The multiple myeloma (MM) genome is heterogeneous and evolves through preclinical and post-diagnosis phases. Here we report a catalog and hierarchy of driver lesions using sequences from 67 MM ...genomes serially collected from 30 patients together with public exome datasets. Bayesian clustering defines at least 7 genomic subgroups with distinct sets of co-operating events. Focusing on whole genome sequencing data, complex structural events emerge as major drivers, including chromothripsis and a novel replication-based mechanism of templated insertions, which typically occur early. Hyperdiploidy also occurs early, with individual trisomies often acquired in different chronological windows during evolution, and with a preferred order of acquisition. Conversely, positively selected point mutations, whole genome duplication and chromoplexy events occur in later disease phases. Thus, initiating driver events, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of evolution that are biologically relevant but heterogeneous across patients.
Of the many types of DNA damage, DNA double-strand breaks (DSBs) are probably the most deleterious. Mounting evidence points to an intricate relationship between DSBs and transcription. A cell system ...in which the impact on transcription can be investigated at precisely mapped genomic DSBs is essential to study this relationship. Here in a human cell line, we map genome-wide and at high resolution the DSBs induced by a restriction enzyme, and we characterize their impact on gene expression by four independent approaches by monitoring steady-state RNA levels, rates of RNA synthesis, transcription initiation and RNA polymerase II elongation. We consistently observe transcriptional repression in proximity to DSBs. Downregulation of transcription depends on ATM kinase activity and on the distance from the DSB. Our study couples for the first time, to the best of our knowledge, high-resolution mapping of DSBs with multilayered transcriptomics to dissect the events shaping gene expression after DSB induction at multiple endogenous sites.
The ribonuclease DIS3 is one of the most frequently mutated genes in the hematological cancer multiple myeloma, yet the basis of its tumor suppressor function in this disease remains unclear. Herein, ...exploiting the TCGA dataset, we found that DIS3 plays a prominent role in the DNA damage response. DIS3 inactivation causes genomic instability by increasing mutational load, and a pervasive accumulation of DNA:RNA hybrids that induces genomic DNA double‐strand breaks (DSBs). DNA:RNA hybrid accumulation also prevents binding of the homologous recombination (HR) machinery to double‐strand breaks, hampering DSB repair. DIS3‐inactivated cells become sensitive to PARP inhibitors, suggestive of a defect in homologous recombination repair. Accordingly, multiple myeloma patient cells mutated for DIS3 harbor an increased mutational burden and a pervasive overexpression of pro‐inflammatory interferon, correlating with the accumulation of DNA:RNA hybrids. We propose DIS3 loss in myeloma to be a driving force for tumorigenesis via DNA:RNA hybrid‐dependent enhanced genome instability and increased mutational rate. At the same time, DIS3 loss represents a liability that might be therapeutically exploited in patients whose cancer cells harbor DIS3 mutations.
Synopsis
The ribonuclease DIS3 is frequently mutated in the blood cancer multiple myeloma. Here, DIS3 inactivation is found to cause accumulation of DNA:RNA hybrids, as well as to increases interferon responses and reduce homologous recombination.
DIS3 loss triggers a genome‐wide increase in DNA:RNA hybrids, which in turn leads to DNA fragmentation and genomic instability.
Hybrids accumulation at the sites of DNA damage prevents BRCA1 binding to DNA, impairing homologous recombination‐based DNA repair.
DIS3 loss is associated with increased mutational rate both in vitro and in patient samples with DIS3 mutations.
Myeloma cells derived from patients presenting DIS3 mutations display an intense interferon response.
DIS3 mutation in hematological cancer causes reduced homologous recombination repair, increased mutational burden, and overactivation of inflammatory interferon responses.
INTRODUCTION: In this paper we present Silico, a new Digital Musical Instrument which ideally represents theperformer itself. This instrument is composed by two parts: an interface (a sensor glove), ...which relies on the movementsof the performer’s hand, and a computational engine (a set of patches developed in Max 7), which generates sound eventsbased on the genomic data of the performer.OBJECTIVES: We want to propose a new reflection on the relation between the body and musical instruments. Moreover,we aim to investigate the voluntary and involuntary aspects of our body, intended as a starting point for a musicalperformance. As a metaphor of these two layers, we used here the hand and the genome of the performer.METHODS: We have investigated our objectives through the whole design process of a Digital Musical Instrument, usinga practice-based approach.RESULTS: Our system is a multilayered composed instrument which maps its computational part and its interface on theperformer’s body. Silico can be used as a standalone musical instrument to generate music in real time.CONCLUSION: Our works shows a new path about the use of genomic data in a musical way, as a new perspective ofhuman-computer interaction in a performative contexts.
Abstract
Esophageal adenocarcinoma (EAC) is associated with a marked genomic instability, which underlies disease progression and development of resistance to treatment. In this study, we used an ...integrated genomics approach to identify a genomic instability signature. Here we show that elevated expression of this signature correlates with poor survival in EAC as well as three other cancers. Knockout and overexpression screens establish the relevance of these genes to genomic instability. Indepth evaluation of three genes (
TTK
,
TPX2
and
RAD54B
) confirms their role in genomic instability and tumor growth. Mutational signatures identified by whole genome sequencing and functional studies demonstrate that DNA damage and homologous recombination are common mechanisms of genomic instability induced by these genes. Our data suggest that the inhibitors of
TTK
and possibly other genes identified in this study have potential to inhibit/reduce growth and spontaneous as well as chemotherapy-induced genomic instability in EAC and possibly other cancers.
There is increasing evidence that therapy-related acute lymphoblastic leukemia (trALL) resulting from chemo- and/or radiotherapy represents a distinct entity. However, apart from
rearrangements, ...which have been repeatedly reported in this subgroup, the relevance of other aberrations remains controversial due to divergent study results and sparse molecular analyses. Within our ALL patient cohort, 15% (
= 19/131) met the criteria for trALL with a high proportion of Ph + and
rearrangements. On the molecular level, the most frequently observed mutation was
, followed by
,
and
. No
mutation was detected. Outcome was particularly poor in Ph + trALL compared to Ph+
ALL, which seemed to be mitigated by allogeneic stem cell transplantation. Our findings further define trALL as a distinct entity but highlight the need for further molecular genome sequencing of somatic and germline variants to advance our understanding of trALL.
Abstract
Microbial communities living in nine vineyards distributed over three altitudinal transects were studied over 2 years. Fungal and bacterial community dynamics were explored using automated ...ribosomal intergenic spacer analysis (ARISA) and by determining bacterial cells and fungal colony-forming units (CFUs). Moreover, extensive chemical and physical analyses of the soils were carried out. Multivariate analyses demonstrated that bacterial and fungal communities are affected by altitude, which acts as a complex physicochemical gradient. In fact, soil moisture, Al, Mg, Mn and clay content are changing with altitude and influencing the bacterial genetic structure, while in the case of fungi, soil moisture, B and clay content are found to be the main drivers of the community. Moreover, other exchangeable cations and heavy metals, not correlating with altitude, are involved in the ordination of the sites, especially Cu. Qualitative ARISA revealed the presence of a stable core microbiome of operational taxonomic units (OTUs) within each transect, which ranged between 57% and 68% of total OTUs in the case of fungi and between 63% and 72% for bacteria. No seasonal effect on the composition of microbial communities was found, demonstrating that bacterial and fungal communities in vineyards are mostly stable over the considered seasons.
High-dose melphalan (HDM) improves progression-free survival in multiple myeloma (MM), yet melphalan is a DNA-damaging alkylating agent; therefore, we assessed its mutational effect on surviving ...myeloma cells by analyzing paired MM samples collected at diagnosis and relapse in the IFM 2009 study. We performed deep whole-genome sequencing on samples from 68 patients, 43 of whom were treated with RVD (lenalidomide, bortezomib, and dexamethasone) and 25 with RVD + HDM. Although the number of mutations was similar at diagnosis in both groups (7137 vs 7230; P = .67), the HDM group had significantly more mutations at relapse (9242 vs 13 383, P = .005). No change in the frequency of copy number alterations or structural variants was observed. The newly acquired mutations were typically associated with DNA damage and double-stranded breaks and were predominantly on the transcribed strand. A machine learning model, using this unique pattern, predicted patients who would receive HDM with high sensitivity, specificity, and positive prediction value. Clonal evolution analysis showed that all patients treated with HDM had clonal selection, whereas a static progression was observed with RVD. A significantly higher percentage of mutations were subclonal in the HDM cohort. Intriguingly, patients treated with HDM who achieved complete remission (CR) had significantly more mutations at relapse yet had similar survival rates as those treated with RVD who achieved CR. This similarity could have been due to HDM relapse samples having significantly more neoantigens. Overall, our study identifies increased genomic changes associated with HDM and provides rationale to further understand clonal complexity.
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