The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis

Vogelsang, Matjaž; Martínez, Carlos Navarro; Rendleman, Justin; Bapodra, Anuj; Malecek, Karolina; Romanchuk, Artur; Kazlow, Esther; Shapiro, Richard L.; Berman, Russell S.; Krogsgaard, Michelle; Osman, Iman; Kirchhoff, Tomas

doi:10.1158/1078-0432.ccr-15-2066

Cited by 21 publications

(30 citation statements)

References 48 publications

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“…The VitD pathway SNPs were reported in previous publications to be significantly associated with melanoma specific survival [3, 4], suggesting its key important role in understanding the biological mechanisms for melanoma progression. To date there are limited evidence for SNPs that significantly predict melanoma survival, and the reported effect sizes of SNP predictability in survival are typically small [25, 26]. The findings from this study yielded similar results.…”

Section: Discussionsupporting

confidence: 76%

No prognostic value added by vitamin D pathway SNPs to current prognostic system for melanoma survival

et al. 2017

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The prognostic improvement attributed to genetic markers over current prognostic system has not been well studied for melanoma. The goal of this study is to evaluate the added prognostic value of Vitamin D Pathway (VitD) SNPs to currently known clinical and demographic factors such as age, sex, Breslow thickness, mitosis and ulceration (CDF). We utilized two large independent well-characterized melanoma studies: the Genes, Environment, and Melanoma (GEM) and MD Anderson studies, and performed variable selection of VitD pathway SNPs and CDF using Random Survival Forest (RSF) method in addition to Cox proportional hazards models. The Harrell’s C-index was used to compare the performance of model predictability. The population-based GEM study enrolled 3,578 incident cases of cutaneous melanoma (CM), and the hospital-based MD Anderson study consisted of 1,804 CM patients. Including both VitD SNPs and CDF yielded C-index of 0.85, which provided slight but not significant improvement by CDF alone (C-index = 0.83) in the GEM study. Similar results were observed in the independent MD Anderson study (C-index = 0.84 and 0.83, respectively). The Cox model identified no significant associations after adjusting for multiplicity. Our results do not support clinically significant prognostic improvements attributable to VitD pathway SNPs over current prognostic system for melanoma survival.

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Section: Discussionsupporting

confidence: 76%

No prognostic value added by vitamin D pathway SNPs to current prognostic system for melanoma survival

et al. 2017

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“…This autoimmune phenotype is likely to result from a combination of host- (germline), environment-, and tumor-specific factors. We previously reported the association between germline genetic variants in immune pathways and melanoma prognosis [ 33 , 34 ]. Thus it is possible that an inherent genetic repertoire may generate a propensity for host immunity and as such might impact production of antibodies, including those that target putative “self” antigens.…”

Section: Discussionmentioning

confidence: 99%

Baseline antibody profiles predict toxicity in melanoma patients treated with immune checkpoint inhibitors

et al. 2018

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BackgroundImmune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, or the combination) enhance anti-tumor immune responses, yielding durable clinical benefit in several cancer types, including melanoma. However, a subset of patients experience immune-related adverse events (irAEs), which can be severe and result in treatment termination. To date, no biomarker exists that can predict development of irAEs.MethodsWe hypothesized that pre-treatment antibody profiles identify a subset of patients who possess a sub-clinical autoimmune phenotype that predisposes them to develop severe irAEs following immune system disinhibition. Using a HuProt human proteome array, we profiled baseline antibody levels in sera from melanoma patients treated with anti-CTLA-4, anti-PD-1, or the combination, and used support vector machine models to identify pre-treatment antibody signatures that predict irAE development.ResultsWe identified distinct pre-treatment serum antibody profiles associated with severe irAEs for each therapy group. Support vector machine classifier models identified antibody signatures that could effectively discriminate between toxicity groups with > 90% accuracy, sensitivity, and specificity. Pathway analyses revealed significant enrichment of antibody targets associated with immunity/autoimmunity, including TNFα signaling, toll-like receptor signaling and microRNA biogenesis.ConclusionsOur results provide the first evidence supporting a predisposition to develop severe irAEs upon immune system disinhibition, which requires further independent validation in a clinical trial setting.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1452-4) contains supplementary material, which is available to authorized users.

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“…A tenuous or lack of associations between HLA polymorphisms and responsiveness to the systemic administration of interleukin ( IL )-2 in metastatic melanoma was reported by early studies [76], while a modest, yet significant, association between HLA variants and survival was detected in melanoma patients treated in adjuvant settings with IFN-α [77]. A recent study testing the effect of immunomodulatory expression quantitative trait loci (eQTLs) identified an association between eQTL in IL-10/BATF3 locus on 1q32 and survival in melanoma, complementing other established clinico-pathological prognostic markers [62]. Interestingly, the associated eQTL is a proxy of variants associated with multiple autoimmune conditions [78], suggesting that propensity to autoimmunity provides survival advantage in immunogenic tumors.…”

Section: Germline Genetic Contributions To Cirmentioning

confidence: 98%

“…Therefore, empirical validation of the contribution of common variants to CIR will be needed as part of larger genome-wide scans, including IO-based GWAS. For example, a recent study of melanoma showed that the functionally relevant common single nucleotide polymorphisms in interleukin pathways may associate with improved melanoma survival independent of the other prognostic predictors [62].…”

Section: Germline Genetic Contributions To Cirmentioning

confidence: 99%

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

Bedognetti¹,

Ceccarelli²,

Galluzzi³

et al. 2019

j. immunotherapy cancer

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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.

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The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis

Cited by 21 publications

References 48 publications

No prognostic value added by vitamin D pathway SNPs to current prognostic system for melanoma survival

No prognostic value added by vitamin D pathway SNPs to current prognostic system for melanoma survival

Baseline antibody profiles predict toxicity in melanoma patients treated with immune checkpoint inhibitors

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

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