Impact of Rs12917 MGMT Polymorphism on [F]FDG-PET Response in Pediatric Hodgkin Lymphoma (PHL)

Overview

Journal Mol Imaging Biol

Publisher Springer

Specialties Molecular Biology
Radiology

Date 2019 Apr 5

PMID 30945122

Authors

Stefanie Kewitz-Hempel

Lars Kurch

Michaela Cepelova

Ines Volkmer

Axel Sauerbrey

Elke Conrad

Stephanie Knirsch

Gabriele Popperl

Daniel Steinbach

Ambros J Beer

Christof M Kramm

Carsten-Oliver Sahlmann

Bernhard Erdlenbruch

Wolf-Dieter Reinbold

Andreas Odparlik

Osama Sabri

Regine Kluge

Martin S Staege

Affiliations

Soon will be listed here.

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-[F]fluoro-D-glucose positron emission tomography ([F]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.

References

Kewitz S, Stiefel M, Kramm C, Staege M . Impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression on dacarbazine resistance of Hodgkin's lymphoma cells. Leuk Res. 2013; 38(1):138-43. DOI: 10.1016/j.leukres.2013.11.001. View

Kuhnol C, Staege M, Kramm C . Lenalidomide in an in vitro Dendritic Cell Model for Malignant Gliomas. Anticancer Agents Med Chem. 2016; 16(11):1468-1473. DOI: 10.2174/1871520616666160219131657. View

Jiao J, Zheng T, Lan Q, Chen Y, Deng Q, Bi X . Occupational solvent exposure, genetic variation of DNA repair genes, and the risk of non-Hodgkin's lymphoma. Eur J Cancer Prev. 2012; 21(6):580-4. PMC: 3397155. DOI: 10.1097/CEJ.0b013e328351c762. View

Mauz-Korholz C, Hasenclever D, Dorffel W, Ruschke K, Pelz T, Voigt A . Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: the GPOH-HD-2002 study. J Clin Oncol. 2010; 28(23):3680-6. DOI: 10.1200/JCO.2009.26.9381. View

Hasenclever D, Kurch L, Mauz-Korholz C, Elsner A, Georgi T, Wallace H . qPET - a quantitative extension of the Deauville scale to assess response in interim FDG-PET scans in lymphoma. Eur J Nucl Med Mol Imaging. 2014; 41(7):1301-8. DOI: 10.1007/s00259-014-2715-9. View

Bugni J, Han J, Tsai M, Hunter D, Samson L . Genetic association and functional studies of major polymorphic variants of MGMT. DNA Repair (Amst). 2007; 6(8):1116-26. DOI: 10.1016/j.dnarep.2007.03.023. View

Kurch L, Mauz-Korholz C, Bertling S, Wallinder M, Kaminska M, Marwede D . The EuroNet paediatric hodgkin network - modern imaging data management for real time central review in multicentre trials. Klin Padiatr. 2013; 225(6):357-61. DOI: 10.1055/s-0033-1354416. View

Mauz-Korholz C, Metzger M, Kelly K, Schwartz C, Castellanos M, Dieckmann K . Pediatric Hodgkin Lymphoma. J Clin Oncol. 2015; 33(27):2975-85. DOI: 10.1200/JCO.2014.59.4853. View

Molina E, Perez-Morales R, Rubio J, Petrosyan P, Hernandez Cadena L, Arlt V . The GSTM1null (deletion) and MGMT84 rs12917 (Phe/Phe) haplotype are associated with bulky DNA adduct levels in human leukocytes. Mutat Res Genet Toxicol Environ Mutagen. 2013; 758(1-2):62-8. DOI: 10.1016/j.mrgentox.2013.09.007. View

10.

Esteller M, Hamilton S, Burger P, Baylin S, Herman J . Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 1999; 59(4):793-7. View

11.

Loh Y, Mitrou P, Wood A, Luben R, McTaggart A, Khaw K . SMAD7 and MGMT genotype variants and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study. Cancer Epidemiol. 2010; 35(4):369-74. DOI: 10.1016/j.canep.2010.09.011. View

12.

Ayi T, Loh K, Ali R, Li B . Intracellular localization of human DNA repair enzyme methylguanine-DNA methyltransferase by antibodies and its importance. Cancer Res. 1992; 52(23):6423-30. View

13.

Bobustuc G, Kassam A, Rovin R, Jeudy S, Smith J, Isley B . MGMT inhibition in ER positive breast cancer leads to CDC2, TOP2A, AURKB, CDC20, KIF20A, Cyclin A2, Cyclin B2, Cyclin D1, ERα and Survivin inhibition and enhances response to temozolomide. Oncotarget. 2018; 9(51):29727-29742. PMC: 6049872. DOI: 10.18632/oncotarget.25696. View

14.

Altinoz M, Elmaci I, Bolukbasi F, Gokhan Ekmekci C, Yenmis G, Sari R . MGMT gene variants, temozolomide myelotoxicity and glioma risk. A concise literature survey including an illustrative case. J Chemother. 2017; 29(4):238-244. DOI: 10.1080/1120009X.2017.1312752. View

15.

Remington M, Chtchetinin J, Ancheta K, Nghiemphu P, Cloughesy T, Lai A . The L84F polymorphic variant of human O6-methylguanine-DNA methyltransferase alters stability in U87MG glioma cells but not temozolomide sensitivity. Neuro Oncol. 2008; 11(1):22-32. PMC: 2718956. DOI: 10.1215/15228517-2008-080. View

16.

Hegi M, Diserens A, Gorlia T, Hamou M, De Tribolet N, Weller M . MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005; 352(10):997-1003. DOI: 10.1056/NEJMoa043331. View

17.

Cheson B, Fisher R, Barrington S, Cavalli F, Schwartz L, Zucca E . Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014; 32(27):3059-68. PMC: 4979083. DOI: 10.1200/JCO.2013.54.8800. View

18.

Korholz D, Claviez A, Hasenclever D, Kluge R, Hirsch W, Kamprad F . The concept of the GPOH-HD 2003 therapy study for pediatric Hodgkin's disease: evolution in the tradition of the DAL/GPOH studies. Klin Padiatr. 2004; 216(3):150-6. DOI: 10.1055/s-2004-822627. View

19.

Hu Y, Zhou M, Li K, Zhang K, Kong X, Zheng Y . Two DNA repair gene polymorphisms on the risk of gastrointestinal cancers: a meta-analysis. Tumour Biol. 2013; 35(3):1715-25. DOI: 10.1007/s13277-013-1320-z. View

20.

KAMESAKI H, Fukuhara S, Tatsumi E, Uchino H, Yamabe H, Miwa H . Cytochemical, immunologic, chromosomal, and molecular genetic analysis of a novel cell line derived from Hodgkin's disease. Blood. 1986; 68(1):285-92. View