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Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma

Lookup NU author(s): Professor Graham Jackson

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Abstract

© 2018 by The American Society of Hematology. Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including IDH1, IDH2, HUWE1, KLHL6, and PTPN11. Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more driver gene abnormalities are associated with worse outcomes, as are identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in FGFR3, DIS3, and PRKD2; t(11;14) with mutations in CCND1 and IRF4; t(14;16) with mutations in MAF, BRAF, DIS3, and ATM; and hyperdiploidy with gain 11q, mutations in FAM46C, and MYC rearrangements. These associations indicate that the genomic landscape of myeloma is predetermined by the primary events upon which further dependencies are built, giving rise to a nonrandom accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens.

Publication metadata

Author(s): Walker BA, Mavrommatis K, Wardell CP, Cody Ashby T, Bauer M, Davies FE, Rosenthal A, Wang H, Qu P, Hoering A, Samur M, Towfic F, Ortiz M, Flynt E, Yu Z, Yang Z, Rozelle D, Obenauer J, Trotter M, Auclair D, Keats J, Bolli N, Fulciniti M, Szalat R, Moreau P, Durie B, Keith Stewart A, Goldschmidt H, Raab MS, Einsele H, Sonneveld P, Miguel JS, Lonial S, Jackson GH, Anderson KC, Avet-Loiseau H, Munshi N, Thakurta A, Morgan GJ

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2018

Volume: 132

Issue: 6

Pages: 587-597

Print publication date: 09/08/2018

Online publication date: 09/08/2018

Acceptance date: 04/06/2018

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology

URL: https://doi.org/10.1182/blood-2018-03-840132

DOI: 10.1182/blood-2018-03-840132

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