.com/abnormal-mgmt-promoter-methylation-in-gastrointestinal-stromal-tumors--peer-reviewed-article-CMARgastrointestinal stromal tumoro6-methylguanine-dna methyltransferasewild-typesuccinate dehydrogenase deficiency |
| spellingShingle | Lou L Zhang W Li J Wang Y Abnormal MGMT Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical Outcome Cancer Management and Research gastrointestinal stromal tumor o6-methylguanine-dna methyltransferase wild-type succinate dehydrogenase deficiency |
| title | Abnormal MGMT Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical Outcome |
| title_full | Abnormal MGMT Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical Outcome |
| title_fullStr | Abnormal MGMT Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical Outcome |
| title_full_unstemmed | Abnormal MGMT Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical Outcome |
| title_short | Abnormal MGMT Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical Outcome |
| title_sort | abnormal mgmt promoter methylation in gastrointestinal stromal tumors genetic susceptibility and association with clinical outcome |
| topic | gastrointestinal stromal tumor o6-methylguanine-dna methyltransferase wild-type succinate dehydrogenase deficiency |
| url | https://www.dovepress.com/abnormal-mgmt-promoter-methylation-in-gastrointestinal-stromal-tumors--peer-reviewed-article-CMAR |
| work_keys_str_mv | AT loul abnormalmgmtpromotermethylationingastrointestinalstromaltumorsgeneticsusceptibilityandassociationwithclinicaloutcome AT zhangw abnormalmgmtpromotermethylationingastrointestinalstromaltumorsgeneticsusceptibilityandassociationwithclinicaloutcome AT lij abnormalmgmtpromotermethylationingastrointestinalstromaltumorsgeneticsusceptibilityandassociationwithclinicaloutcome AT wangy abnormalmgmtpromotermethylationingastrointestinalstromaltumorsgeneticsusceptibilityandassociationwithclinicaloutcome |