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Establishment of cultured primary acral melanoma cells and animal models for Chinese patients.

ABSTRACT: Acral melanoma is the major subtype of melanoma in Chinese patients. However, a majority of current studies focused on non-acral melanoma. Most immortalized melanoma cell lines and primary cells were not from acral melanoma. Besides, there are rarely reports about methods for establishing primary acral melanoma cell cultures and related animal models. Here, we present four new human primary acral melanoma cell lines. To determine the mutational profile of the established primary melanoma cells for future targeted use, we performed exome sequencing. We next examined cell proliferation of the primary acral melanoma cells by colony-formation assays and CCK8 assay. We also evaluated the proliferative and metastatic potential of XYAM-4 in vivo. We report a detailed protocol for establishing cultured primary acral melanoma cells for Chinese patients and related animal models. We also summarize the features in our acral melanoma cell lines and the existing acral melanoma cell lines. This will provide an effective research tool for research on drug responses and individualized treatment for Chinese patients and comparative studies of melanomas between western and Chinese populations.

SUBMITTER: Hu R

PROVIDER: S-EPMC9291188 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Although the National Comprehensive Cancer Network (NCCN) guidelines include clear recommendations for the appropriate resection margins in non-acral cutaneous melanoma, the required margin for acral melanoma is controversial. In this retrospective study, we aimed to investigate whether narrow-margin excision is warranted for thick acral melanoma. Records from 277 melanoma patients with stage T3-T4 disease who underwent radical surgery in three centers in China from September 2010 to October 2018 were reviewed. Clinicopathologic data, including age, gender, excision margin (1-2 cm versus ≥ 2 cm), Clark level, Breslow thickness, ulceration, N stage and adjuvant therapy, were included for survival analysis. The patients were followed up until death or March 31, 2021. Log-rank and Cox regression analyses were used to identify prognostic factors for overall survival (OS), disease-free survival (DFS) and local and in-transit recurrence-free survival (LITRFS). Among all enrolled patients, 207 (74.7%) had acral melanoma, and 70 (25.3%) had non-acral cutaneous melanoma. No significant difference in baseline characteristics was identified between non-acral and acral melanoma, except for age (p = 0.004), gender (p = 0.009) and ulceration (p = 0.048). In non-acral melanoma, a resection margin of 1-2 cm was a poor independent prognostic factor for OS [p = 0.015; hazard ratio (HR) (95% CI), 0.26 (0.009-0.77)] and LITRFS [p = 0.013; HR (95% CI), 0.19 (0.05-0.71)] but not for DFS [p = 0.143; HR (95% CI), 0.51 (0.21-1.25)]. Forty-three (20.8%) patients in the acral melanoma group had a 1-2-cm resection margin. The resection margin was not correlated with patients' OS (p = 0.196 by log-rank analysis, p = 0.865 by multivariate survival analysis), DFS (p = 0.080 by log-rank analysis, p = 0.758 by multivariate survival analysis) or LITRFS (p = 0.354 by log-rank analysis) in acral melanoma. As recommended in the NCCN guidelines, a resection margin ≥ 2 cm is required for non-acral cutaneous melanoma. Meanwhile, a narrow resection margin (1-2 cm) may be safe for patients with acral melanoma.

Project description:BackgroundAcral melanoma is a rare type of melanoma that affects world populations irrespective of skin color and has worse survival than other cutaneous melanomas. It has relatively few single nucleotide mutations without the UV signature of cutaneous melanomas, but instead has a genetic landscape characterized by structural rearrangements and amplifications. BRAF mutations are less common than in other cutaneous melanomas, and knowledge about alternative therapeutic targets is incomplete.MethodsTo identify alternative therapeutic targets, we performed targeted deep-sequencing on 122 acral melanomas. We confirmed the loss of the tumor suppressors p16 and NF1 by immunohistochemistry in select cases.ResultsIn addition to BRAF (21.3%), NRAS (27.9%), and KIT (11.5%) mutations, we identified a broad array of MAPK pathway activating alterations, including fusions of BRAF (2.5%), NTRK3 (2.5%), ALK (0.8%), and PRKCA (0.8%), which can be targeted by available inhibitors. Inactivation of NF1 occurred in 18 cases (14.8%). Inactivation of the NF1 cooperating factor SPRED1 occurred in eight cases (6.6%) as an alternative mechanism of disrupting the negative regulation of RAS. Amplifications recurrently affected narrow loci containing PAK1 and GAB2 (n = 27, 22.1%), CDK4 (n = 27, 22.1%), CCND1 (n = 24, 19.7%), EP300 (n = 20, 16.4%), YAP1 (n = 15, 12.3%), MDM2 (n = 13, 10.7%), and TERT (n = 13, 10.7%) providing additional and possibly complementary therapeutic targets. Acral melanomas with BRAFV600E mutations harbored fewer genomic amplifications and were more common in patients with European ancestry.ConclusionOur findings support a new, molecularly based subclassification of acral melanoma with potential therapeutic implications: BRAFV600E mutant acral melanomas with characteristics similar to nonacral melanomas that could benefit from BRAF inhibitor therapy, and non-BRAFV600E mutant acral melanomas. Acral melanomas without BRAFV600E mutations harbor a broad array of therapeutically relevant alterations. Expanded molecular profiling would increase the detection of potentially targetable alterations for this subtype of acral melanoma.

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Establishment of cultured primary acral melanoma cells and animal models for Chinese patients.

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