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Background Multiple myeloma (MM) is a malignant plasma cell disorder, in which at diagnosis circa 10% of tumors are characterized by a deletion of chromosome 17p (del17p). Previously, others and we reported that this aberration is associated with a significantly inferior prognosis, classifying it as high-risk disease. As TP53 is located on chromosome 17p (Chr17p), most research has thus far been focused on this gene. However, only in a minority of del17p MM patients a mutation could be detected (Lodé et al. - Haematologica 2010, Kortüm et al. - Br J Haematol 2015). We therefore hypothesized that other relevant mutations might be present in TP53, its surrounding genes, or disease relevant pathways. Aim With this study, we sought to identify commonly mutated genes in del17p MM, which could explain its aggressive clinical behavior. Material and Methods We obtained high molecular DNA from CD138+ purified MM cells and matched peripheral blood from patients with a del17p in ≥50% of plasma cells, as detected with fluorescent in situ hybridization (FISH). Libraries were generated using a custom capture of 111 Mb (SeqCap EZ Exome Plus, Nimblegen), comprising the whole exome, Chr17p and the IgH, Igk, IgL and MYC regions. Paired-end sequencing was performed on a HiSeq2500 platform, followed by data-analysis using an in-house bioinformatics pipeline at Erasmus MC. Results Matched tumor and germline DNA was sequenced from 54 patients, with sequential tumor samples available from 12 patients. This resulted in an average coverage of 88x and overall coverage of 94%. Of 44 del17p patients, tumor DNA was obtained before treatment start. Clinical data were collected from 40/44 patients, with a median follow-up time of 18 months. We found TP53 to be mutated most frequently. 31/54 (57%) patients had a somatic nonsynonymous mutation, insertion or deletion (71% missense, 19% stopgain/frameshift, 10% splicing). Although no hotspot mutations were detected, most TP53 mutations resided in the DNA binding domain. Of note, most TP53wt/- patients had no clonal somatic nonsynonymous mutations in other p53 pathway genes, or on Chr17p. To assess the prognostic impact of TP53 mutations in del17p MM, we focused on the 40 chemotherapy-naive patients and stratified for age ≤65 years (n = 25) and >65 years (n = 15). TP53mut/- patients had a significantly worse overall survival (OS) than TP53wt/- patients (p = 0.002). Strikingly, TP53 missense mutations showed the worst OS (p Conclusions (1) In contrast with previous reports, we find TP53 to be somatically mutated in the majority of MM patients with a clonal del17p aberration. (2) Particularly TP53 missense mutations have a significantly negative impact on both PFS and OS in del17p MM patients. This study was supported by the Plaisier Foundation, Erasmus MC Grant and the Dutch CTMM Project. Citation Format: Davine Hofste op Bruinink, Remco Hoogenboezem, Eric Bindels, Mathijs Sanders, Claudia Erpelinck - Verschueren, Paulina van Strien, Jasper Koenders, Kristine Misund, Berna Beverloo, Bronno van der Holt, Ivo Touw, Anders Waage, Hervé Avet-Loiseau, Pieter Sonneveld. Multiple myeloma with a clonal del17p aberration is characterized by somatic TP53 mutations, which negatively affect prognosis in this cytogenetic subgroup. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5023.