Prognostic value of genetic aberrations and tumor immune microenvironment in primary acral melanoma

Abstract

Background Acral melanoma (AM) is the most common subtype in Chinese melanoma patients with a very poor prognosis. However, our understanding of the disease pathogenesis and molecular landscape is limited by the few studies that have been conducted. Here, we profiled the clinical characteristics, mutational landscapes and tumor immune microenvironment of AM patients to gain insights into disease characteristics and potential treatment strategies. Methods A total of 90 AM patients were enrolled and their tissue samples were subjected to next-generation sequencing and multiplexed immunohistochemistry tests. Kaplan–Meier curves and log-rank tests were used to analyze the prognostic potential of various genetic aberrations and immune cell compositions in AM. Results The median disease-free survival was 21.3 months and estimated median overall survival (OS) was 60 months. More advanced stages, older ages and thickness of greater than 4 mm were associated with worse prognosis in AM patients (HR = 2.57, 95% CI 1.25–5.29, p = 0.01; HR = 2.77, 95% CI 1.22–6.28, p = 0.02; HR = 3.43, 95% CI 1.51–7.82, p < 0.01, respectively), while patients who received post-surgical treatments had better survival (HR = 0.36, 95% CI 0.17–0.76, p = 0.01). The most frequently altered genes included BRAF (14.5%), KIT (16.9%), NRAS (12%), NF1 (10.8%), APC (7.2%), and ARID2 (6%). Copy number variations (CNV) were commonly found in CCND1 (19.3%), CDK4 (19.3%), MDM2 (14.5%) and FGF19 (12%). CDK4 amplifications was independently associated with shorter OS in AM patients (HR = 3.61, 95% CI 1.38–9.46, p = 0.01). CD8 + T cells (p < 0.001) and M1 macrophages (p = 0.05) were more highly enriched in the invasive margin than in the tumor center. Patients with higher levels of M1 macrophage infiltration in the invasive margin derived markedly longer OS (HR = 0.43, 95% CI 0.20–0.95, p = 0.03). Interestingly, in CDK4-amplified patients, there tended to be a low level of M1 macrophage infiltration in the invasive margin (p = 0.06), which likely explains the poor prognosis in such patients. Conclusions Our study provided a comprehensive portrait of the clinicopathological features, genetic aberrations and tumor microenvironment profiles in AM patients and identified candidate prognostic factors, which may facilitate development of additional therapeutic options and better inform clinical management of AM patients. Based on these prognostic factors, further studies should focus on enhancing the infiltration of M1 macrophages, especially in CDK4-amplified AM patients.

Primary Undifferentiated/Dedifferentiated Cutaneous Melanomas—A Review on Histological, Immunohistochemical, and Molecular Features with Emphasis on Prognosis and Treatment

“…Due to the rarity of these mutations in cutaneous melanomas, their clinical implications are still unclear [ 66 ]. For example, ARID2 mutations seem more frequent in acral melanomas, but their significance remains unknown [ 82 ]. An in vitro study demonstrated that ARID2 acts as an immunomodulator in melanomas, and ARIDS2 knock-out enhances the effect of immune checkpoint inhibitors in melanoma cell lines [ 83 ].…”

“…An in vitro study demonstrated that ARID2 acts as an immunomodulator in melanomas, and ARIDS2 knock-out enhances the effect of immune checkpoint inhibitors in melanoma cell lines [ 83 ]. FGFR2 mutations have been described in various melanoma subtypes, including ALM or desmoplastic melanomas [ 82 , 84 , 85 ]. These findings are exciting as FGFR2 mutated melanomas can benefit from targeted therapy [ 85 ].…”

Multidisciplinary approach and treatment of acral and mucosal melanoma

“…Indeed, CNV in AM were common in CCND1 (19.3%), CDK4 (cyclin-dependent kinase 4) (19.3%), MDM2 (mouse double minute 2 homolog) (14.5%), and FGF19 (fibroblast growth factor 19) (12%). Moreover, CDK4 amplifications were independently linked to shorter OS ( 32 ). Similarly, frequent alterations in the CDK4 signaling pathway, which facilitates the G1 to S-cell cycle transition and tumor progression, were found in a study of 514 cases of AM.…”

Establishment of a CD8+ T cells‐related prognostic risk model for acral melanoma based on single‐cell and bulk RNA sequencing

“… 14 − 16 AM exhibits significant intra‐tumoral and inter‐tumoral heterogeneity, as well as a highly immune‐suppressive TME and a complex intercellular communication network. 17 , 18 Despite the recognized importance of CD8+ T cells in tumors, our current understanding of them remains limited, particularly in melanoma, where there is a lack of gene markers that accurately describe the characteristics and functions of CD8+ T cells. Furthermore, there is currently no effective gene signature related to CD8+ T cells to predict the prognosis of melanoma patients or guide their treatment decisions.…”