The Role of Caspase Genes Polymorphisms in Genetic Susceptibility to Philadelphia-Negative Myeloproliferative Neoplasms in a Portuguese Population
- 54 Downloads
Our main aim was to evaluate the role of caspases’ genes SNPs in Philadelphia-chromosome negative chronic myeloproliferative neoplasms (PN-MPNs) susceptibility. A case-control study in 133 Caucasian Portuguese PN-MPNs patients and 281 matched controls was carried out, studying SNPs in apoptosis related caspases: rs1045485 and rs1035142 (CASP8), rs1052576, rs2308950, rs1132312 and rs1052571 (CASP9), rs2227309 and rs2227310 (CASP7) and rs13006529 (CASP10). After stratification by pathology diagnosis for essential thrombocythemia (ET), female gender or JAK2 positive, there is a significant increased risk for those carrying at least one variant allele for CASP9 (C653T) polymorphism (OR 2.300 CI 95% [1.180–4.484], P = 0.014). However, when considered individually, none of the studied caspases polymorphisms was associated with PN-MPNs risk. Our results do not reveal a significant involvement of caspase genes polymorphisms on the individual susceptibility towards PN-MPNs as a whole. However, for essential thrombocythemia (ET), female gender or JAK2 positive, there is a significant increased risk to those carrying at least one variant allele for CASP9. Although larger studies are required to confirm these results and to provide conclusive evidence of association between these and other caspases variants and PN-MPNs susceptibility, these new data may contribute to a best knowledge of the pathophysiology of these disorders and, in the future, to a more rational and efficient choice of therapeutic strategies to be adopted in PN-MPNs treatment.
KeywordsPhiladelphia-negative myeloproliferative neoplasms Genetic susceptibility Caspase genes polymorphisms Janus kinase 2
We gratefully acknowledge all patients and controls who generously participated in this study. Our appreciation and thankfulness are extended to Luísa Manso Oliveira and Inês Sousa for expert technical assistance.
This work was supported by funding through project UID/BIM/00009/2013 (Center for Toxicogenomics and Human Health (ToxOmics), from Fundação para a Ciência e Tecnologia (FCT), Portugal.
A BPD grant from FCT to Silva SN (SFRH/BPD/80462/2011) is also acknowledged.
Compliance with Ethical Standards
Conflict of Interest
The authors claim no competing financial or intellectual conflicts of interest in the preparation and submission of this manuscript.
- 1.Swerdlow CESH, Harris NL et al (2008) WHO classification of Tumours of Haematopoieticand lymphoid tissues., 4 edition (October 27, 2008) ed. World Health Organization, LyonGoogle Scholar
- 3.James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144–1148CrossRefPubMedGoogle Scholar
- 5.Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, Boggon TJ, Wlodarska I, Clark JJ, Moore S, Adelsperger J, Koo S, Lee JC, Gabriel S, Mercher T, D'Andrea A, Fröhling S, Döhner K, Marynen P, Vandenberghe P, Mesa RA, Tefferi A, Griffin JD, Eck MJ, Sellers WR, Meyerson M, Golub TR, Lee SJ, Gilliland DG (2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7:387–397CrossRefPubMedGoogle Scholar
- 7.Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, Erber WN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG, Lodish HF, Green AR (2007) JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 356:459–468CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, Aziz A, Godfrey AL, Hinton J, Martincorena I, Van Loo P, Jones AV, Guglielmelli P, Tarpey P, Harding HP, Fitzpatrick JD, Goudie CT, Ortmann CA, Loughran SJ, Raine K, Jones DR, Butler AP, Teague JW, O'Meara S, McLaren S, Bianchi M, Silber Y, Dimitropoulou D, Bloxham D, Mudie L, Maddison M, Robinson B, Keohane C, Maclean C, Hill K, Orchard K, Tauro S, Du MQ, Greaves M, Bowen D, Huntly BJ, Harrison CN, Cross NC, Ron D, Vannucchi AM, Papaemmanuil E, Campbell PJ, Green AR (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369:2391–2405CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Rice KL, Lin X, Wolniak K, Ebert BL, Berkofsky-Fessler W, Buzzai M, Sun Y, Xi C, Elkin P, Levine R, Golub T, Gilliland DG, Crispino JD, Licht JD, Zhang W (2011) Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms. Blood Cancer J 1:e40CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Green DR, Llambi F (2015) Cell death signaling. Cold Spring Harb Perspect Biol 7Google Scholar
- 26.Tognon R, Gasparotto EP, Leroy JM, Oliveira GL, Neves RP, Carrara ReC, Kashima S, Covas DT, Santana M, Souto EX, Zanichelli MA, Velano CE, Simões BP, Alberto FL, Miyashiro K, de Souza AM, Amarante-Mendes GP, de Castro FA (2011) Differential expression of apoptosis-related genes from death receptor pathway in chronic myeloproliferative diseases. J Clin Pathol 64:75–82CrossRefPubMedGoogle Scholar
- 27.Tognon R, Gasparotto EP, Neves RP, Nunes NS, Ferreira AF, Palma PV, Kashima S, Covas DT, Santana M, Souto EX, Zanichelli MA, Simões BP, de Souza AM, Castro FA (2012) Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in essential thrombocythemia and myelofibrosis. J Hematol Oncol 5:2CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Malherbe JA, Fuller KA, Mirzai B, Kavanagh S, So CC, Ip HW, Guo BB, Forsyth C, Howman R, Erber WN (2016) Dysregulation of the intrinsic apoptotic pathway mediates megakaryocytic hyperplasia in myeloproliferative neoplasms. J Clin Pathol 69(11):1017-1024Google Scholar
- 45.Lan Q, Morton LM, Armstrong B, Hartge P, Menashe I, Zheng T, Purdue MP, Cerhan JR, Zhang Y, Grulich A, Cozen W, Yeager M, Holford TR, Vajdic CM, Davis S, Leaderer B, Kricker A, Schenk M, Zahm SH, Chatterjee N, Chanock SJ, Rothman N, Wang SS (2009) Genetic variation in caspase genes and risk of non-Hodgkin lymphoma: a pooled analysis of 3 population-based case-control studies. Blood 114:264–267CrossRefPubMedPubMedCentralGoogle Scholar
- 52.Lindholm Sørensen A, Hasselbalch HC (2015) Smoking and Philadelphia-negative chronic myeloproliferative neoplasms. Eur J Haematol 97(1):63-69Google Scholar