The landscape of structural variants (SVs) in multiple myeloma remains poorly understood. Here, we performed comprehensive analysis of SVs in a large cohort of 752 multiple myeloma patients by low coverage long-insert whole genome sequencing. We identified 68 SV hotspots involving 17 new candidate driver genes, including the therapeutic targets BCMA (TNFRSF17), SLAMF and MCL1. Catastrophic complex rearrangements termed chromothripsis were present in 24% of patients and independently associated with poor clinical outcomes. Templated insertions were the second most frequent complex event (19%), mostly involved in super-enhancer hijacking and activation of oncogenes such as CCND1 and MYC. Importantly, in 31% of patients two or more seemingly independent putative driver events were caused by a single structural event, demonstrating that the complex genomic landscape of multiple myeloma can be acquired through few key events during tumor evolutionary history. Overall, this study reveals the critical role of SVs in multiple myeloma pathogenesis.
We introduce a secure data-independent priority queue which supports polylogarithmic-time insertion operations and constant-time deletions and read-front (aka peek) operations as opposed to the originally introduced queue by Toft (PODC '11). Moreover, we minimize the number of comparisons required to perform different operations on Toft's priority queue. Data-independent data structures—first identified explicitly by Toft, and further elaborated by Mitchell and Zimmerman (STACS '14)—serve the purpose of computing on encrypted data without executing branching code which can be used to avoid prohibitively expensive operations in secure computation applications. Focusing on the costly sorting operations, we show significant asymptotic improvements over prior privacy preserving dark pool applications. Dark pools are securities-trading venues which attain ad-hoc order privacy, by matching orders outside of publicly visible exchanges via the so-called dark pool operators. In this paper, we describe an efficient and secure dark pool (implementing a full continuous double auction) based on our new priority queue. Our construction's security guarantees are cryptographic based on secure multiparty computation (MPC), and do not require that the dark pool operators are trusted. Our construction improves upon the asymptotic efficiency attained by previous efforts. Existing cryptographic dark pools process new orders in time which grows linearly in the size of the standing order book; ours does so in polylogarithmic time. We describe a concrete implementation of our MPC protocol with malicious security in the honest majority setting. We also report benchmarks of our implementation and compare them to prior works. Our protocol reduces the total running time by several orders of magnitude over prior secure dark pool solutions.
Abstract Patients treated with chemotherapy (CT) and/or autologous stem-cell transplantation (ASCT) are at risk for therapy-related myeloid neoplasms (tMN). Certain cytotoxic agents introduce mutations within distinct trinucleotide contexts resulting in a unique barcode for each exposed cell. We leveraged mutational signatures to investigate the role of CT in the genomic landscape of tMN with respect to antecedent clonal hematopoiesis (CH). We analyzed 32 tMN and 2 tALL from 33 patients and interrogated for copy number abnormalities (CNA), structural variants (SV), single nucleotide variants (SNV), and mutational signatures. For 7 patients with tMN post-melphalan/ASCT, we investigated antecedent CH using targeted sequencing on pre-melphalan samples, including autograft products. CH variants that became clonal in tumor were seen in 5/7 pre-melphalan/ASCT samples (TP53, RUNX1, NCOR1, NF1, CREBBP, DNMT3A, and PPM1D). Complex SV were seen in 7 tMNs; including chromothripsis in 6 (19.4%). In 4 cases, chromothripsis involved chromosome 19 with hyper-amplification of the SMARCA4 locus (≥5 copies). Mutational signature analysis revealed 6 known single base substitution (SBS) signatures in tMN including melphalan (SBS-MM1) and platinum signatures (SBS31, SBS35, and E-SBS37). TMNs with CT signatures had higher mutation burden than those without (p = 0.004). 17 patients with exposure to agents other than melphalan/platinum did not have increased mutational burden with respect to de novo AML (TCGA; NEJM, 2013). All patients with prior platinum exposure (including tALL, n=9) had platinum SBS signatures while only 2 of 7 patients with prior melphalan/ASCT had a melphalan signature (SBS-MM1). Detection of CT signatures in bulk sequencing relies on one cell, with its barcode of mutations, to expand to clonal dominance. Given pre-existent CH, including in 3/3 autograft products, absence of a CT signature despite melphalan exposure implies progression by a clone that escaped CT exposure with stem-cell collection and reinfusion. Conversely, all platinum-exposed tAML had signature evidence of exposure confirming existence of CH prior to exposure and supporting post-CT single-cell expansion. TMNs from 3 patients exposed to sequential platinum and melphalan/ASCT had platinum but not melphalan signatures confirming single-cell expansion of the pre-tMN CH clone post-platinum but with escape from exposure to melphalan via leukapheresis. Chromothripsis events bore only non-duplicated CT-induced mutations, indicative of acquisition prior to, and not directly caused by, CT exposure. These disparities suggest that ASCT provides a mechanism for CH clones to escape CT and re-engraft with transplant. Coupled with driver events accrued prior to CT, this suggest that CT-induced mutagenesis may be less important than other factors, such as CT-induced immunosuppression, in the expansion of pre-TMN CH clones. Citation Format: Benjamin Diamond, Bachisio Ziccheddu, Eileen M. Boyle, Kylee Maclachlan, Justin Taylor, Justin M. Watts, Sydney X. Lu, David G. Coffey, Niccolo Bolli, Elli Papaemmanuil, Kelly Bolton, Jae H. Park, Heather Landau, Karuna Ganesh, Mikkael A. Sekeres, Stephen Nimer, David J. Chung, Caleb H. Ho, Mikhail Roshal, Alexander Lesokhin, Gareth Morgan, Ola Landgren, Francesco Maura. Chemotherapy-related mutational signatures reveal the origins of therapy-related myeloid neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5747.
