Searched for: in-biosketch:yes
person:osmani01
TERT, BRAF, and NRAS mutational heterogeneity between paired primary and metastatic melanoma tumors
Chang, Gregory A; Wiggins, Jennifer M; Corless, Broderick C; Syeda, Mahrukh M; Tadepalli, Jyothirmayee S; Blake, Shria; Fleming, Nathaniel; Darvishian, Farbod; Pavlick, Anna; Berman, Russell; Shapiro, Richard; Shao, Yongzhao; Karlin-Neumann, George; Spittle, Cindy; Osman, Iman; Polsky, David
Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequency of inter- and intra-tumoral heterogeneity is controversial. We examined mutational heterogeneity within individual melanoma patients using multi-platform analysis of commonly mutated driver and non-passenger genes. We analyzed paired primary and metastatic tumors from 60 patients, and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n=271 tumors). We used a combination of multiplex SNaPshot assays, Sanger Sequencing, Mutation-specific PCR, or droplet digital PCR to determine the presence of BRAFV600, NRASQ61, and TERT-124C>T and TERT-146C>T mutations. Mutations were detected in BRAF (39%), NRAS (21%) and/or TERT (78%). Thirteen patients had TERTmutant discordant tumors; seven of these had a single tumor with both TERT-124C>T and TERT-146C>T mutations present at different allele frequencies. Two patients had both BRAF and NRAS mutations; one in different tumors and the other had a single tumor with both mutations. One patient with a BRAFmutant primary lacked mutant BRAF in least one of their metastases. Overall, we identified mutational heterogeneity in 18/99 (18%) patients. These results suggest that some primary melanomas may be comprised of subclones with differing mutational profiles. Such heterogeneity may be relevant to treatment responses and survival outcomes.
PMID: 32087194
ISSN: 1523-1747
CID: 4313462
WITHDRAWN: ASSOCIATION OF INITIAL VIRAL LOAD IN SARS-CoV-2 PATIENTS WITH OUTCOME AND SYMPTOMS
Argyropoulos, Kimon V; Serrano, Antonio; Hu, Jiyuan; Black, Margaret; Feng, Xiaojun; Shen, Guomiao; Call, Melissa; Kim, Min Jae; Lytle, Andrew; Belovarac, Brendan; Vougiouklakis, Theodore; Lin, Lawrence Hsu; Moran, Una; Heguy, Adriana; Troxel, Andrea; Snuderl, Matija; Osman, Iman; Cotzia, Paolo; Jour, George
The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.ajpath.2020.07.001. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
PMID: 32650002
ISSN: 1525-2191
CID: 4539692
The urgency of utilizing COVID-19 biospecimens for research in the heart of the global pandemic [Letter]
Osman, Iman; Cotzia, Paolo; Moran, Una; Donnelly, Douglas; Arguelles-Grande, Carolina; Mendoza, Sandra; Moreira, Andre
The outbreak of the novel coronavirus disease 2019 (COVID-19) and consequent social distancing practices have disrupted essential clinical research functions worldwide. Ironically, this coincides with an immediate need for research to comprehend the biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the pathology of COVID-19. As the global crisis has already led to over 15,000 deaths out of 175,000 confirmed cases in New York City and Nassau County, NY alone, it is increasingly urgent to collect patient biospecimens linked to active clinical follow up. However, building a COVID-19 biorepository amidst the active pandemic is a complex and delicate task. To help facilitate rapid, robust, and regulated research on this novel virus, we report on the successful model implemented by New York University Langone Health (NYULH) within days of outbreak in the most challenging hot spot of infection globally. Using an amended institutional biobanking protocol, these efforts led to accrual of 11,120 patients presenting for SARS-CoV-2 testing, 4267 (38.4%) of whom tested positive for COVID-19. The recently reported genomic characterization of SARS-CoV-2 in the New York City Region, which is a crucial development in tracing sources of infection and asymptomatic spread of the novel virus, is the first outcome of this effort. While this growing resource actively supports studies of the New York outbreak in real time, a worldwide effort is necessary to build a collective arsenal of research tools to deal with the global crisis now, and to exploit the virus's biology for translational innovation that outlasts humanity's current dilemma.
PMCID:7266426
PMID: 32487093
ISSN: 1479-5876
CID: 4468952
Oxidative phosphorylation promotes primary melanoma invasion
Salhi, Amel; Jordan, Alexander C; Bochaca, Irineu Illa; Izsak, Allison; Darvishian, Farbod; Houvras, Yariv; Giles, Keith M; Osman, Iman
Dermal invasion is a hallmark of malignant melanoma. Thought the molecular alterations driving the progression of primary melanoma to metastatic disease have been studied extensively, the early progression of non-invasive primary melanoma to an invasive state is poorly understood. To elucidate the mechanisms underlying the transition from radial to vertical growth, the first step in melanoma invasion, we developed a zebrafish melanoma model in which constitutive activation of ribosomal protein S6 kinase A1 (Rps6ka1; RSK1) drives tumor invasion. Transcriptomic analysis of ribosomal protein S6 kinase A1-activated tumors identified metabolic changes, including up-regulation of genes associated with oxidative phosphorylation. Vertical growth phase human melanoma cells show higher oxygen consumption and preferential utilization of glutamine compared to radial growth phase melanoma cells. Peroxisome proliferator activated receptor gamma (PPARG) coactivator 1 alpha (PPARGC1A), also known as PPARG coactivator-1α (PGC1α), has been proposed as a master regulator of tumor oxidative phosphorylation. In human primary melanoma specimens, PGC1α protein expression was found to be positively associated with increased tumor thickness and expression of the proliferative marker Ki-67 and the reactive oxygen species scavenger scavenger receptor class A member 3 . PGC1α depletion modulated cellular processes associated with primary melanoma growth and invasion, including oxidative stress. These results support a role for PGC1α in mediating glutamine-driven oxidative phosphorylation to facilitate the invasive growth of primary melanoma.
PMID: 32142731
ISSN: 1525-2191
CID: 4340052
Functional analysis of RPS27 mutations and expression in melanoma
Floristán, Alfredo; Morales, Leah; Hanniford, Douglas; Martinez, Carlos; Castellano-Sanz, Elena; Dolgalev, Igor; Ulloa-Morales, Alejandro; Vega-Saenz de Miera, Eleazar; Moran, Una; Darvishian, Farbod; Osman, Iman; Kirchhoff, Tomas; Hernando, Eva
Next-generation sequencing has enabled genetic and genomic characterization of melanoma to an unprecedent depth. However, the high mutational background plus the limited deep-coverage whole-genome sequencing performed on cutaneous melanoma samples, make difficult the identification of novel driver mutations. We sought to explore the somatic mutation portfolio in exonic and gene regulatory regions in human melanoma samples, for which we performed targeted sequencing of tumors and matched germline DNA samples from 89 melanoma patients, identifying known and novel recurrent mutations. Two recurrent mutations found in the RPS27 promoter associated with decreased RPS27 mRNA levels in vitro. Data mining and IHC analyses revealed a bimodal pattern of RPS27 expression in melanoma, with RPS27-low patients displaying worse prognosis. In vitro characterization of RPS27-high and -low melanoma cell lines, as well as loss-of-function experiments, demonstrated that high RPS27 status provides increased proliferative and invasive capacities, while low RPS27 confers survival advantage in low-attachment and resistance to therapy. Additionally, we demonstrate that 10 other cancer types harbor bimodal RPS27 expression and in those, similarly to melanoma, RPS27-low expression associates with worse clinical outcomes. RPS27 promoter mutation could thus represent a mechanism of gene expression modulation in melanoma patients, which may have prognostic and predictive implications.
PMID: 31663663
ISSN: 1755-148x
CID: 4162282
Deep learning based on standard H&E images of primary melanoma tumors identifies patients at risk for visceral recurrence and death
Kulkarni, Prathamesh M; Robinson, Eric J; Sarin Pradhan, Jaya; Gartrell-Corrado, Robyn D; Rohr, Bethany R; Trager, Megan H; Geskin, Larisa J; Kluger, Harriet M; Wong, Pok Fai; Acs, Balazs; Rizk, Emanuelle M; Yang, Chen; Mondal, Manas; Moore, Michael R; Osman, Iman; Phelps, Robert; Horst, Basil A; Chen, Zhe S; Ferringer, Tammie; Rimm, David L; Wang, Jing; Saenger, Yvonne M
PURPOSE/OBJECTIVE:Biomarkers for disease specific survival (DSS) in early stage melanoma are needed to select patients for adjuvant immunotherapy and accelerate clinical trial design. We present a pathology-based computational method using a deep neural network architecture for DSS prediction. EXPERIMENTAL DESIGN/METHODS:The model was trained on 108 patients from four institutions and tested on 104 patients from Yale School of Medicine (YSM). A receiver operating characteristic (ROC) curve was generated based on vote aggregation of individual image sequences, an optimized cutoff was selected, and the computational model was tested on a third independent population of 51 patients from Geisinger Health Systems (GHS). RESULTS:Area under the curve (AUC) in the YSM patients was 0.905 (p<0.0001). AUC in the GHS patients was 0.880 (p<0.0001). Using the cutoff selected in the YSM cohort, the computational model predicted DSS in the GHS cohort based on Kaplan-Meier (KM) analysis (p<0.0001). CONCLUSIONS:The novel method presented is applicable to digital images, obviating the need for sample shipment and manipulation and representing a practical advance over current genetic and IHC-based methods.
PMID: 31636101
ISSN: 1078-0432
CID: 4169052
Tumor microenvironment characteristics in early and advanced tert promoter hotspot mutant melanomas [Meeting Abstract]
Hindi, I; Donnelly, D; Kelly, S; Berman, R; de, Miera E V -S; Pavlick, A; Osman, I; Jour, G
Background: TERT promoter mutations in various reports have been associated with poor patient survival in early stage melanomas emphasizing it as a separate subset of melanoma. Thus far, no studies investigated whether the immune composition of the tumor microenvironment (TME) in TERT (HS) mutant melanomas differs from TERT WT melanomas. Furthermore, the mechanism underlying the worse outcome in early stage TPHS melanomas remains unclear. Herein, we aim to characterize the tumor microenvironment (TME) of TERT promoter hotspot (TPHS) mutant melanomas & compare them to TERT WT melanomas in a cohort of early and advanced stage melanomas. We also aim to elucidate the clinical significance of the TME composition.
Design(s): We analyzed tissue from a cohort of 93 melanoma patients. DNA and RNA were extracted from primary and metastatic tumor tissue, resected prior to treatment with immune checkpoint inhibitors. The extracted DNA was genotyped using a customized next generation sequencing high throughput panel that targets 580 cancer-related genes to determine TPHS mutation status. Gene expression analysis was performed on the RNA from 52 patients using a customized 770-gene expression panel combining markers 48 biologically significant signatures with the N-counter system. Differential gene expression (DGE) and Gene set enrichment analysis (GSEA) were performed using R package [(p<0.01; FDR<0.01; FDR<0.30 for GSEA] using TERT WT as a reference.
Result(s): Table 1 illustrates the clinicopathological characteristics of the cohort. TPHS mutant melanoma was associated with downregulation of melanoma-associated antigens (MAGES) and endothelial cells/angiogenesis signature (p<0.01). Notably, MAGEA4, MAGEA1, CTAG1B, PALMD & KDR were among the most downregulated genes in the (lg2fc= -3.2; -2.2; -2.66, -1.23; - 0.66, respectively). GSEA showed a significant enrichment for NOD-like receptor (NLR) signaling pathway including NFKB1, TNF & NLR3P in TPHS mutant melanoma (Figure 1). Within TPHS mutant melanoma, high endothelial cells/angiogenesis signature (score >3.85/median) was more prevalent in stage (I/II) melanomas (p=0.025). No significant association between TERT mutational status, outcome nor histologic subtype were noted. (Table presented)
Conclusion(s): Our findings show that TPHS mutant melanoma and TERT WT have distinct TME composition. The higher endothelial/angiogenesis signature seen in early stage TPHS mutant melanoma compared to stage III/IV TPHS mutant melanomas could contribute to the poor outcome reported in the former group
EMBASE:631879085
ISSN: 1530-0285
CID: 4470602
Epigenetic Silencing of CDR1as Drives IGF2BP3-Mediated Melanoma Invasion and Metastasis
Hanniford, Douglas; Ulloa-Morales, Alejandro; Karz, Alcida; Berzoti-Coelho, Maria Gabriela; Moubarak, Rana S; Sánchez-Sendra, Beatriz; Kloetgen, Andreas; Davalos, Veronica; Imig, Jochen; Wu, Pamela; Vasudevaraja, Varshini; Argibay, Diana; Lilja, Karin; Tabaglio, Tommaso; Monteagudo, Carlos; Guccione, Ernesto; Tsirigos, Aristotelis; Osman, Iman; Aifantis, Iannis; Hernando, Eva
Metastasis is the primary cause of death of cancer patients. Dissecting mechanisms governing metastatic spread may uncover important tumor biology and/or yield promising therapeutic insights. Here, we investigated the role of circular RNAs (circRNA) in metastasis, using melanoma as a model aggressive tumor. We identified silencing of cerebellar degeneration-related 1 antisense (CDR1as), a regulator of miR-7, as a hallmark of melanoma progression. CDR1as depletion results from epigenetic silencing of LINC00632, its originating long non-coding RNA (lncRNA) and promotes invasion in vitro and metastasis in vivo through a miR-7-independent, IGF2BP3-mediated mechanism. Moreover, CDR1as levels reflect cellular states associated with distinct therapeutic responses. Our study reveals functional, prognostic, and predictive roles for CDR1as and expose circRNAs as key players in metastasis.
PMID: 31935372
ISSN: 1878-3686
CID: 4263262
Melanoma-secreted amyloid beta supresses neuroinflammation and promotes brain metastasis [Meeting Abstract]
Kleffman, K; Levinson, G; Dhabaria, A; Galan, F; Wong, E; Itter, R V; De, Miera E; Tranos, J; Osman, I; Li, Y; Ueberheide, B; Liddelow, S; Ruggles, K; Schneider, R; Hernando, E
Melanoma brain metastasis is the largest cause of melanoma morbidity and mortality, and melanoma has the highest rate of brain metastasis of any cancer. The mechanisms that mediate melanoma brain metastasis remain poorly understood. We characterized patient-derived Short-Term Cultures (STCs) as a novel model system for the study of melanoma brain metastasis. Unbiased proteomics analysis of STCs revealed striking alterations in brain metastasis vs non-brain metastasis derived STCs in proteins related to neurodegeneration. Through in-vivo assays, we show that loss of Amyloid Precursor Protein (APP) in melanoma cells dramatically inhibits melanoma brain metastasis formation without affecting metastasis to other organs and that amyloid beta is the form of APP critically required for melanoma brain metastasis. Additionally, we demonstrate that APP is required for late growth and survival of melanoma cells in the brain parenchyma. Furthermore, we demonstrate that melanoma-derived amyloid beta polarizes astrocytes to an anti-inflammatory secretory phenotype that inhibits microglial phagocytosis of melanoma cells. Finally, we show that treatment of mice with a beta secretase inhibitor (LY2886721), which prevents amyloid beta production, decreases brain metastatic burden. Our results demonstrate a critical role for amyloid beta in melanoma brain metastasis, establish a novel connection between brain metastasis and neurodegenerative pathologies, and show that amyloid beta is a promising therapeutic target for brain metastasis treatment. Studies to further characterize how amyloid beta acts in the melanoma brain metastasis microenvironment are currently underway
EMBASE:631885213
ISSN: 1755-148x
CID: 4471292
Oncogenic melanocyte stem cells, driven by regenerative niche signals, give rise to heterogeneous melanoma resembling human melanoma [Meeting Abstract]
Sun, Q.; Katehis, I.; Lee, W.; Mohri, Y.; Takeo, M.; Lim, C.; Xu, X.; Myung, P. S.; Atit, R.; Taketo, M.; Moubarak, R.; Schober, M.; Osman, I.; Gay, D.; Saur, D.; Nishimura, E. K.; Ito, M.
ISI:000554564400573
ISSN: 0022-202x
CID: 4560342