P-050: Whole Exome Sequencing provides novel insights in synonymous and non-synonymous mutational landscapes of Multiple Myeloma

Abstract

<h3>Background</h3> Recent NGS based genomic studies have established the role of temporal precedence of mutational signatures that initiate and drive pathogenesis of Multiple Myeloma (MM). Almost 100 driver genes have been identified and investigated extensively for driver mutations in MM but their clinical impact remains underestimated. While coding nonsynonymous mutations have been well characterized, the synonymous mutations that can regulate and impact gene function have not been investigated in depth. In this study, we have co-analyzed both synonymous and nonsynonymous mutations in whole exomes of MM and compared with reported literature for ethnic differences, if any. <h3>Methods</h3> Whole exome sequencing was performed on malignant plasma cells (PCs) obtained from 71 newly diagnosed MM patients. <h3>Results</h3> Both synonymous (S) and nonsynonymous (NS) substitutions were analyzed. The C>T substitutions were most common. Other than age linked SBS5, SBS1, ID2, ID8; mutational signatures such as APOBEC related DBS11, defective DNA mismatch repair related SBS15 were also identified. The patients had an average tumor mutation burden of ~10. Nearly half of nonsynonymous mutations were clonal. The most common NS mutations were missense (~18000) followed by those in splice (~3000), 3' or 5'UTR regions (~1500) and nonsense or frameshift (~200). The most frequently mutated oncogenes with NS mutations included KRAS, BRAF, DIS3, TET2 and CREBBP while the commonly NS mutated tumor suppressor genes were KMT2C, ATM, KMT2B and TP53. Frequency of NS mutations in TP53 (~7%) in this study were significantly different from those reported for African American (1.6%) and more closer to Caucasian (6.3%). Mutations (NS) in PARP4 were found at a frequency of 3.9% which is similar to African American (3.9%) and different from Caucasian (1%). In addition, 6 different synonymous mutations were also observed in this gene at a frequency ~ 2% in MM patients in this study. Gene IRF4 also had both NS (3%) and S (~1.5%) mutations. The IRF4 NS mutation frequency (3%) is comparable with Caucasian (3.2%) while it doesnot exist among African Americans (0%). <h3>Conclusion</h3> In analogy, oncogenes (e.g., LMO2, ARHGEF28, NOTCH1, RET, NOTCH2, DDR2) and tumor suppressor genes (like KMT2C, EP400, RASA2, CYLD) were enriched in synonymous mutations. A consolidated analysis of co-occurrence of both synonymous and NS mutations may help revisit their mechanistic oncogenic and clinical significance in MM.