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A novel mouse model demonstrates that oncogenic melanocyte stem cells engender melanoma resembling human disease
Sun, Qi; Lee, Wendy; Mohri, Yasuaki; Takeo, Makoto; Lim, Chae Ho; Xu, Xiaowei; Myung, Peggy; Atit, Radhika P; Taketo, M Mark; Moubarak, Rana S; Schober, Markus; Osman, Iman; Gay, Denise L; Saur, Dieter; Nishimura, Emi K; Ito, Mayumi
Melanoma, the deadliest skin cancer, remains largely incurable at advanced stages. Currently, there is a lack of animal models that resemble human melanoma initiation and progression. Recent studies using a Tyr-CreER driven mouse model have drawn contradictory conclusions about the potential of melanocyte stem cells (McSCs) to form melanoma. Here, we employ a c-Kit-CreER-driven model that specifically targets McSCs to show that oncogenic McSCs are a bona fide source of melanoma that expand in the niche, and then establish epidermal melanomas that invade into the underlying dermis. Further, normal Wnt and Endothelin niche signals during hair anagen onset are hijacked to promote McSC malignant transformation during melanoma induction. Finally, molecular profiling reveals strong resemblance of murine McSC-derived melanoma to human melanoma in heterogeneity and gene signatures. These findings provide experimental validation of the human melanoma progression model and key insights into the transformation and heterogeneity of McSC-derived melanoma.
PMCID:6828673
PMID: 31685822
ISSN: 2041-1723
CID: 4172362
Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients
Peters, Brandilyn A; Wilson, Melissa; Moran, Una; Pavlick, Anna; Izsak, Allison; Wechter, Todd; Weber, Jeffrey S; Osman, Iman; Ahn, Jiyoung
BACKGROUND:Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important for determining expression of metagenomic functions in the microbial community. METHODS:In melanoma patients undergoing immunotherapy, gut microbiome was characterized in pre-treatment stool using 16S rRNA gene and shotgun metagenome sequencing (n = 27). Transcriptional expression of metagenomic pathways was confirmed with metatranscriptome sequencing in a subset of 17. We examined associations of taxa and metagenomic pathways with progression-free survival (PFS) using 500 × 10-fold cross-validated elastic-net penalized Cox regression. RESULTS:Higher microbial community richness was associated with longer PFS in 16S and shotgun data (p < 0.05). Clustering based on overall microbiome composition divided patients into three groups with differing PFS; the low-risk group had 99% lower risk of progression than the high-risk group at any time during follow-up (p = 0.002). Among the species selected in regression, abundance of Bacteroides ovatus, Bacteroides dorei, Bacteroides massiliensis, Ruminococcus gnavus, and Blautia producta were related to shorter PFS, and Faecalibacterium prausnitzii, Coprococcus eutactus, Prevotella stercorea, Streptococcus sanguinis, Streptococcus anginosus, and Lachnospiraceae bacterium 3 1 46FAA to longer PFS. Metagenomic functions related to PFS that had correlated metatranscriptomic expression included risk-associated pathways of L-rhamnose degradation, guanosine nucleotide biosynthesis, and B vitamin biosynthesis. CONCLUSIONS:This work adds to the growing evidence that gut microbiota are related to immunotherapy outcomes, and identifies, for the first time, transcriptionally expressed metagenomic pathways related to PFS. Further research is warranted on microbial therapeutic targets to improve immunotherapy outcomes.
PMID: 31597568
ISSN: 1756-994x
CID: 4130672
The immune landscape of melanoma significantly influences survival in patients with highly mutated tumours [Meeting Abstract]
Ferguson, R; Morales, L; Simpson, D; Cadley, J; Esteva, E; Chat, V; Martinez, C; Weber, J S; Osman, I; Kirchhoff, T
Background: Tumor-specific indicators, such as tumor mutation burden (TMB) have been shown to affect overall survival (OS) in melanoma. Recently, pan-cancer analyses from The Cancer Genome Atlas (TCGA) discovered specific tumor immune signatures predictive of overall survival (OS), yet it is unclear how these interact with other prognostic markers, independently of immunotherapy (IT). We aimed to combine the immune landscape signatures with TMB and other prognostic markers to improve melanoma OS prediction in patients, independent of IT.
Method(s): We examined the whole-exome data in conjunction with the molecular, clinical and immune features from 278 metastatic melanomas from TCGA, not treated by IT, to develop an improved prognostic model of melanoma OS. Using the discovery (N=139) and validation (N=139) design we performed multivariate Cox proportional hazards (Cox HR) models, adjusted for age and tumor stage at primary diagnosis, to identify interaction between TMB and melanoma immune features (n=59), refining the prediction of melanoma OS.
Result(s): We identified 4 immune features that were significantly associated with OS in both the discovery and validation cohorts. The multivariate Cox HR models revealed that IFN-c response (IFN-c R) and macrophage regulation (MR) signatures in combination with TMB were the most significantly associated with OS (p=8.80E-14). After further refinement, we observed that patients with high TMB, high IFN-c R and high MRhad significantly better OS compared to high TMB, low IFN-y R and low MR (HR=2.8, p=3.55E-08). This association was not observed in low TMB patients.
Conclusion(s): We show, for the first time, that TMB and tumor immune features are significantly associated with improved OS, independent of IT. Further analysis of patients revealed that high TMB associates with improved OS in patients with high IFN- c R and MR but not in low IFN- c R and MR. Hence, this data provides first evidence that patients with high TMB have distinct OS outcome depending on other tumor immune features. Beside biological link between TMB and IFN-y and MR, our data suggest that these associations may significantly improve the current melanoma prognostic models
EMBASE:630607219
ISSN: 1569-8041
CID: 4286052
The complex relationship between body mass index and response to immune checkpoint inhibition in metastatic melanoma patients
Donnelly, Douglas; Bajaj, Shirin; Yu, Jaehong; Hsu, Miles; Balar, Arjun; Pavlick, Anna; Weber, Jeffrey; Osman, Iman; Zhong, Judy
Despite major improvements in combatting metastatic melanoma since the advent of immunotherapy, the overall survival for patients with advanced disease remains low. Recently, there is a growing number of reports supporting an "obesity paradox," in which patients who are overweight or mildly obese may exhibit a survival benefit in patients who received immune checkpoint inhibitors. We studied the relationship between body mass index and progression-free survival and overall survival in a cohort of 423 metastatic melanoma patients receiving immunotherapy, enrolled and prospectively followed up in the NYU Interdisciplinary Melanoma Cooperative Group database. We analyzed this association stratified by first vs. second or greater-line of treatment and treatment type adjusting for age, gender, stage, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, number of metastatic sites, and body mass index classification changes. In our cohort, the patients who were overweight or obese did not have different progression-free survival than patients with normal body mass index. Stratifying this cohort by first vs. non-first line immunotherapy revealed a moderate but insignificant association between being overweight or obese and better progression-free survival in patients who received first line. Conversely, an association with worse progression-free survival was observed in patients who received non-first line immune checkpoint inhibitors. Specifically, overweight and obese patients receiving combination immunotherapy had a statistically significant survival benefit, whereas patients receiving the other treatment types showed heterogeneous trends. We caution the scientific community to consider several important points prior to drawing conclusions that could potentially influence patient care, including preclinical data associating obesity with aggressive tumor biology, the lack of congruence amongst several investigations, and the limited reproduced comprehensiveness of these studies.
PMID: 31426863
ISSN: 2051-1426
CID: 4046622
Immunomodulatory germline variation associated with the development of multiple primary melanoma (MPM)
Ferguson, Robert; Archambault, Alexi; Simpson, Danny; Morales, Leah; Chat, Vylyny; Kazlow, Esther; Lax, Rebecca; Yoon, Garrett; Moran, Una; Shapiro, Richard; Pavlick, Anna; Polsky, David; Osman, Iman; Kirchhoff, Tomas
Multiple primary melanoma (MPM) has been associated with a higher 10-year mortality risk compared to patients with single primary melanoma (SPM). Given that 3-8% of patients with SPM develop additional primary melanomas, new markers predictive of MPM risk are needed. Based on the evidence that the immune system may regulate melanoma progression, we explored whether germline genetic variants controlling the expression of 41 immunomodulatory genes modulate the risk of MPM compared to patients with SPM or healthy controls. By genotyping these 41 variants in 977 melanoma patients, we found that rs2071304, linked to the expression of SPI1, was strongly associated with MPM risk reduction (OR = 0.60; 95% CI = 0.45-0.81; p = 0.0007) when compared to patients with SPM. Furthermore, we showed that rs6695772, a variant affecting expression of BATF3, is also associated with MPM-specific survival (HR = 3.42; 95% CI = 1.57-7.42; p = 0.0019). These findings provide evidence that the genetic variation in immunomodulatory pathways may contribute to the development of secondary primary melanomas and also associates with MPM survival. The study suggests that inherited host immunity may play an important role in MPM development.
PMID: 31308438
ISSN: 2045-2322
CID: 3977742
Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition
Chat, Vylyny; Ferguson, Robert; Simpson, Danny; Kazlow, Esther; Lax, Rebecca; Moran, Una; Pavlick, Anna; Frederick, Dennie; Boland, Genevieve; Sullivan, Ryan; Ribas, Antoni; Flaherty, Keith; Osman, Iman; Weber, Jeffrey; Kirchhoff, Tomas
Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568-a risk variant for allergy, colitis and type 1 diabetes-was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12-0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.
PMID: 30863922
ISSN: 1432-0851
CID: 3733172
Impact of initial stage on metastatic melanoma survival
Wilson, Melissa A; Zhong, Judy; Rosenbaum, Brooke E; Utter, Kierstin; Moran, Una; Darvishian, Farbod; Polsky, David; Berman, Russell S; Shapiro, Richard L; Pavlick, Anna C; Osman, Iman
Patients diagnosed with metastatic melanoma have varied clinical courses, even in patients with similar disease characteristics. We examine the impact of initial stage of melanoma diagnosis, BRAF status of primary melanoma, and receiving adjuvant therapy on postmetastatic overall survival (pmOS). We studied melanoma patients presenting to Perlmutter Cancer Center at New York University and prospectively enrolled in New York University melanoma biospecimen database and followed up on protocol-driven schedule. Patients were stratified by stage at initial melanoma diagnosis as per AJCC 7th ed. guidelines. pmOS was determined using the Kaplan-Meier method and Cox's proportional hazards models were used to assess hazard ratios (HRs). Three hundred and four out of 3204 patients developed metastatic disease over the time of follow-up (median follow-up 2.2 years, range: 0.08-35.2 years). Patients diagnosed with stage I (n=96) melanoma had longer pmOS (29.5 months) than those diagnosed with stage II (n=99, pmOS 14.9 months) or stage III (n=109, pmOS 15.1 months) melanoma (P=0.036). Initial stage of diagnosis remained significant in multivariate analysis when controlling for lactate dehydrogenase and site of metastases [primary diagnosis stage II (HR 1.44, P=0.046), stage III (HR 1.5, P=0.019)]. Adjuvant treatment was associated with better survival but BRAF mutation status did not show an association. Our data challenge the general assumption that primary melanomas converge upon diagnosis of metastatic disease and behave uniformly. Primary stage of melanoma at the time of diagnosis may be prognostic of outcome, similar to lactate dehydrogenase and metastatic disease sites.
PMID: 31026246
ISSN: 1473-5636
CID: 3821792
Human biospecimens collection for bio-medical research: Obstacles and solutions. the NYU langone health (NYULH) experience [Meeting Abstract]
Cotzia, P; Moran, U; Arguelles-Grande, C; Donnelly, D; Mendoza, S; Moreira, A; Osman, I
Background: Banking of human biospecimens linked to prospective, well-annotated clinical information is critical for advancing biomedical research. However, the establishment of an efficient biobank encompasses many issues including adherence to federal regulations, institutional policies and governance of the relationship between the biobank, investigators and funding agents. Here we report on the efforts of the Center for Biospecimen Research and Development (CBRD) at NYULH to establish a state-of-the-art biobank. Method(s): In 2015, we identified the need to establish a centralized infrastructure to facilitate research collaborations and support clinical trial studies. The four main considerations were: 1) creating a centralized mechanism to consent, collect and bank human biospecimens 2) Organizing, de-identifying, and annotating subjects' samples linked to their clinical data 3) Establishing multidisciplinary involvement of pathology departments 4) Enhancing quality control measures to achieve CAP and NYS DOH accreditation. To address these considerations, we created a Universal Consent (UC) form; developed a Laboratory Information Management System that assists in specimen organization and links subject samples to clinical data in their electronic medical record and fostered a partnership between the pathology department, individual researchers and the CBRD to develop best practices in biobanking. Result(s): Since June 2016, using the UC, 18,906 of 27,355 (70%) subjects agreed to use their specimens and data for research. 9,054 patients had specimens collected using the UC and additional specific consent if needed. We collected 4,178 unique samples (tissue, blood and fluids)-13,969 aliquots by the UC method and 7,713 samples from fresh and archival collections for specific research studies or clinical trials. The CBRD supported 93 research projects and 251 clinical trials. Conclusion(s): Establishment of the CBRD permitted the increase in absolute number of patients approached for research; enhancement of specimen quality and organization and introduction of the electronic crosslink to minimize the time and overhead needed for clinical data retrieval. Building on this success, we are upgrading our IT infrastructure to expand upon the data collected, digitalizing tissue slides to improve quality control and building an automated molecular genotyping database using existing NGS data to increase the number of trans-lational research projects
EMBASE:628796543
ISSN: 1947-5543
CID: 4034712
A Deep Learning Approach for Rapid Mutational Screening in Melanoma [PrePrint]
Kim, Randie H; Nomikou, Sofia; Dawood, Zarmeena; Jour, George; Donnelly, Douglas; Moran, Una; Weber, Jeffrey S; Razavian, Narges; Snuderl, Matija; Shapiro, Richard; Berman, Russell S; Coudray, Nicloas; Osman, Iman; Tsirigos, Aristotelis
ORIGINAL:0014818
ISSN: 2692-8205
CID: 4662142
Microglandular Adenosis is an advanced precursor breast lesion with evidence of molecular progression to matrix-producing metaplastic carcinoma
Schwartz, Christopher J; Dolgalev, Igor; Yoon, Esther; Osman, Iman; Heguy, Adriana; de Miera, Eleazar Vega-Saenz; Nimeh, Diana; Jour, George; Darvishian, Farbod
Microglandular adenosis (MGA) is a rare breast lesion reported to be associated with invasive carcinoma in up to 20-30% of cases, and has been proposed as a non-obligate precursor to basal-like breast cancers. We identified a case of matrix-producing metaplastic carcinoma with morphologic and immunohistochemical evidence of progression from MGA to atypical MGA (AMGA), carcinoma in situ (CIS) and invasive carcinoma. We performed whole exome sequencing of each component (MGA, AMGA, CIS and cancer) to characterize the mutational landscape of these foci. There was significant copy number overlap between all foci, including a segmental amplification of the CCND1 locus (partial chromosome 11 trisomy) and MYC (8q24.12-13). Using a bioinformatics approach, we were able to identify three putative mutational clusters and recurrent, stop-gain non-synonymous mutations in both ZNF862 and TP53 that were shared across all foci. Finally, we identified a novel deleterious splice-acceptor site mutation of chr5:5186164G>T (chromosome 5p15) encoding the gene, ADAMTS16, in the invasive component.
PMID: 30428388
ISSN: 1532-8392
CID: 3457342