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

Lookup NU author(s): Professor Graham Jackson

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Abstract

©2020 American Association for Cancer Research.PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: As expected, the most commonly mutated genes were NRAS, KRAS, and BRAF, making up 44% of patients. Double-Hit and BRAF and DIS3 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 BRAF mutations, 58% of which were predicted to be hypoactive or kinase dead. Interestingly, 44% of the hypoactive/kinase dead BRAF-mutated patients showed co-occurring alterations in KRAS, NRAS, or activating BRAF mutations, suggesting that they play a role in the oncogenesis of multiple myeloma by facilitating MAPK activation and may lead to chemoresistance. CONCLUSIONS: 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.


Publication metadata

Author(s): Boyle EM, Ashby C, Tytarenko RG, Deshpande S, Wang H, Wang Y, Rosenthal A, Sawyer J, Tian E, Flynt E, Hoering A, Johnson SK, Rutherford MW, Wardell CP, Bauer MA, Dumontet C, Facon T, Thanendrarajan S, Schinke CD, Zangari M, van Rhee F, Barlogie B, Cairns D, Jackson G, Thakurta A, Davies FE, Morgan GJ, Walker BA

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2020

Volume: 26

Issue: 10

Pages: 2422-2432

Online publication date: 27/01/2020

Acceptance date: 22/01/2020

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research

URL: https://doi.org/10.1158/1078-0432.CCR-19-1507

DOI: 10.1158/1078-0432.CCR-19-1507

PubMed id: 31988198


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