Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma
Walker BA (1), Mavrommatis K (2), Wardell CP (3), Ashby TC (3), Bauer M (3), Davies FE (3), Rosenthal A (4), Wang H (4), Qu P (4), Hoering A (4), Samur M (5), Towfic F (6), Ortiz M (7), Flynt E (6), Yu Z (6), Yang Z (6), Rozelle D (8), Obenauer J (9), Trotter M (7), Auclair D (10), Keats J (11), Bolli N (12), Fulciniti M (5), Szalat R (5), Moreau P (13), Durie B (14), Stewart AK (15), Goldschmidt H (16), Raab MS (17), Einsele H (18), Sonneveld P (19), San Miguel J (20), Lonial S (21), Jackson GH (22), Anderson KC (5), Avet-Loiseau H (23), Munshi N (5), Thakurta A (6), Morgan GJ (3).
(1) Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States
(2) Celgene Corporation, San Francisco, CA, United States.
(3) Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
(4) Cancer Research and Biostatistics, Seattle, WA, United States.
(5) Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States.
(6) Celgene Corporation, Summit, NJ, United States.
(7) Celgene Institute of Translational Research Europe, Sevilla, Spain.
(8) Rancho BioSciences, San Diego, CA, United States.
(9) Rancho BioSciences, San Diego, CA, United Kingdom.
(10) Multiple Myeloma Research Foundation, Norwalk, CT, United States.
(11) Translational Genomics Research Institute, Phoenix, AZ, United States.
(12) University of Milan, Italy.
(13) University of Nantes, France.
(14) Cedars-Sinai Samuel Oschin Cancer Center, Los Angeles, CA, United States.
(15) Department of Hematology, Mayo Clinic, Scottsdale, AZ, United States.
(16) Department of Medicine V, Hematology and Oncology, University Hospital of Heidelberg, Heidelberg, Germany.
(17) German Cancer Research Center (DKFZ), Heidelberg, Heidelberg, Germany.
(18) Department of Internal Medicine II, Wurzburg University, Wurzburg, Germany.
(19) Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
(20) Clinica Universidad de Navarra, Centro Investigacion Medica Aplicada (CIMA), IDISNA, CIBERONC, Pamplona, Spain.
(21) Winship Cancer Institute, Emory University, Atlanta, GA, United States.
(22) Department of Haematology, Newcastle University, Newcastle, United Kingdom.
(23) L'Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire, Toulouse, France.
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 1,273 newly diagnosed patients with multiple myeloma we identify 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 mutations in driver genes are associated with a worse outcome, as are those with 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 pre-determined by the primary events upon which further dependencies are built, giving rise to a non-random accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens.
CITATION Blood. 2018 Jun 8. pii: blood-2018-03-840132. doi: 10.1182/blood-2018-03-840132.