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

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.

Symptomatic burden amongst myeloproliferative neoplasm patients: mpn-10 prospective assessment in a portuguese cohort

“…Additionally, males have higher PV and MF incidence rates, while females have higher incidence of ET (Byun et al, 2017;Deadmond & Smith-Gagen, 2015;Moulard et al, 2014;Roaldsnes et al, 2017;Shallis et al, 2020). Yet, and although a slight bias of MPN for males over females is often referred in the literature (Anderson et al, 2012;Deadmond & Smith-Gagen, 2015;Heppner et al, 2019;Moulard et al, 2014;Shallis et al, 2020;Titmarsh et al, 2014), the gender distribution in this population, as well as the distribution of patients per MNP subtype and mean age, were consistent with previous data regarding a Portuguese population (Ana P. Azevedo et al, , 2018Ana Paula Azevedo et al, 2017) and other studies and reports worldwide (Duncombe et al, 2020;Roaldsnes et al, 2017;R. Scherber et al, 2011;Seguro et al, 2020).…”

DNA repair in cancer initiation, progression, and therapy—a double-edged sword

“…Hence, the alternative polymorphic site at XRCC1 is playing a double role in breast cancer with antitumor activity and promotion of metastasis as well (Li et al 2018). Next, another study done on almost the same set of genes but on myeloproliferative neoplasm ( n = 133) treated with hydroxyurea has established a role of BER genes in progression and clinical evolution of neoplasm (Azevedo et al 2018). Further, the study by Santana et al (2016) has shown overexpression of AP-1 and XRCC-1 in oral tongue squamous cell carcinoma ( n = 82).…”

CometChip enables parallel analysis of multiple DNA repair activities

“…Both pathways have strong relevance to human health. People with BER gene polymorphisms and deficiencies have been shown to have increased cancer susceptibility (2,25,(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74) and show a link to degenerative diseases (75)(76)(77)(78). Similarly, reduced NER capacity is also associated with increased risk of cancer (33,(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91).…”