Cell-cell interaction in skin homeostasis is tightly controlled by adherens junctions (AJs). Alterations in such regulation lead to melanoma development. However, mutations in AJs and their functional consequences are still largely unknown./nMethods: Cadherin mutations in skin cutaneous melanoma were identified using sequencing data from TCGA dataset, followed by cross-validation with data from non-TCGA cohorts. Mutations with significant occurrence were subjected to structural prediction using MODELLER and functional protein simulation using GROMACS software. Neo-antigen prediction was carried out using NetMHCpan tool. Cell-based fluorescence reporter assay was used to validate β-catenin activity in the presence of cadherin mutations. Clinical significance was analyzed using datasets from TCGA and other non-TCGA cohorts. Targeted gene exon sequencing and immunofluorescence staining on melanoma tissues were performed to confirm the in silico findings./nResults: Highly frequent mutations in type-II classical cadherins were found in melanoma with one unique recurrent mutation (S524L) in the fifth domain of CDH6, which potentially destabilizes Ca²⁺-binding and cell-cell contacts. Mutational co-occurrence and physical dynamics analyses placed CDH6 at the center of the top-four mutated cadherins (core CDHs; all type-II), suggesting altered heterophilic interactions in melanoma development. Mutations in the intracellular domains significantly disturbed CDH6/β-catenin complex formation, resulting in β-catenin translocation into cytosol or nucleus and dysregulation of canonical Wnt/β-catenin signaling. Although mutations in core CDH genes correlated with advanced cancer stages and lymph node invasion, the overall and disease-free survival times in those patients were longer in patients with wild-type. Peptide/MHC-I binding affinity predictions confirmed overall increased neo-antigen potentials of mutated cadherins, which associated with T-lymphocyte infiltration and better clinical outcomes after immunotherapy./nConclusion: Changes in cell-cell communications by somatic mutations in AJ cadherins function as one of mechanisms to trigger melanoma development. Certain mutations in AJs may serve as potential neo-antigens which conversely benefit patients for longer survival times.

中文翻译：

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粘附连接的体细胞突变景观及其在皮肤黑色素瘤发展中的功能后果

皮肤稳态中的细胞间相互作用受到粘附连接（AJs）的严格控制。这种调节的改变导致黑色素瘤的发展。然而，在AJS和其功能的后果突变在很大程度上仍然是unknown./n方法：使用来自TCGA数据集的测序数据鉴定皮肤皮肤黑色素瘤中的钙黏着蛋白突变，然后与来自非TCGA队列的数据进行交叉验证。使用MODELLER对发生的重大突变进行结构预测，并使用GROMACS软件对功能蛋白进行模拟。使用NetMHCpan工具进行新抗原预测。基于细胞的荧光报告基因测定法用于在存在钙粘蛋白突变的情况下验证β-catenin的活性。使用来自TCGA和其他非TCGA队列的数据集分析了临床意义。在黑色素瘤组织上进行靶向基因外显子测序和免疫荧光染色，以确认计算机领域的发现。在黑色素瘤中发现II型经典钙黏着蛋白的高频率突变，在CDH6的第五个结构域中有一个独特的复发突变（S524L），这可能使Ca ²⁺不稳定-结合和细胞间接触。突变共现和物理动力学分析将CDH6置于前四个突变的钙粘着蛋白（核心CDH；所有II型）的中心，这表明黑素瘤发展过程中的异种相互作用发生了改变。细胞内结构域中的突变会显着干扰CDH6 /β-catenin复合物的形成，导致β-catenin易位进入细胞质或细胞核，并规范Wnt /β-catenin信号传导失调。尽管核心CDH基因的突变与晚期癌症阶段和淋巴结浸润相关，但在野生型患者中，这些患者的总体生存时间和无病生存时间更长。肽/ MHC-1结合亲和力的预测证实了突变的钙黏着蛋白的整体新抗原潜力增加，结论： AJ钙粘着蛋白的体细胞突变引起的细胞间通讯改变是触发黑色素瘤发展的机制之一。AJ中的某些突变可能会充当潜在的新抗原，从而使患者受益，延长其生存时间。