Poster presented at the 18th Annual Reunion of Sociedade Portuguesa de Genética Humana. Lisboa, 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 APOPTOSIS 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 kinase2 gene (JAK2) occur in many Philadelphia-chromosome negative chronic myeloproliferati-ve neoplasms (PN-MPNs), disease evolution,distinct phenotypes and the continuous clinicalevidence of an increasing number of cases, withyounger patients affected, have been pointing toa growing involvement of environmental factorsin the pathogenesis of these diseases. Althoughthis association is well established in somesolid tumors, like breast and thyroid, this aspectWe intend to evaluate the role of apoptosis SNPs in PN-MPNs susceptibility.2. ObjectivesOur results do not reveal a significant involvement of apoptosis polymorphisms on theindividually susceptibility towards PN-MPNs.However, larger studies are required to confirm these results and to provide conclusive evidenceof non association between these and other apoptosis variants and PN-MPNs and therapeuticresponse.On the other hand, there are studies that show modifications in the expression of molecules thatparticipate in the regulation of apoptosis, indicating that this mechanism is involved in thepathophysiology of these diseases.Identification of the main molecules that are altered in MPNs allows the development of drugsmore directly targeted to the pathophysiology of the disease, with high efficacy, fewer adverseeffects, contributing to compliance of the patients with treatments.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- Tognon R. et al. Apoptosis deregulation in myeloproliferative neoplasms. Einstein.(2013);11(4):540-4- Calzada A. et al. Givinostat and hydroxyurea sinergize in vitro to induce apoptosis of cells from JAK2V617Fmyeloproliderativeneoplasms patients. Experimental Hematology (2013); 253-60We performed a case-control study in 121 Caucasian Portuguese PN-MPNs patients (73 with Essentialthrombocythaemia (ET), 35 with Polycythaemia vera (PV) and 13 with Primary Myelofibrosis (PMF)) and 280matched controls. Most of the patients were diagnosed and are followed by some of the elements of thisworking group. rs2227309 and rs2227310 (CASP7), rs1045485 and rs1035142 (CASP8), rs2308950, rs1820204and rs1052571 (CASP9) and rs13006529 (CASP10) were genotyped using real-time PCR (RT-PCR 7300 AppliedBiosystem), through TaqMan® SNP genotyping assays (Life Technology), according to manufacturer instructions.Differences in genotype frequency, smoking status, age class, gender, therapeutic and pathology distributionsbetween patients and controls were evaluated using SPSS 22.0 (SPSS Inc.).3. MethodsNone of the apoptosis polymorphisms studied, individually considered, is associated with PN-MPNs risk.No significant difference was found between the case and control groups concerning agedistribution, gender, smoking habits or genotype frequencies (Table 1). No significant change incrude or adjusted OR was observed for any of the genotypes considered (Table 2).Studies related with therapeutic response are still ongoing.4. ResultsCharacteristics Cases, n (%) Controls, n (%) P valueGenderMaleFemale55 (45.8)65 (54.2)132 (47.1)148 (52.9)0.8Age a, b30-4950-69≥7016 (13.2)47 (38.8)58 (47.9)43 (15.4)106 (37.9)131 (46.8)0.9Smoking habitsNeverCurrent93 (76.9)28 (23.1)212 (76.0)67 (24.0)0.9CASP7 (Arg249Lys)Arg/ArgLys/ArgLys/Lys70 (57.9)45 (37.2)6 (5.0)153 (55.0)109 (39.2)16 (5.8)0.9CASP7 (Asp255Glu)Asp/AspAsp/GluGlu/Glu7 (5.8)47 (39.2)66 (55.0)16 (5,8)106 (38.5)153 (55.6)1.0CASP8 (Asp302His)Asp/AspAsp/HisHis/His91 (75.8)24 (20.0)5 (4.2)219 (78.8)51 (18.3)8 (2.9)0.7CASP8 (Tyr12STOP)Tyr/TyrTyr/StopStop/Stop20 (16.5)53 (43.8)48 (39.7)45 (16.2)136 (48.9)97 (34.9)0.6CASP9 (Phe136Leu)Phe/PhePhe/LeuLeu/Leu28 (23.1)66 (54.5)27 (22.3)87 (31.3)128 (46.0)63 (22.7)0.2CASP9 (Arg173HisArg/ArgArg/HisArg/His117 (96.7)3 (2.5)1 (0.8)275 (98.9)3 (1.1)0 (0.0)0.2CASP9 (Val762Ala)Val/ValVal/AlaAla/Ala24 (19.8)66 (54.5)31 (25.6)69 (24.8)129 (46.4)80 (28.8)0.3CASP10 (Ile522Leu)Ile/IleIle/LeuLeu/Leu27 (22.3)58 (47.9)36 (29.8)74 (26.6)122 (43.9)82 (29.5)0.6a Age of diagnosis for casesb Age of control population at the time of diagnosis for the matched caseTable 1 – General characteristics for the PN-MPNs cases (n=121) and control population (n=280).Table 2 – ORs (95% CI) for apoptosis polymorphisms and PN-MPNs association.Fig. 1 – Megakaryocytes in primary myelofibrosis, bonemarrow aspirate smear (x100). nOR crude(95% CI)OR adjusted (95% CI)aCASP7 (Arg249Lys)Arg/ArgArg/LysLys/Lys1211 (Reference)0.9 (0.6-1.4)0.8 (0.3-2.2)1 (Reference)0.9 (0.6-1.4)0.9 (0.3-2.6)CASP7 (Asp255Glu)Asp/AspAsp/GluGlu/Glu1201 (Reference)1.0 (0.7-1.6)1.0 (0.4-2.6)1 (Reference)1.0 (0.6-1.6)1.1 (0.4-2.9)CASP8 (Asp302His)Asp/AspbAsp/HisHis/His1201 (Reference)1.1 (0.7-2.0)1.5 (0.5-4.7)1 (Reference)1.1 (0.6-1.9)1.3 (0.4-4.3)CASP8 (Tyr12STOP)Tyr/TyrTyr/StopStop/Stop1211 (Reference)0.8 (0.5-1.3)0.9 (0.5-1.7)1 (Reference)0.8 (0.5-1.3)1.0 (0.5-1.9)CASP9 (Phe136Leu)Leu/LeuLeu/PhePhe/Phe1211 (Reference)1.6 (1.0-2.7)1.3 (0.7-2.5) 1 (Reference)1.6 (1.0-2.8)1.4 (0.7-2.6)CASP9 (Arg173HisArg/ArgArg/His + His/His1171 (Reference)3.1 (0,7-14.2)1 (Reference)2.4 (0.5-11.0)CASP9 (Val762Ala)Val/ValVal/AlaAla/Ala1211 (Reference)1.3 (0.8-2.2)0.9 (0.5-1.7)1 (Reference)1.3 (0.8-2.2)0.9 (0.5-1.7)CASP10 (Ile522Leu)Ile/IleIle/LeuLeu/Leu1211 (Reference)1.1 (0.7-1.8)0.8 (0.5-1.5)1 (Reference)1.1 (0.6-1.8)0.8 (0.5-1.6)a ORs were adjusted for age (30-49, 50-69 and  ≥70), smoking status (never and current)b Reference classis now being considered for some solid tumors,like breast and thyroid, this aspect is now being considered for hematological malignancies.Exposure to hazardous agents in the environment on a continual basis, can lead to changes at thegenome level, alterations in cell cycle regulation and consequently to cancer. Several singlenucleotide polymorphisms (SNPs) have been identified, that may influence the DNA repaircapacity and apoptotic status, that, in turn, confer genetic predisposition to disease anddetermine therapeutic response.Expression deregulation of pro and anti-apoptotic genes promotes cell resistance to apoptosis,culminating with the accumulation of myeloid cells and establishing neoplasms (Fig.1).

The role of apoptosis polymorphisms in individual susceptibility to Philadelphia-negative myeloproliferative neoplasms

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The role of apoptosis polymorphisms in individual susceptibility to Philadelphia-negative myeloproliferative neoplasms

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