Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

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., Baxter, E.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., Dohner, 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. and Cross N.C. 2015. Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms. Nature Communications . 6 6691. https://doi.org/10.1038/ncomms7691

TitleGenetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms
TypeJournal article
AuthorsTapper, 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., Baxter, E.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., Dohner, 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. and Cross N.C.
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 JAK2V617F-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 JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 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.

Article number6691
JournalNature Communications
Journal citation6
ISSN2041-1723
Year2015
PublisherNature Publishing Group
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1038/ncomms7691
Publication dates
Published07 Apr 2015

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