Melanoma is a major public health concern that is responsible for significant morbidity and mortality, particularly in countries such as New Zealand and Australia where it is the commonest cause of cancer death in young adults. Until recently, there were no effective drug therapies for patients with advanced melanoma however significant advances in our understanding of the biological and molecular basis of melanoma in recent decades have led to the development of revolutionary treatments, including targeted molecular therapy and immunotherapy. This review summarizes our current understanding of the key events in the pathway of melanomagenesis and discusses the role of genomic analysis as a potential tool for improved diagnostic evaluation, prognostication and treatment strategies. Ultimately, it is hoped that a continued deeper understanding of the mechanisms of melanomagenesis will lead to the development of even more effective treatments that continue to provide better outcomes for patients with melanoma.
<b>Purpose:</b> To examine the relationship between immune activity, PD-L1 expression, and tumor cell signaling, in metastatic melanomas prior to and during treatment with targeted MAPK inhibitors.<b>Experimental Design:</b> Thirty-eight tumors from 17 patients treated with BRAF inhibitor (<i>n</i> = 12) or combination BRAF/MEK inhibitors (<i>n</i> = 5) with known PD-L1 expression were analyzed. RNA expression arrays were performed on all pretreatment (PRE, <i>n</i> = 17), early during treatment (EDT, <i>n</i> = 8), and progression (PROG, <i>n</i> = 13) biopsies. HLA-A/HLA-DPB1 expression was assessed by IHC.<b>Results:</b> Gene set enrichment analysis (GSEA) of PRE, EDT, and PROG melanomas revealed that transcriptome signatures indicative of immune cell activation were strongly positively correlated with PD-L1 staining. In contrast, MAPK signaling and canonical Wnt/-β-catenin activity was negatively associated with PD-L1 melanoma expression. The expression of PD-L1 and immune activation signatures did not simply reflect the degree or type of immune cell infiltration, and was not sufficient for tumor response to MAPK inhibition.<b>Conclusions:</b> PD-L1 expression correlates with immune cells and immune activity signatures in melanoma, but is not sufficient for tumor response to MAPK inhibition, as many PRE and PROG melanomas displayed both PD-L1 positivity and immune activation signatures. This confirms that immune escape is common in MAPK inhibitor-treated tumors. This has important implications for the selection of second-line immunotherapy because analysis of mechanisms of immune escape will likely be required to identify patients likely to respond to such therapies. <i>Clin Cancer Res; 23(20); 6054-61. ©2017 AACR</i>.
Supplementary data are available at Bioinformatics online.
The accurate recognition of subtle melanomas and their distinction from benign mimics is an oft-recurring diagnostic problem, critical for patient management. Melanomas that bear resemblance to benign nevi (so-called nevoid melanomas, NMs) and benign mitotically active nevi in pregnancy (MANP) are 2 lesions particularly prone to error. Molecular data, including analysis of noncoding regions, in MANP and NM are very limited. This study sought to identify differences in clinical, pathologic, and molecular characteristics between MANP and NMs to facilitate correct diagnosis and reduce the risk of overtreatment or undertreatment. Clinicopathologic characteristics of NM (n=18) and MANP (n=30) were evaluated, and mutation data were analyzed using next-generation sequencing for available cases in each group (NM, n=8; MANP, n=12). All MANP showed innocent histopathologic characteristics apart from increased mitotic activity, frequently in both superficial and deep parts of the lesion (median dermal mitotic rate: 2/mm, range: 1 to 7/mm). All cases of NM demonstrated a characteristic nevoid silhouette, subtle atypical architectural and cytologic features, and variable mitoses (median mitotic rate: 3/mm, range: 1 to 5/mm). Median NM tumor thickness was 1.4 mm. Four of 10 NM patients with follow-up had metastatic disease, including 3 patients who developed widespread metastases, with 1 disease-related death. No other recurrences have been identified (follow-up period: 24 to 60 mo). None of the 15 MANP patients with available follow-up had a recurrence. Most NMs harbored hotspot mutations in NRAS (6/8, 75%). Noncoding mutations were significantly more common in NMs than in MANP (median: 4 vs. 0, P=0.0014). Copy number alterations were infrequent but, when present, were seen in NMs (3/8 NMs vs. 0/12 MANP). All NMs but only 1 of 12 MANP had >1 abnormality in the noncoding regions. Similar to conventional common acquired nevi, MANP mostly harbored driver BRAF mutations, while activating NRAS mutations, noncoding mutations, and copy number alterations were rare. NM and MANP have subtle but recognizable distinguishing histopathologic characteristics that are underpinned by molecular differences. Mutation analysis of targeted noncoding mutations may assist in the diagnosis of difficult lesions.
Read moreOptimal treatment of brain metastases is often hindered by limitations in diagnostic capabilities. To meet this challenge, here we profile DNA methylomes of the three most frequent types of brain metastases: melanoma, breast, and lung cancers (n = 96). Using supervised machine learning and integration of DNA methylomes from normal, primary, and metastatic tumor specimens (n = 1860), we unravel epigenetic signatures specific to each type of metastatic brain tumor and constructed a three-step DNA methylation-based classifier (BrainMETH) that categorizes brain metastases according to the tissue of origin and therapeutically relevant subtypes. BrainMETH predictions are supported by routine histopathologic evaluation. We further characterize and validate the most predictive genomic regions in a large cohort of brain tumors (n = 165) using quantitative-methylation-specific PCR. Our study highlights the importance of brain tumor-defining epigenetic alterations, which can be utilized to further develop DNA methylation profiling as a critical tool in the histomolecular stratification of patients with brain metastases.
Read moreAbstract Melanoma is the deadliest form of human skin cancer. The incidence of melanoma continues to rise. Recent advances in knowledge of melanoma genetics, genomics and biology has led to an optimistic view of the therapeutic outlook for melanoma patients. We analyzed sequence data from &gt;500 melanoma genomes/exomes to identify novel tumor suppressor genes in melanoma. RASA2 was identified as the most highly somatically mutated novel tumor suppressor gene. RASA2 was mutated in 5% of melanomas and deleted in an additional 16.4% of cases. RASA2 is a GTPase Activating Protein (GAP) that regulates RAS; which is one of the most highly mutated oncogenes in melanoma but drugs targeting RAS have as yet shown poor efficacy. The role of RASA2 has not been investigated in melanoma. NF1, which encodes another RAS- specific GAP, was found to be frequently mutated in melanoma. Interestingly, mutations in RASA2 and NF1 co-occur in the same patients with high frequency. We plan to elucidate the roles of RASA2 in melanomagenesis and to understand why RASA2 and NF1 mutations co-occur despite the fact that both proteins are RasGAPs. Ras includes three isoforms: NRas, KRas and HRas. Our preliminary data show that RASA2 is more specific to NRAS and that NF1 is more specific to KRAS and HRAS. This finding highlights the existence of a paradigm of cooperativity in which combined loss of multiple negative regulators (RASA2 and NF1) of the RAS pathway is required for melanoma development. Therefore, this type of enhancement of RAS signaling is possibly selected for in some melanomas. We will apply a proteomic screen using BioID to identify RASA2 and NF1 binding partners to provide insights into the functional effects and consequences of alterations in RASA2 and NF1. We expect that these studies will not only identify the cellular components that contribute to the Ras signaling pathway but will also identify potential novel therapeutic targets. Citation Format: Rand Arafeh, Nouar Qutob, Rafi Rafi Emmanuel, Jason Madore, Abdel Elkahloun, James S. James S. Wilmott, Jared J. Gartner, Antonella Di Pizio, Ron Rotkopf, Ken Dutton-Regester, Victoria Hill, Antonia Pritchard, Jimmy C. Lin, Steven A Rosenberg, Javed Khan, Shifra Ben-Dor, Masha Y. Masha Y. Niv, Igor Ulitsky, Graham J Mann, Richard A. Scolyer, Nicholas K. Hayward, Yardena Samuels. Deciphering distinct roles of RASA2 in melanomagenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-031. doi:10.1158/1538-7445.AM2017-LB-031
Read moreIntroduction Prior to 2011 there were no effective systemic therapies for advanced stage melanoma patients and the overall survival was 7.5 months. Recently, immune checkpoint inhibitors, anti-PD-1 and anti-CTLA-4 inhibitors, have produced response rates as high as 50% and doubled overall survival, but only 30% of patients have a durable response. One important resistance mechanism to immunotherapies is the downregulation of MHC Class I, resulting in the expansion of melanoma cells resistant to CD8 +T cell killing. Natural Killer (NK) cells monitor MHC Class I expression and eliminate cells that fail to express it; thus, NK cells are likely critical in preventing resistance to anti-PD-1 therapy. This study sought to investigate whether tumour-infiltrating NK cells in the presence of MHC class I loss improved survival outcome of patients treated with anti-PD-1. Material and methods Twenty-five stage IV metastatic melanoma patients treated with anti-PD-1 therapy were categorised into responders (CR/PR/SD >6 mo, n=13) and non-responders (SD Results and discussions Differential expression analysis identified nine up-regulated NK cell specific genes in responders when compared to non-responders (adjusted p Conclusion This study showed that the presence of higher numbers of NK cells are associated with improved responses to anti-PD-1 therapy. Most importantly, responding patients with MHC class I loss had higher NK cell densities, suggesting that NK cells play an important role in mediating response to anti-PD-1 in patients whose tumour down regulates MHC class I expression.
Read moreAbstract Male gender is independently and significantly associated with poor prognosis in melanoma of all clinical stages. The biological underpinnings of this sex difference remain largely unknown, but we hypothesize that gene expression from gonosomes may play an important role. The current study demonstrates that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis-free survival, suggesting a dosage benefit of two X-chromosomes. The gonosomal PPP2R3B gene is located on the pseudo-autosomal region (PAR) of the X-chromosome in females and on the Y-chromosome in males. We observed that despite its location on the PAR that predicts equal dosage across genders, PPP2R3B expression is lower in males than in females, and is independently correlated with poor clinical outcome. PPP2R3B codes for the PR70 protein, a regulatory substrate recognizing subunit of PP2A, that decreases melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing CDC6/CDT1 interaction that delays the firing of origins of DNA replication. As such, PR70 behaves functionally as an X-linked tumor suppressor gene. Citation Format: Léon C.L. Van Kempen, Margaret Redpath, Mounib Elchebly, Kathleen Oros Klein, Andreas Papadakis, James Willmott, Richard Scolyer, Per-Henrik Edqvist, Fredrik Ponten, Dirk Schadendorf, Anke van Rjk, Stefan Michiels, Anne Dumay, Anne Helbling-Leclerc, Philippe Dessen, Jasper Wouters, Marguerite Stass, Celia Greenwood, G. Elias Ghanem, Joost van den Oord, Jean Feunteun, Alan Spatz. The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5528. doi:10.1158/1538-7445.AM2017-5528
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Read morepresent a study that evaluates the reproducibility and concordance of microstaging of melanoma using the 7th vs 8th editions of the AJCC Cancer Staging Manual. The authors report modest but significant improvements (up to 10%) in the reproducibility and concordance for both T1a and T1b or greater melanomas when categorized according to the AJCC Cancer Staging Manual, 8th edition (AJCC 8). The authors conclude that AJCC 8 will improve the accuracy of staging of invasive cutaneous melanoma and may have a positive impact on patient care.
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