Shared Gene Expression and Immune Pathway Changes Associated with Progression from Nevi to Melanoma.

Elizabeth S Borden,Melissa A Wilson,Bonnie J Lafleur,Anngela C Adams,Karen Taraszka Hastings,Kenneth H Buetow,H.-H Sherry Chow,Clara Curiel-Lewandrowski,Julie E Bauman

doi:10.3390/cancers14010003

Elizabeth S Borden, Melissa A Wilson + Show 7 more

Open Access

https://doi.org/10.3390/cancers14010003

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Abstract

Simple SummaryMelanoma is a deadly skin cancer, and the incidence of melanoma is rising. Chemoprevention, using small molecule drugs to prevent the development of cancer, is a key strategy that could reduce the burden of melanoma on society. The long-term goal of our study is to develop a gene signature biomarker of progression from nevi to melanoma. We found that a small number of genes can distinguish nevi from melanoma and identified shared genes and immune-related pathways that are associated with progression from nevi to melanoma across independent datasets. This study demonstrates (1) a novel approach to aid melanoma chemoprevention trials by using a gene signature as a surrogate endpoint and (2) the feasibility of determining a gene signature biomarker of melanoma progression.There is a need to identify molecular biomarkers of melanoma progression to assist the development of chemoprevention strategies to lower melanoma incidence. Using datasets containing gene expression for dysplastic nevi and melanoma or melanoma arising in a nevus, we performed differential gene expression analysis and regularized regression models to identify genes and pathways that were associated with progression from nevi to melanoma. A small number of genes distinguished nevi from melanoma. Differential expression of seven genes was identified between nevi and melanoma in three independent datasets. C1QB, CXCL9, CXCL10, DFNA5 (GSDME), FCGR1B, and PRAME were increased in melanoma, and SCGB1D2 was decreased in melanoma, compared to dysplastic nevi or nevi that progressed to melanoma. Further supporting an association with melanomagenesis, these genes demonstrated a linear change in expression from benign nevi to dysplastic nevi to radial growth phase melanoma to vertical growth phase melanoma. The genes associated with melanoma progression showed significant enrichment of multiple pathways related to the immune system. This study demonstrates (1) a novel application of bioinformatic approaches to aid clinical trials of melanoma chemoprevention and (2) the feasibility of determining a gene signature biomarker of melanomagenesis.

Highlights

Melanoma is the sixth most common cancer in both men and women in the US.The vast majority of melanoma cases are cutaneous malignant melanoma (CMM)
Our study has identified many immune genes that are known to be associated with melanoma progression and new genes of interest that are likely associated with melanoma progression
While PReferentially expressed Antigen in MElanoma (PRAME) was not identified in the pathway analysis, because PRAME is not annotated in the Reactome database, we found that PRAME RNA expression was increased in CMM compared to nevi in each of the three datasets

Summary

Introduction

Melanoma is the sixth most common cancer in both men and women in the US. The vast majority of melanoma cases are cutaneous malignant melanoma (CMM). Solar ultraviolet radiation (UVR) exposure remains the major environmental risk factor for developing CMM. According to recent predictions from the American Cancer Society, an estimated 106,110 new cases of invasive melanoma and 101,280 cases of melanoma in situ will be diagnosed in the US in 2021 [3]. Despite recent advances in targeted therapies as well as immunotherapies, 7180 melanoma-related deaths are estimated for 2021 [3]. The increasing incidence of CMM, poor prognosis, and societal cost in treating advanced stages support the investigation of novel approaches to prevention such as chemoprevention

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