BRAF and DIS3 Mutations Associate with Adverse Outcome in a Long-term Follow-up of Patients with Multiple Myeloma

• Published in: Clinical cancer research 2020-05, Vol.26 (10), p.2422-2432
• Main Authors: Boyle, Eileen M, Ashby, Cody, Tytarenko, Ruslana G, Deshpande, Shayu, Wang, Hongwei, Wang, Yan, Rosenthal, Adam, Sawyer, Jeffrey, Tian, Erming, Flynt, Erin, Hoering, Antje, Johnson, Sarah K, Rutherford, Michael W, Wardell, Christopher P, Bauer, Michael A, Dumontet, Charles, Facon, Thierry, Thanendrarajan, Sharmilan, Schinke, Carolina D, Zangari, Maurizio, van Rhee, Frits, Barlogie, Bart, Cairns, David, Jackson, Graham, Thakurta, Anjan, Davies, Faith E, Morgan, Gareth J, Walker, Brian A
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor - genetics; DNA Mutational Analysis; Exosome Multienzyme Ribonuclease Complex - genetics; Female; Follow-Up Studies; Humans; Life Sciences; Male; Middle Aged; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - mortality; Multiple Myeloma - pathology; Mutation; Prognosis; Proto-Oncogene Proteins B-raf - genetics; Survival Rate
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-1507

Copy-number changes and translocations have been studied extensively in many datasets with long-term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets. We performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the total therapy trials. As expected, the most commonly mutated genes were , and , making up 44% of patients. Double-Hit and and mutations had an impact on outcome alongside classical risk factors in the context of an intensive treatment approach. We were able to identify both V600E and non-V600E mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead -mutated patients showed co-occurring alterations in , or activating mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance. Overall, these data highlight the importance of mutational screening to better understand newly diagnosed multiple myeloma and may lead to patient-specific mutation-driven treatment approaches.