Meta-analysis using a novel database, miRStress, reveals miRNAs that are frequently associated with the radiation and hypoxia stress-responses.

Organisms are often exposed to environmental pressures that affect homeostasis, so it is important to understand the biological basis of stress-response. Various biological mechanisms have evolved to help cells cope with potentially cytotoxic changes in their environment. miRNAs are small non-coding RNAs which are able to regulate mRNA stability. It has been suggested that miRNAs may tip the balance between continued cytorepair and induction of apoptosis in response to stress. There is a wealth of data in the literature showing the effect of environmental stress on miRNAs, but it is scattered in a large number of disparate publications. Meta-analyses of this data would produce added insight into the molecular mechanisms of stress-response. To facilitate this we created and manually curated the miRStress database, which describes the changes in miRNA levels following an array of stress types in eukaryotic cells. Here we describe this database and validate the miRStress tool for analysing miRNAs that are regulated by stress. To validate the database we performed a cross-species analysis to identify miRNAs that respond to radiation. The analysis tool confirms miR-21 and miR-34a as frequently deregulated in response to radiation, but also identifies novel candidates as potentially important players in this stress response, including miR-15b, miR-19b, and miR-106a. Similarly, we used the miRStress tool to analyse hypoxia-responsive miRNAs. The most frequently deregulated miRNAs were miR-210 and miR-21, as expected. Several other miRNAs were also found to be associated with hypoxia, including miR-181b, miR-26a/b, miR-106a, miR-213 and miR-192. Therefore the miRStress tool has identified miRNAs with hitherto unknown or under-appreciated roles in the response to specific stress types. The miRStress tool, which can be used to uncover new insight into the biological roles of miRNAs, and also has the potential to unearth potential biomarkers for therapeutic response, is freely available at http://mudshark.brookes.ac.uk/MirStress

Longitudinal expression profiling identifies a poor risk subset of patients with ABC-type diffuse large B-cell lymphoma

Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but fell short of providing a consistent relapse-specific genetic signature. In our study, we have focused attention on the changes in GEP accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo patients with DLBCL. COO remained stable from diagnosis to relapse in 80% of patients, with only a single patient showing COO switching from activated B-cell–like (ABC) to germinal center B-cell–like (GCB). Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC–DLBCLs derived from relapse-associated genes that defined clinically distinct high- and low-risk subgroups in ABC–DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of <60-year–old patients with superior PFS and OS treated with ibrutinib–R-CHOP as part of the PHOENIX trial. Altogether this new signature adds to the existing toolkit of putative genetic predictors now available in DLBCL that can be readily assessed as part of prospective clinical trials

Genome wide whole blood transcriptome profiling across inherited bone marrow failure subtypes.

Gene expression profiling has long been used in understanding the contribution of genes and related pathways in disease pathogenesis and susceptibility. We have performed whole blood transcriptomic profiling in a subset of inherited bone marrow failure (IBMF) cases that are clinically and genetically characterised as Fanconi anemia (FA), dyskeratosis congenita (DC) and Shwachman Diamond syndrome (SDS). We hypothesized that annotating whole blood transcripts genome wide will aid in understanding the complexity of gene regulation across these IBMF subtypes. Initial analysis of these blood derived transcriptomes revealed significant skewing towards upregulated genes in FA cases when compared to controls. Both DC and SDS cases also showed similar skewing profiles in their transcriptional status revealing a common pattern across these different IBMF subtypes. Gene set enrichment analysis revealed shared pathways involved in protein translation and elongation (ribosome constituents), RNA metabolism (nonsense mediated decay) and mitochondrial function (electron transport chain). We further identified a discovery set of 26 upregulated genes at stringent cut-off (FDR<0.05) that appeared as a unified signature across the IBMF subtypes. Subsequent transcriptomic analysis on genetically uncharacterised BMF cases revealed a striking overlap of genes, including 22 from the discovery set indicating a unified transcriptional drive across the classic (FA, DC and SDS) and uncharacterised BMF subtypes. This study has relevance in disease pathogenesis, for example in explaining the features (including the BMF) common to all IBMF cases and suggests harnessing this "transcriptional signature" for patient benefit

Clinical outcomes, Kadish-INSICA staging and therapeutic targeting of somatostatin receptor 2 in olfactory neuroblastoma

INTRODUCTION: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy. METHODS: We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT](177Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763). RESULTS: Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD). CONCLUSIONS: This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease

Clinical outcomes, Kadish-INSICA staging and therapeutic targeting of somatostatin receptor 2 in olfactory neuroblastoma

101siIntroduction: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy. Methods: We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT](177Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763). Results: Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD). Conclusions: This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease.nonenoneLechner M.; Takahashi Y.; Turri-Zanoni M.; Liu J.; Counsell N.; Hermsen M.; Kaur R.P.; Zhao T.; Ramanathan M.; Schartinger V.H.; Emanuel O.; Helman S.; Varghese J.; Dudas J.; Riechelmann H.; Sprung S.; Haybaeck J.; Howard D.; Engel N.W.; Stewart S.; Brooks L.; Pickles J.C.; Jacques T.S.; Fenton T.R.; Williams L.; Vaz F.M.; O'Flynn P.; Stimpson P.; Wang S.; Hannan S.A.; Unadkat S.; Hughes J.; Dwivedi R.; Forde C.T.; Randhawa P.; Gane S.; Joseph J.; Andrews P.J.; Royle G.; Franchi A.; Maragliano R.; Battocchio S.; Bewicke-Copley H.; Pipinikas C.; Webster A.; Thirlwell C.; Ho D.; Teschendorff A.; Zhu T.; Steele C.D.; Pillay N.; Vanhaesebroeck B.; Mohyeldin A.; Fernandez-Miranda J.; Park K.W.; Le Q.-T.; West R.B.; Saade R.; Manes R.P.; Omay S.B.; Vining E.M.; Judson B.L.; Yarbrough W.G.; Sansovini M.; Silvia N.; Grassi I.; Bongiovanni A.; Capper D.; Schuller U.; Thavaraj S.; Sandison A.; Surda P.; Hopkins C.; Ferrari M.; Mattavelli D.; Rampinelli V.; Facchetti F.; Nicolai P.; Bossi P.; Henriquez O.A.; Magliocca K.; Solares C.A.; Wise S.K.; Llorente J.L.; Patel Z.M.; Nayak J.V.; Hwang P.H.; Lacy P.D.; Woods R.; O'Neill J.P.; Jay A.; Carnell D.; Forster M.D.; Ishii M.; London N.R.; Bell D.M.; Gallia G.L.; Castelnuovo P.; Severi S.; Lund V.J.; Hanna E.Y.Lechner, M.; Takahashi, Y.; Turri-Zanoni, M.; Liu, J.; Counsell, N.; Hermsen, M.; Kaur, R. P.; Zhao, T.; Ramanathan, M.; Schartinger, V. H.; Emanuel, O.; Helman, S.; Varghese, J.; Dudas, J.; Riechelmann, H.; Sprung, S.; Haybaeck, J.; Howard, D.; Engel, N. W.; Stewart, S.; Brooks, L.; Pickles, J. C.; Jacques, T. S.; Fenton, T. R.; Williams, L.; Vaz, F. M.; O'Flynn, P.; Stimpson, P.; Wang, S.; Hannan, S. A.; Unadkat, S.; Hughes, J.; Dwivedi, R.; Forde, C. T.; Randhawa, P.; Gane, S.; Joseph, J.; Andrews, P. J.; Royle, G.; Franchi, A.; Maragliano, R.; Battocchio, S.; Bewicke-Copley, H.; Pipinikas, C.; Webster, A.; Thirlwell, C.; Ho, D.; Teschendorff, A.; Zhu, T.; Steele, C. D.; Pillay, N.; Vanhaesebroeck, B.; Mohyeldin, A.; Fernandez-Miranda, J.; Park, K. W.; Le, Q. -T.; West, R. B.; Saade, R.; Manes, R. P.; Omay, S. B.; Vining, E. M.; Judson, B. L.; Yarbrough, W. G.; Sansovini, M.; Silvia, N.; Grassi, I.; Bongiovanni, A.; Capper, D.; Schuller, U.; Thavaraj, S.; Sandison, A.; Surda, P.; Hopkins, C.; Ferrari, M.; Mattavelli, D.; Rampinelli, V.; Facchetti, F.; Nicolai, P.; Bossi, P.; Henriquez, O. A.; Magliocca, K.; Solares, C. A.; Wise, S. K.; Llorente, J. L.; Patel, Z. M.; Nayak, J. V.; Hwang, P. H.; Lacy, P. D.; Woods, R.; O'Neill, J. P.; Jay, A.; Carnell, D.; Forster, M. D.; Ishii, M.; London, N. R.; Bell, D. M.; Gallia, G. L.; Castelnuovo, P.; Severi, S.; Lund, V. J.; Hanna, E. Y

Clinical outcomes, Kadish-INSICA staging and therapeutic targeting of somatostatin receptor 2 in olfactory neuroblastoma

Introduction: olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy.Methods: we conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT](177Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763).Results: dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD).Conclusions: this study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease.</p