Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma

Abstract

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 ,, ,, and 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, , and; t(11;14) with mutations in and; t(14;16) with mutations in ,, , and; and hyperdiploidy with gain 11q, mutations in , and 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.

Microhomology-mediated end joining drives complex rearrangements and over-expression of MYC and PVT1 in multiple myeloma

“…Data analysis was performed as described previously, with minor differences between sequencing modalities. 32 For details see Supplementary Methods.…”

Multiple Myeloma DREAM Challenge Reveals Epigenetic RegulatorPHF19As Marker of Aggressive Disease

“…This strong association was likely missed in earlier studies given that PHF19 expression is not associated with any cytogenetic feature while several therapeutic advances over the last 20 years have made it difficult to model outcome across multiple studies from different periods. Furthermore, PHF19 has not been found to be significantly mutated in sequencing-based studies 28,29 , suggesting that its overexpression is not directly related to genomic alterations within the PHF19 gene. We also show that a simple four feature predictor composed of age, ISS, and expression of PHF19 and MMSET performs similarly to more complex models with many more gene expression features included (Supplemental Figure 4).…”

Integrated Phosphoproteomics and Transcriptional Classifiers Reveal Hidden RAS Signaling Dynamics in Multiple Myeloma

“…MM is a unique case study of Ras biology as approximately 40% of MM patient tumors have predicted activating mutations in KRAS or NRAS 4,5 , with an almost equal distribution between the two, but essentially none in HRAS. Notably, these KRAS and NRAS mutations are very rare in the precursor lesion monoclonal gammopathy of uncertain significance (MGUS), suggesting that RAS mutations are important for transformation to MM 16 .…”

“…In vitro overexpression studies in myeloma cell lines indicated that KRAS may lead to more rapid proliferation in the absence of interleukin-6 (IL-6) stimulation than NRAS 20,21 . More recent sequencing studies have suggested that NRAS mutations tend to cluster with specific genomic aberrations in MM 5 . Finally, immunohistochemistry studies on MM bone marrow have suggested possible differences in ERK phosphorylation depending on RAS isoform and specific mutation 22 .…”