Poster presented at the 6th International Conference on Myeloproliferative Neoplasms. European School of Haematology, Estoril, 2014

Azevedo, Ana Paula

Gaspar, Jorge F.

Júnior, Esmeraldina

Lima, Fernando

Lima, João P. de

Reichert, Alice

Rueff, José

Silva, Susana Nunes

English

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THE ROLE OF BASE EXCISION REPAIR POLYMORPHISMS IN INDIVIDUAL SUSCEPTIBILITY TO PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMSAna Paula Azevedo1,2, Susana Nunes Silva1, João P. de Lima1, Alice Reichert3, Fernando Lima3, Esmeraldina Júnior2, José Rueff1 and Jorge F. Gaspar1Corresponding author: Ana Paula Azevedo – anpazevedo@gmail.com1Department of Genetics and Biochemistry, Faculty of Medical Sciences, Universidade Nova de Lisboa (UNL), Lisbon2Department of Clinical Pathology, Hospital de S. Francisco Xavier, Centro Hospitalar de Lisboa Ocidental (CHLO), Lisbon3Department of Clinical Haematology, Hospital de S. Francisco Xavier, Centro Hospitalar de Lisboa Ocidental (CHLO), Lisbon1. BackgroundAlthough somatic mutations in the Janus kinase 2 gene (JAK2) occur in manyPhiladelphia-chromosome negative chronic myeloproliferative neoplasms (PN-MPNs),disease evolution, distinct phenotypes and the continuous clinical evidence of anincreasing number of cases, with younger patients affected, have been pointing to agrowing involvement of environmental factors in the pathogenesis of these diseases.Although this association is well established in some solid tumors, like breast andthyroid, this aspect is now being considered for hematological malignancies.Exposure to hazardous agents in the environment on a continual basis, can lead tochanges at the genome level, alterations in cell cycle regulation and consequently tocancer. Several single nucleotide polymorphisms (SNPs) have been identified, that mayinfluence the DNA repair capacity and, in turn, confer genetic predisposition to diseaseand determine therapeutic response (e.g. DNA repair, apoptosis).On the other hand, the phenotypic pleiotropy of these disorders seems to be the resultof a combination of somatic mutation(s), inherited genetic variability, post-geneticregulation and host modifiers (Fig. 1).We intend to evaluate the role of base excision repair (BER) pathway SNPs in PN-MPNssusceptibility.2. ObjectivesOur results suggest that BER polymorphisms such as rs1799782 (XRCC1-194) mayinfluence PN-MPNs susceptibility.The more significant association between women can be due to the predominance of ETcases, which has been referred in the literature as having a slight female sexpredilection. On the other hand, the lack of association in IMF cases can be due to thesmall sample size.However, larger studies are required to confirm these results and to provide conclusiveevidence of association between these and other BER variants and PN-MPNs andtherapeutic response.5. Conclusions6. References- Bolufer P. et al.. Influence of genetic polymorphisms on the risk of developing leukemia and on disease progression. LeukemiaResearch 30 (2006) 1471–1491- Delhommeau F. et al. Molecular aspects of myeloproliferative neoplasms. Int J Hematol (2010) 91:165–173- Beaute J. et al. Base Excision Repair and its role in maintaining genome stability. Critical Reviews in Biochemistry and Molecular Biology, 43:239–276, 2008We performed a case-control study in 121 Caucasian Portuguese PN-MPNs patients (73 with Essentialthrombocythaemia (ET), 35 with Polycythaemia vera (PV) and 13 with Idiopatic Myelofibrosis (IMF)) and 280matched controls. Most of the patients were diagnosed and are followed by some of the elements of thisworking group. rs1799782 and rs25487 (XRCC1), rs1052133 (OGG1), rs1136410 (PARP1), rs13428 andrs1050112 (PARP4), rs1130409 (APEX1) and rs3219489 (MUTYH) were genotyped using real-time PCR (RT-PCR 7300 Applied Biosystem), through TaqMan® SNP genotyping assays (Life Technology), according tomanufacturer instructions.Differences in genotype frequency, smoking status, age class, gender and pathology distributions betweenpatients and controls were evaluated using SPSS 22.0 (SPSS Inc.).3. MethodsWhen considering all PN-MPNs cases, rs1799782 (XRCC1_194) was associated withMPNs risk. A consistent increase in overall PN-MPNs risk was observed for the presenceof at least one variant allele carriers (Arg/Trp or Trp/Trp; OR=2.2, 95% CI=1.4-3.5), moresignificant between women (Tables 1 and 2).It seems that alcohol consumption also increases the risk for PN-MPNs development.Concerning pathology stratification, IMF did not show an increased risk in associationwith this polymorphism.JAK2V617F positive cases revealed a borderline effect for the presence of at least onevariant allele carriers of XRCC1_194 (OR=1.8, 95% CI=0.98-3.4, P=0.059).Results for PARP4_13 were not shown, since it is in linkage disequilibrium withPARP4_01. Our data did not reveal a positive association between the otherpolymorphisms individually and PN-MPNs susceptibility.Studies related with therapeutic response are still ongoing.4. ResultsFig. 1 – Megakaryocytes in essential thrombocythaemia, bone marrowaspirate smear (x100). Characteristics Cases, n (%) Controls, n (%) P valueGenderMaleFemale56 (29.6)65 (30.7)133 (70.4)147 (69.3)0.8Age a, b30-4950-69≥7016 (27.1)47 (30.5)58 (30.9)43 (72.9)107 (69.5)130 (69.1)0.9Smoking habitsNeverCurrent93 (30.5)28 (29.5)212 (69.5)67 (70.5)0.9Alcohol habitsNeverSocialRegular92 (32.6)20 (44.4)9 (12.3)190 (67.4)25 (55.6)64 (87.7)<0.0001MUTYH (Gln335His)Gln/GlnGln/HisHis/His13 (36.1)47 (29.6)61 (30.2)23 (63.9)112 (70.4)141 (69.8)0.7APEX1 (Asp148Glu)Asp/AspAsp/GluGlu/Glu34 (31.8)57 (29.7)30 (30.6)73 (68.2)135 (70.3)68 (69.4)0.9OGG1 (Ser326Cys)Ser/SerSer/CysCys/Cys76 (29.6)37 (30.8)8 (40.0)181 (70.4)83 (69.2)12 (60.0)0.6PARP1 (Val762Ala)Val/ValVal/AlaAla/Ala96 (31.1)25 (28.4)0 (0.0)213 (68.9)63 (71.6)1 (100.0)0.7PARP4_01 (Gly280Arg)Gly/GlyGly/ArgArg/Arg48 (31.4)56 (28.6)17 (35.4)105 (68.6)140 (71.4)31 (64.6)0.6XRCC1_399 (Gln399Arg)Gln/GlnGln/ArgArg/Arg15 (34.1)54 (28.7)52 (31.5)29 (65.9)134 (71.3)113 (68.5)0.7XRCC1_194 (Arg194Trp)Arg/ArgArg/TrpTrp/Trp77 (26.1)28 (33.3)16 (94.1)218 (73.9)56 (66.7)1 (5.9)<0.0001a Age of diagnosis for casesb Age of control population at the time of diagnosis for the matched casen XRCC1_194(Arg194Trp)OR crude(95% CI)OR adjusted (95% CI)aAll cases 121 Arg/ArgbArg/TrpTrp/TrpArg/Trp or Trp/Trp1 (Reference)1.4 (0.8-2.4)45.3 (5.9-347.3)c2.2 (1.4-3.5)*1 (Reference)1.5 (0.9-2.5)40.1 (5.2-309.9)2.3 (1.4-3.7)*GenderMaleFemale5665Arg/ArgbArg/Trp or Trp/TrpArg/ArgbArg/Trp or Trp/Trp1 (Reference)1.8 (0.96-3.4)1 (Reference)2.6 (1.4-4.5)*1 (Reference)2.1 (1.1-4.1)*1 (Reference)2.7 (1.5-4.9)*Pathology stratificationETPVCIM    733513Arg/ArgbArg/Trp or Trp/TrpArg/ArgbArg/Trp or Trp/TrpArg/ArgbArg/Trp or Trp/Trp1 (Reference)2.4 (1.4-4.1)*1 (Reference)2.6 (1.2-5.3)*1 (Reference)0.7 (0.2-3.2)1 (Reference)2.5 (1.4-4.4)*1 (Reference)2.7 (1.3-5.8)*1 (Reference)0.9 (0.2-4.5)a ORs were adjusted for age (30-49, 50-69 and  ≥70), smoking status (never and current)b The individuals with Arg/Arg genotype were considered as reference classc Statistical error type 1 ; * P < 0.05Table 1 – General characteristics for the PN-MPNs cases (n=121) and control population (n=280).Table 2 – ORs (95% CI) for XRCC1_194 (Arg194Trp) polymorphism and PN-MPNs association.

The role of base excision repair polymorphisms in individual susceptibility to Philadelphia-negative myeloproliferative neoplasms

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The role of base excision repair polymorphisms in individual susceptibility to Philadelphia-negative myeloproliferative neoplasms

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