Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms.
| Τίτλος | Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. |
| Publication Type | Journal Article |
| Year of Publication | 2015 |
| Authors | Tapper, W., Jones A. V., Kralovics R., Harutyunyan A. S., Zoi K., Leung W., Godfrey A. L., Guglielmelli P., Callaway A., Ward D., Aranaz P., White H. E., Waghorn K., Lin F., Chase A., E Baxter J., Maclean C., Nangalia J., Chen E., Evans P., Short M., Jack A., Wallis L., Oscier D., Duncombe A. S., Schuh A., Mead A. J., Griffiths M., Ewing J., Gale R. E., Schnittger S., Haferlach T., Stegelmann F., Döhner K., Grallert H., Strauch K., Tanaka T., Bandinelli S., Giannopoulos A., Pieri L., Mannarelli C., Gisslinger H., Barosi G., Cazzola M., Reiter A., Harrison C., Campbell P., Green A. R., Vannucchi A., & Cross N. C. P. |
| Journal | Nat Commun |
| Volume | 6 |
| Pagination | 6691 |
| Date Published | 2015 |
| ISSN | 2041-1723 |
| Λέξεις κλειδιά | Adult, Aged, Alleles, Calreticulin, Case-Control Studies, Cohort Studies, DNA-Binding Proteins, Female, Gene Frequency, Genes, myb, Genetic Predisposition to Disease, Genetic Variation, Genotype, GTP-Binding Proteins, HSP70 Heat-Shock Proteins, Humans, Janus Kinase 2, Male, Middle Aged, Mutation, Myeloproliferative Disorders, Peptide Elongation Factors, Polycythemia Vera, Polymorphism, Single Nucleotide, Proto-Oncogenes, Receptors, Thrombopoietin, Telomerase, Thrombocythemia, Essential, Transcription Factors |
| Abstract | Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype. |
| DOI | 10.1038/ncomms7691 |
| Alternate Journal | Nat Commun |
| PubMed ID | 25849990 |
| PubMed Central ID | PMC4396373 |
| Grant List | 07611 / / Wellcome Trust / United Kingdom 263 MD 821336 / MD / NIMHD NIH HHS / United States 263 MD 9164 / MD / NIMHD NIH HHS / United States 8961 / / Cancer Research UK / United Kingdom / / Department of Health / United Kingdom |
