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Mol Med Rep. 2018 Dec;18(6):5243-5255. doi: 10.3892/mmr.2018.9535. Epub 2018 Oct 8.

Effects of polymorphic DNA genes involved in BER and caspase pathways on the clinical outcome of myeloproliferative neoplasms under treatment with hydroxyurea.

Author information

1
Centre for Toxicogenomics and Human Health (Toxomics), Genetics, Oncology and Human Toxicology, NOVA Medical School/Faculty of Medical Sciences, Universidade Nova de Lisboa, 1150‑082 Lisbon, Portugal.
2
Department of Clinical Haematology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, 1449‑005 Lisbon, Portugal.
3
Department of Clinical Pathology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, 1449‑005 Lisbon, Portugal.

Abstract

Several single nucleotide polymorphisms (SNPs) influencing DNA repair capacity and apoptotic status may confer genetic predisposition to Philadelphia‑chromosome negative myeloproliferative neoplasms (PN‑MPNs), and influence therapeutic response and the clinical course. In the present study, whether SNPs in genes involved in apoptosis and the base excision repair (BER) pathway was evaluated. In addition, some known risk factors in PN‑MPNs that may influence survival and therapeutic response to hydroxyurea (HU) were analyzed, taking into account three items: Disease progression, predisposition to new non‑myeloid neoplasms and thrombotic events. The present study involved a total of 133 Caucasian Portuguese PN‑MPNs patients treated with HU, whereby 17 cases showed progression to myelofibrosis/leukemia, 11 developed new non‑myeloid neoplasms and 22 presented with thrombotic events. Progression to secondary myelofibrosis/leukemia is influenced by exposure to cytoreductive agents, and caspase and BER polymorphisms {globally, CASP8 3'untranslated region [odds ratio (OR)=0.24; 95% confidence interval (CI), 0.08‑0.69], XRCC1 Arg194Trp [OR=3.58; 95% CI, 0.98‑13.01]; for essential thrombocythemia patients CASP9 Arg173His [OR=11.27; 95% CI, 1.13‑112.28], APEX1 Asp148Glu [OR=0.28; 95% CI, 0.74‑1.03], and XRCC1 Arg194Trp [OR=6.60; 95% CI, 1.60‑27.06]}. Moreover, globally caspase and BER polymorphisms influenced the development of new nonmyeloid malignancies [CASP8 Asp270His (OR=5.90; 95% CI, 1.42‑24.62) and XRCC1 Arg399Gln (OR=0.27; 95% CI, 0.07‑1.03)]. On the other hand, only the BER pathway had a role in the presence of thrombotic events [XRCC1 Gln399Arg (OR=0.35; 95% CI, 0.14‑0.88)]. JAK2 mutation had no influence on these complications. Larger studies are required to confirm these results, and to provide conclusive evidence of association between these and other variants with PN‑MPNs therapeutic response and clinical evolution. However, this study may allow the development of drugs more directly targeted to the pathophysiology of the disease, with high efficacy, fewer adverse effects, contributing to compliance of patients with treatments. The clinical indication for classical drugs, including HU, may be guided by variant genes, which may provide additional beneficial effects.

PMID:
30320340
DOI:
10.3892/mmr.2018.9535

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