Stefanie Kewitz-Hempel1,2,3, Lars Kurch4, Michaela Cepelova5, Ines Volkmer1, Axel Sauerbrey6, Elke Conrad7, Stephanie Knirsch8, Gabriele Pöpperl9, Daniel Steinbach10, Ambros J Beer11, Christof M Kramm1,12, Carsten-Oliver Sahlmann13, Bernhard Erdlenbruch14, Wolf-Dieter Reinbold15, Andreas Odparlik16, Osama Sabri4, Regine Kluge17, Martin S Staege18. 1. Department of Pediatrics I, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle, Germany. 2. Department of Pediatric Hematology and Oncology, Justus Liebig University, Giessen, Germany. 3. Department of Dermatology and Venereology, Martin Luther University Halle-Wittenberg, Halle, Germany. 4. Department of Nuclear Medicine, University Hospital of Leipzig, 04103, Leipzig, Germany. 5. Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Praha, Czech Republic. 6. Helios Childrens Hospital, Erfurt, Germany. 7. Department of Nuclear Medicine, Helios Hospital Erfurt, Erfurt, Germany. 8. Pediatrics 5 (Oncology, Hematology, and Immunology), Klinikum Stuttgart, Olgahospital, Stuttgart, Germany. 9. Department of Nuclear Medicine, Klinikum Stuttgart, Olgahospital, Stuttgart, Germany. 10. Department of Pediatric Hematology and Oncology, University Hospital Ulm, Ulm, Germany. 11. Department of Nuclear Medicine, University Hospital, Ulm, Germany. 12. Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany. 13. Department of Nuclear Medicine, Georg August University, Göttingen, Germany. 14. University Hospital for Children and Adolescents, Johannes Wesling Klinikum Minden, Ruhr University Hospital, Bochum, Germany. 15. Universitätsinstitut für Diagnostische Radiologie, Neuroradiologie und Nuklearmedizin, Johannes Wesling Klinikum Minden, Ruhr University Hospital, Bochum, Germany. 16. Department of Nuclear Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany. 17. Department of Nuclear Medicine, University Hospital of Leipzig, 04103, Leipzig, Germany. Regine.Kluge@medizin.uni-leipzig.de. 18. Department of Pediatrics I, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle, Germany. martin.staege@medizin.uni-halle.de.
Abstract
PURPOSE: The enzyme O6-methylguanine-DNA methyltransferase (MGMT) is an important component of the DNA repair machinery. MGMT removes O6-methylguanine from the DNA by transferring the methyl group to a cysteine residue in its active site. Recently, we detected the single nucleotide polymorphism (SNP) rs12917 (C/T) in the MGMT sequence adjacent to the active site in Hodgkin lymphoma (HL) cell line KM-H2. We now investigated whether this SNP is also present in other HL cell lines and patient samples. Furthermore, we asked whether this SNP might have an impact on metabolic response in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET), and on overall treatment outcome based on follow-up intervals of at least 34 months. PROCEDURES: We determined the frequency of this MGMT polymorphism in 5 HL cell lines and in 29 pediatric HL (PHL) patients. The patient cohort included 17 female and 12 male patients aged between 4 and 18 years. After characterization of the sequence, we tested a possible association between rs12917 and age, gender, Ann Arbor stage, treatment group, metabolic response following two courses of OEPA (vincristine, etoposide, prednisone, and doxorubicin) chemotherapy, radiotherapy indication, and relapse status. RESULTS: We detected the minor T allele in four of five HL cell lines. 11/29 patients carried the minor T allele whereas 18/29 patients showed homozygosity for the major C allele. Interestingly, we observed significantly better metabolic response in PHL patients carrying the rs12917 C allele resulting in a lower frequency of radiotherapy indication. CONCLUSION: MGMT polymorphism rs12917 seems to affect chemotherapy response in PHL. The prognostic value of this polymorphism should be investigated in a larger patient cohort.
PURPOSE: The enzyme O6-methylguanine-DNA methyltransferase (MGMT) is an important component of the DNA repair machinery. MGMT removes O6-methylguanine from the DNA by transferring the methyl group to a cysteine residue in its active site. Recently, we detected the single nucleotide polymorphism (SNP) rs12917 (C/T) in the MGMT sequence adjacent to the active site in Hodgkin lymphoma (HL) cell line KM-H2. We now investigated whether this SNP is also present in other HL cell lines and patient samples. Furthermore, we asked whether this SNP might have an impact on metabolic response in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET), and on overall treatment outcome based on follow-up intervals of at least 34 months. PROCEDURES: We determined the frequency of this MGMT polymorphism in 5 HL cell lines and in 29 pediatric HL (PHL) patients. The patient cohort included 17 female and 12 male patients aged between 4 and 18 years. After characterization of the sequence, we tested a possible association between rs12917 and age, gender, Ann Arbor stage, treatment group, metabolic response following two courses of OEPA (vincristine, etoposide, prednisone, and doxorubicin) chemotherapy, radiotherapy indication, and relapse status. RESULTS: We detected the minor T allele in four of five HL cell lines. 11/29 patients carried the minor T allele whereas 18/29 patients showed homozygosity for the major C allele. Interestingly, we observed significantly better metabolic response in PHL patients carrying the rs12917 C allele resulting in a lower frequency of radiotherapy indication. CONCLUSION:MGMT polymorphism rs12917 seems to affect chemotherapy response in PHL. The prognostic value of this polymorphism should be investigated in a larger patient cohort.
Authors: Christine Mauz-Körholz; Monika L Metzger; Kara M Kelly; Cindy L Schwartz; Mauricio E Castellanos; Karin Dieckmann; Regine Kluge; Dieter Körholz Journal: J Clin Oncol Date: 2015-08-24 Impact factor: 44.544
Authors: L Kurch; C Mauz-Körholz; S Bertling; M Wallinder; M Kaminska; D Marwede; L Tchavdarova; T W Georgi; A Elsner; A Barthel; D Stoevesandt; D Hasenclever; B Sattler; O Sabri; D Körholz; R Kluge Journal: Klin Padiatr Date: 2013-10-28 Impact factor: 1.349
Authors: Edith Molina; Rebeca Pérez-Morales; Julieta Rubio; Pavel Petrosyan; Leticia Hernández Cadena; Volker M Arlt; David H Phillips; María E Gonsebatt Journal: Mutat Res Date: 2013-09-29 Impact factor: 2.433