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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

Germline Genetics in Immuno-oncology: From Genome-Wide to Targeted Biomarker Strategies

Kirchhoff, Tomas; Ferguson, Robert
In immuno-oncology (IO), the baseline host factors attract significant clinical interest as promising predictive biomarker candidates primarily due to the feasibility of noninvasive testing and the personalized potential of IO outcome prediction catered to individual patients. Growing evidence from experimental or population-based studies suggests that the host genetic factors contribute to the immunological status of a patient as it plays out at the multiple rate-limiting steps of the cancer immunity cycle. Recent observations suggest that germline genetics may be associated with tumor microenvironment phenotypes, autoimmune toxicities, and/or efficacy of immunotherapy regimens and overall cancer survival. Despite these highly intriguing indications, the potential of germline genetic factors as personalized biomarkers of immune-checkpoint inhibition (ICI) remains vastly unexplored. In this chapter, we review the rationale for exploring the germline genetic factors as novel biomarkers predictive of IO outcomes, including ICI efficacy, toxicity, or survival, and discuss the approaches for the identification of such germline genetic surrogates. Specifically, we focus on strategies for mapping the germline genetic biomarkers of ICI using genome-wide scans (genome-wide association analyses, next-generation sequencing technologies), followed by targeted assays, to be applied in clinical use. As we discuss the limitations, we highlight a need for large collaborative consortia in these efforts and sketch possible avenues for incorporating germline genetic factors into emerging multifactorial approaches for more personalized prediction of ICI outcomes.
PMID: 31502148
ISSN: 1940-6029
CID: 4087742

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

Germline genetic host factors as predictive biomarkers in immuno-oncology

Chat, Vylyny; Ferguson, Robert; Kirchhoff, Tomas
In immuno-oncology (IO), the baseline host factors attract significant clinical interest as promising predictive biomarker candidates. Growing evidence from experimental or population-based studies suggests that the host genetic factors contribute to the immunological status of a patient as it plays out at the multiple rate-limiting steps of the cancer immunity cycle. Recent observations suggest that germline genetics may be associated with tumor microenvironment phenotypes, autoimmune toxicities and/or efficacy of immunotherapy regimens and overall cancer survival. Despite these highly intriguing indications, the potential of germline genetic factors as personalized biomarkers of immune-checkpoint inhibition (ICI) remains vastly unexplored. Here, we review the rationale for exploring the germline genetic factors as novel biomarkers predictive of IO outcomes, including ICI efficacy, toxicity and survival, and discuss the comprehensive approaches for the identification of such germline genetic indicators. In addressing the current limitations, we highlight a need for large collaborative consortia in these efforts. We also outline possible avenues for incorporating germline genetic factors into emerging multifactorial tools for a more personalized prediction of ICI outcomes.
PMCID:9216465
PMID: 35756849
ISSN: 2590-0188
CID: 5367362

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

Incense Burning is Associated with Human Oral Microbiota Composition

Vallès, Yvonne; Inman, Claire K; Peters, Brandilyn A; Wareth, Laila Abdel; Abdulle, Abdishakur; Alsafar, Habiba; Anouti, Fatme Al; Dhaheri, Ayesha Al; Galani, Divya; Haji, Muna; Hamiz, Aisha Al; Hosani, Ayesha Al; Houqani, Mohammed Al; Aljunaibi, Abdulla; Kazim, Marina; Kirchhoff, Tomas; Mahmeed, Wael Al; Maskari, Fatma Al; Alnaeemi, Abdullah; Oumeziane, Naima; Ramasamy, Ravichandran; Schmidt, Ann Marie; Vallès, Henri; Zaabi, Eiman Al; Sherman, Scott; Ali, Raghib; Ahn, Jiyoung; Hayes, Richard B
Incense burning is common worldwide and produces environmental toxicants that may influence health; however, biologic effects have been little studied. In 303 Emirati adults, we tested the hypothesis that incense use is linked to compositional changes in the oral microbiota that can be potentially significant for health. The oral microbiota was assessed by amplification of the bacterial 16S rRNA gene from mouthwash samples. Frequency of incense use was ascertained through a questionnaire and examined in relation to overall oral microbiota composition (PERMANOVA analysis), and to specific taxon abundances, by negative binomial generalized linear models. We found that exposure to incense burning was associated with higher microbial diversity (p < 0.013) and overall microbial compositional changes (PERMANOVA, p = 0.003). Our study also revealed that incense use was associated with significant changes in bacterial abundances (i.e. depletion of the dominant taxon Streptococcus), even in occasional users (once/week or less) implying that incense use impacts the oral microbiota even at low exposure levels. In summary, this first study suggests that incense burning alters the oral microbiota, potentially serving as an early biomarker of incense-related toxicities and related health consequences. Although a common indoor air pollutant, guidelines for control of incense use have yet to be developed.
PMID: 31296925
ISSN: 2045-2322
CID: 3976832

Correction to: Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop

Bedognetti, Davide; Ceccarelli, Michele; Galluzzi, Lorenzo; Lu, Rongze; Palucka, Karolina; Samayoa, Josue; Spranger, Stefani; Warren, Sarah; Wong, Kwok-Kin; Ziv, Elad; Chowell, Diego; Coussens, Lisa M; De Carvalho, Daniel D; DeNardo, David G; Galon, Jérôme; Kaufman, Howard L; Kirchhoff, Tomas; Lotze, Michael T; Luke, Jason J; Minn, Andy J; Politi, Katerina; Shultz, Leonard D; Simon, Richard; Thórsson, Vésteinn; Weidhaas, Joanne B; Ascierto, Maria Libera; Ascierto, Paolo Antonio; Barnes, James M; Barsan, Valentin; Bommareddy, Praveen K; Bot, Adrian; Church, Sarah E; Ciliberto, Gennaro; De Maria, Andrea; Draganov, Dobrin; Ho, Winson S; McGee, Heather M; Monette, Anne; Murphy, Joseph F; Nisticò, Paola; Park, Wungki; Patel, Maulik; Quigley, Michael; Radvanyi, Laszlo; Raftopoulos, Harry; Rudqvist, Nils-Petter; Snyder, Alexandra; Sweis, Randy F; Valpione, Sara; Zappasodi, Roberta; Butterfield, Lisa H; Disis, Mary L; Fox, Bernard A; Cesano, Alessandra; Marincola, Francesco M
Following publication of the original article [1], the author reported that an author name, Roberta Zappasodi, was missed in the authorship list.
PMID: 31272507
ISSN: 2051-1426
CID: 3968252

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

Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop

Bedognetti, Davide; Ceccarelli, Michele; Galluzzi, Lorenzo; Lu, Rongze; Palucka, Karolina; Samayoa, Josue; Spranger, Stefani; Warren, Sarah; Wong, Kwok-Kin; Ziv, Elad; Chowell, Diego; Coussens, Lisa M; De Carvalho, Daniel D; DeNardo, David G; Galon, Jérôme; Kaufman, Howard L; Kirchhoff, Tomas; Lotze, Michael T; Luke, Jason J; Minn, Andy J; Politi, Katerina; Shultz, Leonard D; Simon, Richard; Thórsson, Vésteinn; Weidhaas, Joanne B; Ascierto, Maria Libera; Ascierto, Paolo Antonio; Barnes, James M; Barsan, Valentin; Bommareddy, Praveen K; Bot, Adrian; Church, Sarah E; Ciliberto, Gennaro; De Maria, Andrea; Draganov, Dobrin; Ho, Winson S; McGee, Heather M; Monette, Anne; Murphy, Joseph F; Nisticò, Paola; Park, Wungki; Patel, Maulik; Quigley, Michael; Radvanyi, Laszlo; Raftopoulos, Harry; Rudqvist, Nils-Petter; Snyder, Alexandra; Sweis, Randy F; Valpione, Sara; Butterfield, Lisa H; Disis, Mary L; Fox, Bernard A; Cesano, Alessandra; Marincola, Francesco M
Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host's response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14-15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual's recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4-5, 2019.
PMID: 31113486
ISSN: 2051-1426
CID: 3920522

Primary Melanoma Histologic Subtype: Impact on Survival and Response to Therapy

Lattanzi, Michael; Lee, Yesung; Simpson, Danny; Moran, Una; Darvishian, Farbod; Kim, Randie H; Hernando, Eva; Polsky, David; Hanniford, Doug; Shapiro, Richard; Berman, Russell; Pavlick, Anna C; Wilson, Melissa A; Kirchhoff, Tomas; Weber, Jeffrey S; Zhong, Judy; Osman, Iman
Background/UNASSIGNED:Two primary histologic subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM), comprise the majority of all cutaneous melanomas. NM is associated with worse outcomes, which have been attributed to increased thickness at presentation, and it is widely expected that NM and SSM would exhibit similar behavior once metastasized. Herein, we tested the hypothesis that primary histologic subtype is an independent predictor of survival and may impact response to treatment in the metastatic setting. Methods/UNASSIGNED:We examined the most recent Surveillance, Epidemiology, and End Results (SEER) cohort (n = 118 508) and the New York University (NYU) cohort (n = 1621) with available protocol-driven follow-up. Outcomes specified by primary histology were studied in both the primary and metastatic settings with respect to BRAF-targeted therapy and immunotherapy. We characterized known driver mutations and examined a 140-gene panel in a subset of NM and SSM cases using next-generation sequencing. All statistical tests were two-sided. Results/UNASSIGNED:NM was an independent risk factor for death in both the SEER (hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.41 to 1.70, P < .001) and NYU (HR = 1.47, 95% CI = 1.05, 2.07, P = .03) cohorts, controlling for thickness, ulceration, stage, and other variables. In the metastatic setting, NM remained an independent risk factor for death upon treatment with BRAF-targeted therapy (HR = 3.33, 95% CI = 1.06 to 10.47, P = .04) but showed no statistically significant difference with immune checkpoint inhibition. NM was associated with a higher rate of NRAS mutation (P < .001), and high-throughput sequencing revealed NM-specific genomic alterations in NOTCH4, ANK3, and ZNF560, which were independently validated. Conclusions/UNASSIGNED:Our data reveal distinct clinical and biological differences between NM and SSM that support revisiting the prognostic and predictive impact of primary histology subtype in the management of cutaneous melanoma.
PMID: 29912415
ISSN: 1460-2105
CID: 3158042