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Genetic associations of the interleukin locus at 1q32.1 with clinical outcomes of cutaneous melanoma
Rendleman, Justin; Vogelsang, Matjaz; Bapodra, Anuj; Adaniel, Christina; Silva, Ines; Moogk, Duane; Martinez, Carlos N; Fleming, Nathaniel; Shields, Jerry; Shapiro, Richard; Berman, Russell; Pavlick, Anna; Polsky, David; Shao, Yongzhao; Osman, Iman; Krogsgaard, Michelle; Kirchhoff, Tomas
BACKGROUND: Due to high melanoma immunogenicity, germline genetic variants in immune pathways have been studied for association with melanoma prognosis. However, limited candidate selection, inadequate power, or lack of independent validation have hampered the reproducibility of these prior findings, preventing personalised clinical applicability in melanoma prognostication. Our objective was to assess the prognostic utility of genetic variants in immunomodulatory pathways for prediction of melanoma clinical outcomes. METHODS: We genotyped 72 tag single nucleotide polymorphisms (SNPs) in 44 immunomodulatory genes in a population sample of 1022 melanoma patients and performed Cox regression analysis to test the association between SNPs and melanoma recurrence-free (RFS) and overall survival (OS). We have further investigated the most significant associations using a fine mapping strategy and followed with functional analyses in CD4+ T cells in a subset of 75 melanoma patients. RESULTS: The most significant associations were found with melanoma OS for rs3024493 in IL10 at chromosome 1q32.1 (heterozygous HR 0.58, 95% CI 0.39 to 0.86; p=0.0006), a variant previously shown to be linked with autoimmune conditions. Multiple additional SNPs at 1q32.1 were also nominally associated with OS confirming at least two independent association signals in this locus. In addition, we found rs3024493 associated with the downregulation of interleukin 10 (IL10) secretion in CD4+ T cells. CONCLUSIONS: We discovered novel associations of IL10 with melanoma survival at 1q32.1, suggesting this locus should be considered as a novel melanoma prognostic biomarker with potential for aiding melanoma patient management. Our findings also provide further support for an alternative role of IL10 in stimulation of anti-tumour immune response.
PMCID:5166523
PMID: 25604082
ISSN: 0022-2593
CID: 1440102
Phosphorylation of eIF2alpha triggered by mTORC1 inhibition and PP6C activation is required for autophagy and is aberrant in PP6C-mutated melanoma
Wengrod, Jordan; Wang, Ding; Weiss, Sarah; Zhong, Hua; Osman, Iman; Gardner, Lawrence B
Amino acid deprivation promotes the inhibition of the kinase complex mTORC1 (mammalian target of rapamycin complex 1) and activation of the kinase GCN2 (general control nonrepressed 2). Signaling pathways downstream of both kinases have been thought to independently induce autophagy. We showed that these two amino acid-sensing systems are linked. We showed that pharmacological inhibition of mTORC1 led to activation of GCN2 and phosphorylation of the eukaryotic initiation factor 2alpha (eIF2alpha) in a mechanism dependent on the catalytic subunit of protein phosphatase 6 (PP6C). Autophagy induced by pharmacological inhibition of mTORC1 required PP6C, GCN2, and eIF2alpha phosphorylation. Although some of the PP6C mutants found in melanoma did not form a strong complex with PP6 regulatory subunits and were rapidly degraded, these mutants paradoxically stabilized PP6C encoded by the wild-type allele and increased eIF2alpha phosphorylation. Furthermore, these PP6C mutations were associated with increased autophagy in vitro and in human melanoma samples. Thus, these data showed that GCN2 activation and phosphorylation of eIF2alpha in response to mTORC1 inhibition are necessary for autophagy. Additionally, we described a role for PP6C in this process and provided a mechanism for PP6C mutations associated with melanoma.
PMCID:4580977
PMID: 25759478
ISSN: 1937-9145
CID: 1495922
Identification of Metastasis-Suppressive microRNAs in Primary Melanoma
Hanniford, Doug; Segura, Miguel F; Zhong, Judy; Philips, Elliot; Jirau-Serrano, Xavier; Darvishian, Farbod; Berman, Russell S; Shapiro, Richard L; Pavlick, Anna C; Brown, Brian; Osman, Iman; Hernando, Eva
BACKGROUND: Surgical management of primary melanoma is curative for most patients with clinically localized disease at diagnosis; however, a substantial number of patients recur and progress to advanced disease. Understanding molecular alterations that influence differential tumor progression of histopathologically similar lesions may lead to improved prognosis and therapies to slow or prevent metastasis. METHODS: We examined microRNA dysregulation by expression profiling of primary melanoma tumors from 92 patients. We screened candidate microRNAs selected by differential expression between recurrent and nonrecurrent tumors or associated with primary tumor thickness (Student's t test, Benjamini-Hochberg False Discovery Rate [FDR] < 0.05), in in vitro invasion assays. We performed in vivo metastasis assays, matrix remodeling experiments, and molecular studies to identify metastasis-regulating microRNAs and their cellular and molecular mechanisms. All statistical tests were two-sided. RESULTS: We identified two microRNAs (hsa-miR-382, hsa-miR-516b) whose expression was lower in aggressive vs nonaggressive primary tumors, which suppressed invasion in vitro and metastasis in vivo (mean metastatic foci: control: 37.9, 95% confidence interval [CI] = 25.6 to 50.2; miR-382: 19.5, 95% CI = 12.2 to 26.9, P = .009; miR-516b: 12.5, 95% CI = 7.7 to 17.4, P < .001, Student's t test). Mechanistically, miR-382 overexpression inhibits extracellular matrix degradation by melanoma cells. Moreover, we identified actin regulators CTTN, RAC1, and ARPC2 as direct targets of miR-382. Depletion of CTTN partially recapitulates miR-382 effects on matrix remodeling, invasion, and metastasis. Inhibition of miR-382 in a weakly tumorigenic melanoma cell line increased tumor progression and metastasis in vivo. CONCLUSIONS: Aberrant expression of specific microRNAs that can functionally impact progression of primary melanoma occurs as an early event of melanomagenesis.
PMCID:4565532
PMID: 25677173
ISSN: 0027-8874
CID: 1461902
FBXW7 modulates cellular stress response and metastatic potential through HSF1 post-translational modification
Kourtis, Nikos; Moubarak, Rana S; Aranda-Orgilles, Beatriz; Lui, Kevin; Aydin, Iraz T; Trimarchi, Thomas; Darvishian, Farbod; Salvaggio, Christine; Zhong, Judy; Bhatt, Kamala; Chen, Emily I; Celebi, Julide T; Lazaris, Charalampos; Tsirigos, Aristotelis; Osman, Iman; Hernando, Eva; Aifantis, Iannis
Heat-shock factor 1 (HSF1) orchestrates the heat-shock response in eukaryotes. Although this pathway has evolved to help cells adapt in the presence of challenging conditions, it is co-opted in cancer to support malignancy. However, the mechanisms that regulate HSF1 and thus cellular stress response are poorly understood. Here we show that the ubiquitin ligase FBXW7alpha interacts with HSF1 through a conserved motif phosphorylated by GSK3beta and ERK1. FBXW7alpha ubiquitylates HSF1 and loss of FBXW7alpha results in impaired degradation of nuclear HSF1 and defective heat-shock response attenuation. FBXW7alpha is either mutated or transcriptionally downregulated in melanoma and HSF1 nuclear stabilization correlates with increased metastatic potential and disease progression. FBXW7alpha deficiency and subsequent HSF1 accumulation activates an invasion-supportive transcriptional program and enhances the metastatic potential of human melanoma cells. These findings identify a post-translational mechanism of regulation of the HSF1 transcriptional program both in the presence of exogenous stress and in cancer.
PMCID:4401662
PMID: 25720964
ISSN: 1465-7392
CID: 1474022
RSK1 Activation Promotes Invasion in Nodular Melanoma
Salhi, Amel; Farhadian, Joshua A; Giles, Keith M; Vega-Saenz de Miera, Eleazar; Silva, Ines P; Bourque, Caitlin; Yeh, Karen; Chhangawala, Sagar; Wang, Jinhua; Ye, Fei; Zhang, David Y; Hernando-Monge, Eva; Houvras, Yariv; Osman, Iman
The two major melanoma histologic subtypes, superficial spreading and nodular melanomas, differ in their speed of dermal invasion but converge biologically once they invade and metastasize. Herein, we tested the hypothesis that distinct molecular alterations arising in primary melanoma cells might persist as these tumors progress to invasion and metastasis. Ribosomal protein S6 kinase, 90 kDa, polypeptide 1 (RSK1; official name RPS6KA1) was significantly hyperactivated in human melanoma lines and metastatic tissues derived from nodular compared with superficial spreading melanoma. RSK1 was constitutively phosphorylated at Ser-380 in nodular but not superficial spreading melanoma and did not directly correlate with BRAF or MEK activation. Nodular melanoma cells were more sensitive to RSK1 inhibition using siRNA and the pharmacological inhibitor BI-D1870 compared with superficial spreading cells. Gene expression microarray analyses revealed that RSK1 orchestrated a program of gene expression that promoted cell motility and invasion. Differential overexpression of the prometastatic matrix metalloproteinase 8 and tissue inhibitor of metalloproteinases 1 in metastatic nodular compared with metastatic superficial spreading melanoma was observed. Finally, using an in vivo zebrafish model, constitutive RSK1 activation increased melanoma invasion. Together, these data reveal a novel role for activated RSK1 in the progression of nodular melanoma and suggest that melanoma originating from different histologic subtypes may be biologically distinct and that these differences are maintained as the tumors invade and metastasize.
PMCID:4348467
PMID: 25579842
ISSN: 0002-9440
CID: 1474572
Serum-based miRNAs in the prediction and detection of recurrence in melanoma patients
Fleming, Nathaniel H; Zhong, Judy; da Silva, Ines Pires; Vega-Saenz de Miera, Eleazar; Brady, Bobbi; Han, Sung Won; Hanniford, Doug; Wang, Jinhua; Shapiro, Richard L; Hernando, Eva; Osman, Iman
BACKGROUND: Identification of primary melanoma patients at the highest risk of recurrence remains a critical challenge, and monitoring for recurrent disease is limited to costly imaging studies. We recently reported our array-based discovery of prognostic serum miRNAs in melanoma. In the current study, we examined the clinical utility of these serum-based miRNAs for prognosis as well as detection of melanoma recurrence. METHODS: Serum levels of 12 miRNAs were tested using qRT-PCR at diagnosis in 283 melanoma patients (training cohort, n = 201; independent validation, n = 82; median follow-up, 68.8 months). A refined miRNA signature was chosen and evaluated. We also tested the potential clinical utility of the miRNAs in early detection and monitoring of recurrence using multiple longitudinal samples (pre- and postrecurrence) in a subset of 82 patients (n = 225). In addition, we integrated our miRNA signature with publicly available Cancer Genome Atlas data to examine the relevance of these miRNAs to melanoma biology. RESULTS: Four miRNAs (miR-150, miR-30d, miR-15b, and miR-425) in combination with stage separated patients by recurrence-free survival (RFS) and overall survival (OS) and improved prediction of recurrence over stage alone in both the training and validation cohorts (training RFS and OS, P < .001; validation RFS, P < .001; OS, P = .005). Serum miR-15b levels significantly increased over time in recurrent patients (P < .001), adjusting for endogenous controls as well as age, sex, and initial stage. In nonrecurrent patients, miR-15b levels were not significantly changed with time (P =.17). CONCLUSIONS: Data demonstrate that serum miRNAs can improve melanoma patient stratification over stage and support further testing of miR-15b to guide patient surveillance. Cancer 2015;121:51-59. (c) 2014 American Cancer Society.
PMCID:4270907
PMID: 25155861
ISSN: 0008-543x
CID: 1449312
Association between TERT promoter mutations and BRAF/NRAS mutations in patients with primary and metastatic melanoma tumors [Meeting Abstract]
Chang, Gregory A; Tadepalli, Jyothirmayee S; Fleming, Nathaniel H; Lui, Kevin; Shao, Yongzhao; Darvishian, Farbod; Pavlick, Anna; Berman, Russell; Shapiro, Richard; Osman, Iman; Polsky, David
ISI:000370972700021
ISSN: 1538-7445
CID: 2029702
Revisiting the mechanisms of PTEN loss in melanoma [Meeting Abstract]
Giles, Keith; Li, Yang; Salhi, Amel; Wang, Jinhua; Robinson, Eric; Osman, Iman
ISI:000371578504269
ISSN: 1538-7445
CID: 2056842
The expression and methylation quantitative trait loci (eQTLs and mQTLs) predict melanoma clinical outcomes [Meeting Abstract]
Kirchhoff, T; Vogelsang, M; Martinez, CN; Hecht, C; Tella, A; Shapiro, RL; Berman, RS; Osman, I
ISI:000361887403195
ISSN: 1879-0852
CID: 1812602
Hyperactivation of RSK1 is a hallmark of metastatic nodular melanoma [Meeting Abstract]
Salhi, Amel; Farhadian, Joshua A; Giles, Keith M; de Miera, Eleazar CVega-Saenz; Da Silva, Ines Pires; Bourque, Caitlin; Yeh, Karen; Chhangawala, Sagar; Wang, Jinhua; Ye, Fei; Zhang, David Y; Hernando-Monge, Eva; Houvras, Yariv; Osman, Iman
ISI:000370972700009
ISSN: 1538-7445
CID: 2029692