Occurrence Of Melanoma Research Articles

Long Non-Coding RNA ZSCAN16-AS1 Promotes the Malignant Progression of Melanoma Through Regulating the miR-503-5p/ARL2 Axis.

LncRNA zinc finger and SCAN domain containing 16 antisense RNA 1 (ZSCAN16-AS1), a newly identified lncRNA, has been proven to accelerate hepatocellular carcinoma progression. However, the function and molecular mechanism of ZSCAN16-AS1 in melanoma are still unknown. The level of ZSCAN16-AS1 in melanoma tissues was detected and reported in The Cancer Genome Atlas (TCGA) and GEO#GSE15605. CCK-8, Transwell and flow cytometry assays were used to explore the role of ZSCAN16-AS1 in melanoma cells. Luciferase reporter assays and RNA pull-down assays were used to verify the molecular mechanism of ZSCAN16-AS1. Here, we found that ZSCAN16-AS1 expression was increased in melanoma. We confirmed that ZSCAN16-AS1 promotes the growth and metastasis of melanoma. ZSCAN16-AS1 exerts its pro-tumour role through sponging of miR-503-5p to liberate ADP-ribosylation factor-like protein 2 (ARL2) mRNA transcripts. These results demonstrated the role and molecular mechanism of ZSCAN16-AS1 in the occurrence and development of melanoma. Therefore, ZSCAN16-AS1 may be used as a specific biomarkerin the diagnosis and treatment of melanoma patients.

Development and validation of a novel T cell proliferation-related prognostic model for predicting survival and immunotherapy benefits in melanoma.

T cell plays a crucial role in the occurrence and progression of Skin cutaneous melanoma (SKCM). This research aims to identify the actions of T cell proliferation-related genes (TRGs) on the prognosis and immunotherapy response of tumor patients. The clinical manifestation and gene expression data of SKCM patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. T cell proliferation-related molecular subtypes were identified utilizing consensus clustering. Subsequently, Cox and Lasso regression analysis was conducted to identify six prognostic genes, and a prognostic signature was constructed. A series of experiments, such as qRT-PCR, Western blotting and CCK8 assay, were then conducted to verify the reliability of the six genes. In this study, a grading system was established to forecast survival time and responses to immunotherapy, providing an overview of the tumoral immune landscape. Meanwhile, we identified six prognostic signature genes. Notably, we also found that C1RL protein may inhibit the growth of melanoma cell lines. The scoring system depending on six prognostic genes showed great efficiency in predicting survival time. The system could help to forecast prognosis of SKCM patients, characterize SKCM immunological condition, assess patient immunotherapy response.

Multi-omics analysis of Siglec family genes in cutaneous melanoma.

Melanoma is widely recognized as the most aggressive and fatal type of skin cancer; however, effective prognostic markers are lacking. The sialic acid-binding immunoglobulin-type lectin (Siglec) gene family plays an important role in the development of tumors and immune escape, but its prognostic role in melanoma remains unknown. Siglec genes have a high mutation frequency, with up to 8% in SIGLEC7. High expression levels of Siglecs in tumor bulk suggests a better prognosis. Siglecs also show a high degree of synergistic expression. Immunohistochemistry was used to analyze the expression of SIGLEC9 in tumor tissue microarray. The expression of SIGLEC9 in tumor tissue without metastasis was higher than that in tumor tissue with metastasis. We used unsupervised clustering to create a high expression of Siglec (HES) cluster and a low expression of Siglec (LES) cluster. The HES cluster correlated with high overall survival and increased expression levels of Siglec genes. The HES cluster also showed significant immune cell infiltration and activation of immune signaling pathways. We used least absolute shrinkage and selection operator (LASSO) regression analysis to reduce the dimensionality of Siglec cluster-related genes and constructed a prognostic model composed of SRGN and GBP4, which can risk-stratify patients in both the training and test datasets. We conducted a multi-omics analysis of the Siglec family genes in melanoma and found that Siglecs play an important role in the occurrence and development of melanoma. Typing constructed using Siglecs can show risk stratification and derived prognostic models can predict a patient's risk score. In summary, Siglec family genes are potential targets for melanoma treatment as well as prognostic markers that can direct individualized treatments and improve overall survival.

Discovery of novel CDK2 inhibitors using multistage virtual screening and in vitro melanoma cell lines.

Cyclin-dependent kinases 2 (CDK2) is a serine/threonine-protein kinase, which plays a key role in the regulation of cell cycle and is related to the occurrence and development of melanoma. In this study, we identified potent inhibitors for CDK2 by combining a multistage virtual screening strategy with bioassay validations. The biochemical activity of compounds was validated with ADP-Glo™ Kinase assay in vitro, and the results indicated that the biochemical activity of compound 1 (C1) was better than other selected compounds. Cell viability assay showed that the minimum inhibition concentration of C1 for CDK2 was lower than 4μM. Further functional test results showed that C1 exerted significant antiproliferative, pro-apoptosis, and anti-migration activity in melanoma cell lines (A375 cells, WM35 cells, and A875 cells). Our findings suggested that the C1, virtually screened from compound libraries, as the novel inhibitor of CDK2, may be further developed as an effective therapeutic agent in the treatment of melanoma lines.

Therapeutic Effects of WT1 Silencing via Respiratory Administration of Neutral DOPC Liposomal-siRNA in a Lung Metastasis Melanoma Murine Model

The lungs represent a frequent target for metastatic melanoma as they offer a high-oxygen environment for tumor development. The overexpression of the WT1 protein has been associated with the occurrence of melanoma. In this study, we evaluated the effects of silencing the WT1 protein by siRNA in both in vitro in the B16F10 melanoma cell line and in vivo in a murine model of lung metastatic melanoma. We did this by implementing a novel respiratory delivery strategy of a neutral DOPC liposomal-siRNA system (L-siRNA). In vitro studies showed an effective silencing of the WT1 protein in the siRNAs' WT1-treated cells when compared with controls, resulting in a loss of the cell's viability and proliferation by inducing G1 arrest, the inhibition of the migration and invasion capacities of the cells, as well as the induction of apoptosis. In vivo, the respiratory administration of L-WT1 siRNA showed an efficient biodistribution on the lungs. After two weeks of treatment, the silencing of the WT1 protein resulted in an important antitumor activity that reduced the tumor weight. In the survival study, L-WT1 treatment could significantly delay the death of the animals. This work demonstrates the efficacy of the L-siRNA respiratory administration as a novel therapy to reduce pulmonary tumors and to increase survivability by silencing specific cancer oncogenes as WT1.

Rough Nanovaccines Boost Antitumor Immunity Through the Enhancement of Vaccination Cascade and Immunogenic Cell Death Induction.

Nanovaccines have attracted intense interests for efficient antigen delivery and tumor-specific immunity. It is challenging to develop a more efficient and personalized nanovaccine to maximize all steps of the vaccination cascade by exploiting the intrinsic properties of nanoparticles. Here, biodegradable nanohybrids (MP) composed of manganese oxide nanoparticles and cationic polymers are synthesized to load a model antigen ovalbumin to form MPO nanovaccines. More interestingly, MPO could serve as autologous nanovaccines for personalized tumor treatment taking advantage of in situ released tumor-associated antigens induced by immunogenic cell death (ICD). The intrinsic properties of MP nanohybrids including morphology, size, surface charge, chemical, and immunoregulatory functions are fully exploited to enhance of all steps of the cascade and induce ICD. MP nanohybrids are designed to efficiently encapsulate antigens by cationic polymers, drain to lymph nodes by appropriate size, be internalized by dendritic cells (DCs) by rough morphology, induce DCmaturation through cGAS-STING pathway, and enhance lysosomal escape and antigen cross-presentation through the "proton sponge effect". The MPO nanovaccines are found to efficiently accumulate in lymph nodes and elicit robust specific T-cell immune responses to inhibit the occurrence of ovalbumin-expressing B16-OVA melanoma. Furthermore, MPO demonstrate great potential to serve as personalized cancer vaccines through the generation of autologous antigen depot through ICD induction, activation of potent antitumor immunity, and reversal of immunosuppression. This work provides a facile strategy for the construction of personalized nanovaccines by exploiting the intrinsic properties of nanohybrids.

A Newborn with a Giant Congenital Melanocytic Nevus and Hyperbilirubinemia: What to do Now

Giant congenital melanocytic nevi (GCMN) are rare skin lesions that affect approximately 1 in 20,000 live births. GCMN must be followed up closely because of its association with an increased risk of malignant degeneration. We report a newborn with a giant lession of 14 cm in diameter which was located on the chest and multiple satellite lesions were present on the body. The patient required phototherapy due to hyperbilirubinemia. Some studies suggest that phototherapy can increase the incidence of neonatalnevi, and melanocytic nevi is the most important risk factor for the occurrence of skin melanoma. Considering the risk of developing kernicterus, we concluded that the most appropriate solution for the patient was to cover the lesions and apply phototherapy in the prone position.

The role of lncRNAs in the tumor microenvironment and immunotherapy of melanoma.

Melanoma is one of the most lethal tumors with highly aggressive and metastatic properties. Although immunotherapy and targeted therapy have certain therapeutic effects in melanoma, a significant proportion of patients still have drug resistance after treatment. Recent studies have shown that long noncoding RNAs (lncRNAs) are widely recognized as regulatory factors in cancer. They can regulate numerous cellular processes, including cell proliferation, metastasis, epithelial-mesenchymal transition (EMT) progression and the immune microenvironment. The role of lncRNAs in malignant tumors has received much attention, whereas the relationship between lncRNAs and melanoma requires further investigation. Our review summarizes tumor suppressive and oncogenic lncRNAs closely related to the occurrence and development of melanoma. We summarize the role of lncRNAs in the immune microenvironment, immunotherapy and targeted therapy to provide new targets and therapeutic methods for clinical treatment.

Histological and Immunohistochemical Features of Pulmonary Metastatic Oral Melanoma in a Labrador dog

Melanoma is a malignant tumour that originates from melanocytes. It has been reported in human beings as well as in many domesticated animal species (Reddy et al., 1998), and wild terrestrial and marine animals. Melanomas are the most commonly diagnosed malignant tumours in the oral cavity of canines (Goldschmidt, 1985; Faramade et al., 2017). Gingiva is the most common site for canine oral malignant melanoma (OMM) but other parts like palatine, labile or buccal mucosa also act as the sites of origin (Delverdier et al., 1991). It is generally an aggressive tumour, often locally invasive, and frequently metastasizes to regional lymph nodes and lungs but metastasis to other organs like the brain, heart, spleen, and liver is not common (Goldschmidt and Hendrick, 2002). Canine OMM accounts for about 7% of all malignant tumours of canine, 11.5% to 17.1% of all oral tumours (Mikiewicz et al., 2019), and 33% to 35.8% of all malignant oral tumours (Sarowitz et al., 2017). OMM is reported in old age group animals mainly ranging from 7 to 14 years age (Esplin, 2008). Most common breeds affected by OMM include Cocker Spaniels, Golden Retrievers, Dachshunds, mixed-breed dogs (Gillard et al., 2014) but histologically well-differentiated melanocytic neoplasms (HWDMN) also reported in Golden Retrievers, Labrador, Doberman Pinscher, Irish Setters, Cocker Spaniels, Beagles, etc. (Esplin, 2008). The diagnosis of melanoma is difficult mainly in tumors without appreciable melanin. Histological appearance resembles carcinoma, lymphoma, sarcoma, and osteogenic tumours. Therefore, immunohistochemistry with numerous melanoma specific markers is mostly used for confirmatory diagnosis in human and veterinary pathology (Wick, 2008). This case report is on the occurrence of oral melanoma with pulmonary metastasis in a Labrador dog.

A Single-Institution Cohort Study With Nevi of Special Site: Recurrence, Progression to Melanoma, and Patterns of Management.

Nevi of specialized sites (NOSS) occur on the scalp, ears, flexural, acral, and genital areas and display atypical clinical and histologic features. We assessed NOSS recurrence and progression to melanoma, management patterns, and associations between histologic features and treatment recommendations. We queried all histologic diagnoses of NOSS (n = 275) from 2012 to 2017 from a large U.S. academic medical center with reference dermatopathology laboratory and matched these to clinical records. A blinded panel of dermatopathologists re-evaluated lesions, catalogued histologic findings, and gave management recommendation. Associations with dermatopathologist decision and concordance between new and original recommendations were assessed. Of 117 cases with follow-up, 2 locally recurred (1.46%) and none eventuated in melanoma. Clinical features were not associated with original treatment recommendations. After histopathologic review, large melanocytes [odds ratio ratio (ORR) = 8.00, 95% CI, 1.35-47.4] and junctional mitotic figures (ORR = 65.0, 6.5-650) predicted excision recommendation. Likewise, accumulation of many (>9) high-risk features was associated with excision recommendation. Panel review changed treatment recommendation in 27% of cases. Fair concordance existed between original and panel recommendations (κ = 0.29, 0.15-0.44). The low rate of recurrence and lack of melanoma occurrence suggest that despite an atypical clinical and histopathologic appearance, these nevi have limited potential for malignant transformation. Histopathologic findings seem to be principal drivers behind the recommendation for excision in this analysis. Variability existed in treatment recommendations; the panel's consensus recommendation tended to downgrade treatment. This highlights the importance of further outcomes-based studies to identify true high-risk features and refine management guidelines.

Methylation-driven gene DLL3 is a potential prognostic biomarker in ocular melanoma correlating with metastasis.

Ocular melanoma is an aggressive malignancy with a high rate of metastasis and poor prognosis. Increasing evidence indicated that DNA methylation plays an important role in the occurrence and development of ocular melanoma. Hence, exploring new diagnostic and prognostic biomarkers at the genetic level may be beneficial to the prognosis of patients with ocular melanoma. We collected DNA methylation and gene expression profiles of human UM (uveal melanoma) and CM (conjunctival melanoma) samples from various datasets. We conducted differential methylation and expression analyses to screen the potential biomarkers. Correlation analysis was performed to investigate the relationships between the expression level of DLL3 (delta-like protein 3) and the methylation level of its corresponding CpGs. We explored the prognostic and diagnostic value of DLL3 in UM and CM. Functional annotation and GSEA (gene set enrichment analysis) were applied to get insight into the possible biological roles of DLL3. A cohort of 60 ocular melanoma patients as well as UM and CM cell lines were used to validate our findings in bioinformatic analyses. We found that DLL3 was a methylation-driven gene correlating with UM metastasis. The CpGs of DLL3 are mainly located in the gene body and their methylation level positively correlated to DLL3 expression. Multivariate Cox regression analysis revealed that DLL3 was an independent protective factor for UM patients. High DLL3 expression significantly prolonged the overall survival and disease-free survival of UM patients. DLL3 also showed a promising power to distinguish CM from normal tissues. Functional annotation exhibited that DLL3 may suppress UM progression through modulating immune activities and down-regulating various signaling pathways. External datasets, biospecimens, and cell lines further validated the aberrant expression and prognostic role of DLL3 in ocular melanoma. Methylation-driven gene DLL3 could serve as a new potential diagnostic and prognostic biomarker in ocular melanoma. Our findings may contribute to improving the clinical outcomes of patients with UM or CM.

S2225 A Rare Finding of Primary Cecal Melanoma as a Cause of Lower GI Bleed

Introduction: Primary melanomas of the GI tract are relatively uncommon. Cases in the Gi tract have been confirmed in the esophagus, small bowel and anorectum from prior published reports. The occurrence of primary malignant melanoma or secondary primary melanoma in the colon is very rare. In this case, we report secondary primary melanoma presenting as lower GI bleed. Case Description/Methods: A 78-year-old male with history of melanoma of the scalp removed 10 years ago presented for anemia. GI was consulted for lower GI bleed. He underwent endoscopy and colonoscopy for evaluation of lower gastrointestinal bleed. Colonoscopy revealed a large circumferential ulcerative mass occupying the entirety of the cecum past the ileocecal valve. The biopsy showed sheets of malignant cells with prominent nuclear pleomorphism on a background of abundant necrosis. The pathology report was consistent with metastatic malignant melanoma based on morphology and immunophenotype. He underwent extensive workup to identify the primary lesion. PET-CT showed abnormal focal uptake only within the right colon and no other primary lesion identified. MRI brain with contrast did not show any abnormal enhancing lesions. The patient further underwent complete dermatological evaluation along with examining the previous melanoma area of the scalp. The conclusion was that the colonic mass is likely secondary primary melanoma (Figure). Discussion: Presentation of melanomas within the alimentary tract are usually metastatic in origin. The occurrence of melanoma in the colon is atypical, because melanocytes are embryologically absent in the large colon. In a 2018 report there were less than 35 cases of right colon melanoma reported up to that date. Primary melanoma survivors have an increased risk of second primary melanoma. A population-based study conducted from 1973-2006 that included 89,515 patients showed overall subsequent primary cancer increased to 28%. One quarter of these were subsequent melanoma. They also had an elevated risk of breast, prostate and Non-Hodgkins lymphoma. There were no reports of second primary colonic melanoma. Currently, there is no current guideline for screening for second primary colonic neoplasm. Treatment and diagnosis require a multidisciplinary treatment approach including chemotherapy, radiation, surgery and immunotherapy. This case demonstrates that even though it is rare, health care providers have to be cognizant about a possible second primary colonic melanoma in the setting of prior history of melanoma.Figure 1.: A: Colonoscopy image showing large circumferential ulcerative mass occupying the entirety of the cecum B: Colonoscopy imaging showing circumferential mass with blood clots identified at the cecum C: Abnormal Uptake in the right colon.

HLA-DRB1: A new potential prognostic factor and therapeutic target of cutaneous melanoma and an indicator of tumor microenvironment remodeling.

Cutaneous melanoma (CM) is the most common skin cancer and one of the most aggressive cancers and its incidence has risen dramatically over the past few decades. The tumor microenvironment (TME) plays a crucial role in the occurrence and development of cutaneous melanoma. Nevertheless, the dynamics modulation of the immune and stromal components in the TME is not fully understood. In this study, 471 CM samples were obtained from TCGA database, and the ratio of tumor-infiltrating immune cells (TICs) in the TME were estimated using the ESTIMATE algorithms and CIBERSORT computational method. The differently expressed genes (DEGs) were applied to GO and KEGG function enrichment analysis, establishment of protein-protein interaction (PPI) network and univariate Cox regression analysis. Subsequently, we identified a predictive factor: HLA-DRB1 (major histocompatibility complex, class II, DR beta 1) by the intersection analysis of the hub genes of PPI network and the genes associated with the prognosis of the CM patients obtained by univariate Cox regression analysis. Correlation analysis and survival analysis showed that the expression level of HLA-DRB1 was negatively correlated with the Stage of the patients while positively correlated with the survival, prognosis and TME of melanoma. The GEPIA web server and the representative immunohistochemical images of HLA-DRB1 in the normal skin tissue and melanoma tissue from the Human Protein Atlas (HPA) database were applied to validate the expression level of HLA-DRB1. CIBERSORT analysis for the ratio of TICs indicated that 9 types of TICs were positively correlated with the expression level of HLA-DRB1 and only 4 types of TICs were negatively correlated with the expression level of HLA-DRB1. These results suggested that the expression level of HLA-DRB1 may be related to the immune activity of the TME and may affect the prognosis of CM patients by changing the status of the TME.

Identification of 5 microRNA biomarkers associated with the prognosis of uveal melanoma.

To uncover the role of microRNAs in the occurrence and development of uveal melanoma (UM), we used R language packages in this study to analyze the correlations between the expression of microRNA isoforms, their target genes, and the clinical data for UM patients retrieved from The Cancer Genome Atlas (TCGA). We used Weighted Correlation Network Analysis (WGCNA) to divide the expression profiles of different microRNAs into 10 modules, among which blue and yellow modules were associated with UM survival. Hsa-miR-513a-5p, miR-506-3p, miR-508-3p, miR-140-3p, and miR-103a-2-5p were further identified as the top 5 node microRNAs based on the risk scores in both modules using least absolute shrinkage and selection operator (LASSO) Cox regression analysis. After combining these 5 microRNAs into an integrated risk signature, the prognostic performance of the risk signature was evaluated by area under the receiver operating characteristic (AUROC) curve, and their association with UM clinical characteristics was further analyzed using multiple Cox regression. Our results showed that this risk signature was sensitivity and specificity, and could serve as an independent prognostic factor. In addition, Spearman correlation analysis showed that expression of almost all target mRNAs were significantly positively or negatively correlated with the associated microRNAs. The gene ontology (GO), pathways, and disease enrichment analyses also showed that these 5 microRNAs were closely related to the incidence and progression of tumor, indicating their potential for predicting the outcome of UM.

Malignant Ocular Melanoma with Intradural Cervical Metastasis: Case Report and Literature Review

Abstract Introduction The occurrence of malignant ocular melanomas is uncommon, and the association of these tumors with intradural extramedullary metastases in the cervical spine is exceptionally rare. Case Report A 62-year-old woman undergoing adjuvant chemotherapy after surgical treatment for malignant ocular melanoma begins to experience vertigo and headache. The condition evolved with walking difficulty and neck pain that was exacerbated by swallowing and mobilizing the neck. During her ocular melanoma follow-up, lesions suggestive of metastasis in the central nervous system were not evidenced until this moment. The physical examination did not show significant findings, and a cranial computed tomography scan was performed. The image showed a hyperdense lesion with postcontrast enhancement inside the vertebral canal, at the level of C1-C2. Spinal decompression and subtotal resection were performed. The anatomopathological report revealed intradural metastasis of a malignant ocular melanoma. The postoperative period was uneventful, with significant pain improvement and no recurrences. Conclusion Intradural extramedullary metastases are rare presentations of malignant ocular melanoma. In addition, less than ten similar cases have been reported in the literature. When caring for a patient with melanoma and neurological deficits, always consider evaluating central nervous system metastases. To evaluate this patient, a sensible and detailed neurological exam is extremely important to recognize the location of the deficits and guide the best approach, such as an indication for surgery.

33792 Outcomes in organ transplants from donors with melanoma: A systematic review

Background: Melanoma transmitted through organ transplantation is an increasingly reported event. While the rate of melanoma following organ transplantation is increased due to immunosuppression, transmission of malignancy from transplanted organs is a distinct aetiology of melanoma occurrence. The risk of transmission of melanoma from an organ donor with melanoma has yet to be determined. The authors aimed to review published literature regarding this topic.

Novel lncRNA SNHG16 Promotes the Growth and Metastasis of Malignant Melanoma by Regulating miR-205-5p/PAK2 Axis.

BackgroundLong non-coding RNAs (lncRNAs) play an key role in the biological processes of various malignant tumors. SNHG16 has been confirmed to be associated with the progression of various cancers. However, function and molecular mechanism of SNHG16 in melanoma have not been studied by scholars.MethodsThe expression of SNHG16 in melanoma tissues were detected by using qRT-PCR. Melanoma cases from The Cancer Genome Atlas (TCGA) and GEO#GSE15605 were included in this study. CCK-8 assay, EdU assay, transwell and scratch wound assay were used to explore the role of SNHG16 in melanoma cells. Luciferase reporter assays and RNA pull-down assay were used to explore the molecular mechanism of SNHG16 in melanoma.ResultsHere, we found that SNHG16 was up-regulated in melanoma. SNHG16 enhances the growth and metastasis of melanoma. SNHG16 can promote the expression of P21-activated kinases 2 (PAK2) by sponging miR-205-5p. PAK2 is the target gene of miR-205-5p. We demonstrated that SNHG16 promotes the metastasis and growth of melanoma through miR-205-5p/PAK2 axis.ConclusionThis study firstly confirmed the role and mechanism of SNHG16 in the occurrence and development of melanoma. Therefore, SNHG16 may become a key point in the diagnosis, prognosis and treatment of melanoma patients in the future.

TERT Promoter Mutations and Telomerase in Melanoma.

Malignant melanoma is an extremely malignant tumor with a high mortality rate and an increasing incidence with a high mutation load. The frequency of mutations in the TERT promoter exceeds the frequency of any known noncoding mutations in melanoma. A growing number of recent studies suggest that the most common mutations in the TERT promoter (ATG start site −124C>T and −146C>T) are associated with increased TERT mRNA expression, telomerase activity, telomere length, and poor prognosis. Recently, it has been shown that TERT promoter mutations are more correlated with the occurrence, development, invasion, and metastasis of melanoma, as well as emerging approaches such as the therapeutic potential of chemical inhibition of TERT promoter mutations, direct telomerase inhibitors, combined targeted therapy, and immunotherapies. In this review, we describe the latest advances in the role of TERT promoter mutations and telomerase in promoting the occurrence, development, and poor prognosis of melanoma and discuss the clinical significance of the TERT promoter and telomerase in the treatment of melanoma.

Abstract 2554: Impact of the aged bone marrow on the anti-tumor response to melanoma

Abstract Melanoma is responsible for the most skin cancer-related deaths in the United States. Melanoma occurrence and severity increase with age while the anti-tumor responses decrease. There have been robust responses to immunotherapy treatments, however, there remains a subset of patients who do not benefit from these modalities. Understanding more about immune cell development and age-related changes in the bone marrow can improve patient outcomes. Our hypothesis suggests that during aging, changes in Wnt signaling reshape the aged bone marrow niche, driving precursor cells to become suppressive. This ultimately decreases the anti-tumor response to melanoma due to the skewing of hematopoiesis to yield decreased immune function. In a young and aged setting, we assess the effect of a Wnt inhibitor, sFRP1, on the development of immune cell subtypes by using flow cytometry. We have preliminarily observed in situ that sFRP1 is increased in the aged bone marrow through immunohistochemical staining. We also saw a decrease in CD4 and CD8 T-cells and an increase in CD11b positive myeloid cells in the tumors of young mice treated with recombinant sFRP1 compared to age-matched mice treated with PBS by using immunohistochemical staining. We hypothesize that the increase in sFRP1 in the bone marrow niche will impact immune cell development in the niche and the immune response at the tumor site. As a future direction, we plan to investigate combination treatments of anti-sFRP1 with immunotherapies, such as anti-PD-1. These insights could lead to improve outcomes for elderly patients with melanoma. Citation Format: Alexis Erasta Carey, Yash Chhabra, Mitchell Fane, Laura Hueser, Gloria Marino, Daniel Zabransky, Ashani Weeraratna. Impact of the aged bone marrow on the anti-tumor response to melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2554.

FLG Is a Potential Biomarker of Prognosis and Immunotherapy in Skin Cutaneous Melanoma

Background Skin cutaneous melanoma is one of most aggressive type of cancers worldwide. Therefore, the identification of SKCM biomarkers is of great importance. FLG gene is one of the genes that encode proteins involved in epidermal formation. This was the first time to study the role of FLG in the prognosis and immune infiltrates of skin cutaneous melanoma. Methods We downloaded the somatic mutation data of 471 SKCM patients from the Cancer Genome Atlas (TCGA) database and analyzed the mutation profiles with “MafTools” package. The expression of FLG and the overall survival in SKCM were analyzed by GEPIA. Additionally, univariate and multivariate Cox analyses were used to compare several clinical features with survival rates. We used TIMER to investigate FLG expression and collection of immune infiltration levels in SKCM, as well as cumulative survival in SKCM. Meanwhile, we also used CIBERSORT to investigate the association between FLG and cancer immune infiltration. In addition, gene set enrichment analysis (GSEA) was performed using the TCGA dataset. Furthermore, data from GEO and HPA was used to validate the results. Results Single nucleotide polymorphism (SNP) happened more frequently than insertion or deletion, and C > T was the most common of SNV in SKCM. We selected the first 15 mutated genes by analyzing 471 melanoma samples, and the prognosis analysis showed that only the high expression of mutated FLG gene was significantly correlated with the poor prognosis of SKCM. Multivariate Cox analysis showed that age, the worse tumor status, less lymph node metastasis, and FLG expression were independent factors for prognosis. Specifically, lower infiltration levels of B cell, CD8+ T cells, neutrophils, and dendritic cells correlated with poor survival outcomes in SKCM. GSEA revealed that FLG is closely related to cancer pathways and epidermal cell proliferation. In addition, the previous conclusions can be verified from external data from GEO and HPA. Conclusion The discovery of mutant gene FLG as a biomarker of SKCM helps elucidate how changes in the immune environment promote the occurrence of cutaneous melanoma. Further analysis suggested that FLG might be a new predictor of SKCM prognosis.