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Tissue methylation and demethylation influence translesion synthesis DNA polymerases (TLS) contributing to the genesis of chromosomal abnormalities in myelodysplastic syndrome
  1. Gabrielle Melo Cavalcante1,2,
  2. Daniela Paula Borges2,3,
  3. Roberta Taiane Germano de Oliveira2,3,
  4. Cristiana Libardi Miranda Furtado4,5,
  5. Ana Paula Negreiros Nunes Alves6,
  6. Alceu Machado Sousa7,
  7. Dayrine Silveira de Paula8,
  8. Francisco Dário Rocha Filho9,
  9. Silvia Maria Meira Magalhães2,3,
  10. Howard Lopes Ribeiro-Jr1,2,
  11. Ronald Feitosa Pinheiro1,2,3
  1. 1Postgraduate Program in Pathology, Federal University of Ceara, Fortaleza, Ceara, Brazil
  2. 2Cancer Cytogenomic Laboratory, Drug Research and Development Center, Federal University of Ceara, Fortaleza, Ceara, Brazil
  3. 3Postgraduate Program in Medical Science, Federal University of Ceara, Fortaleza, Ceara, Brazil
  4. 4Postgraduate Program in Medical and Surgical Sciences, Universidade Federal do Ceara, Fortaleza, Ceara, Brazil
  5. 5Drug Research and Development Center, Federal University of Ceara, Fortaleza, Ceara, Brazil
  6. 6Department of Dental Clinic, Faculty of Pharmacy, Dentistry and Nursing, Universidade Federal do Ceara, Fortaleza, Ceara, Brazil
  7. 7Department of Odontology Clinic, Universidade Federal do Ceara, Fortaleza, Ceara, Brazil
  8. 8Postgraduate Program in Odontology, Universidade Federal do Ceara, Fortaleza, Ceara, Brazil
  9. 9Department of Pathology, Universidade Federal do Ceara, Fortaleza, Ceara, Brazil
  1. Correspondence to Dr Ronald Feitosa Pinheiro, Department of Clinical Medicine, Universidade Federal do Ceara, Fortaleza 60441750, Brazil; pinheirorfeitosa{at}gmail.com

Abstract

Aims DNA methylation has its distribution influenced by DNA demethylation processes with the catalytic conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). Myelodysplastic syndrome (MDS) has been associated with epigenetic dysregulation of genes related to DNA repair system, chronic immune response and cell cycle.

Methods We evaluated the tissue DNA methylation/hydroxymethylation in bone marrow trephine biopsies of 73 patients with MDS, trying to correlate with the mRNA expression of 21 genes (POLH, POLL, REV3L, POLN, POLQ, POLI, POLK, IRF-1, IRF-2, IRF-3, IRF-4, IRF-5, IRF6, IRF-7, IRF-8,IRF-9, MAD2, CDC20, AURKA, AURKB and TPX2).

Results The M-score (5mC) was significantly higher in patients with chromosomal abnormalities than patients with normal karyotype (95% CI –27.127779 to –2.368020; p=0.022). We observed a higher 5mC/5hmC ratio in patients classified as high-risk subtypes compared with low-risk subtypes (95% CI –72.922115 to –1.855662; p=0.040) as well as patients with hypercellular bone marrow compared with patients with normocellular/hypocellular bone marrow (95% CI –69.189259 to –0.511828; p=0.047) and with the presence of dyserythropoiesis (95% CI 17.077703 to 51.331388; p=0.001). DNA pols with translesion activity are significantly influenced by methylation. As 5mC immunoexpression increases, the expressions of POLH (r=−0.816; r2 =0.665; p=0.000), POLQ (r=−0.790; r2=0.624; p=0.001), PCNA (r=−0.635; r2=0.403; p=0.020), POLK (r=−0.633; r2=0.400; p=0.036 and REV1 (r=−0.578; r2=0.334; p=0.049) decrease.

Conclusions Our results confirm that there is an imbalance in the DNA methylation in MDS, influencing the development of chromosomal abnormalities which may be associated with the low expression of DNA polymerases with translesion synthesis polymerases activity.

  • myelodysplastic syndromes
  • DNA
  • medical oncology
  • immunohistochemistry
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Footnotes

  • GMC and DPB are joint first authors.

  • Handling editor Mary Frances McMullin.

  • GMC and DPB contributed equally.

  • Contributors GMC, APNNA and RFP designed the study. GMC, DSdP and AMS constructed the tissue microarray and IHC. TMA scoring was done by GMC, DPB, FDRF and RFP. GMC and DPB performed all the statistical analyses under supervision from HLR-J and RFP. SMMM, CLMF and RTGdO contributed to the acquisition and interpretation of the data. The manuscript was written by DPB, GMC and RFP. All authors read and approved the final manuscript.

  • Funding This study has been supported by CAPES, CNPq (PRONEX) and FUNCAP.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the local scientific ethical committee of Federal University of Ceara and all participants provided written informed consent.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplemental information.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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