查看“TRIM24-BRAF”的源代码

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            <strong>TRIM24-BRAF</strong> 基因融合是一种高致病性的激酶变异，由 7 号染色体长臂（7q33-q34）内约 7.6 Mb 的片段缺失或重排引起。该融合将 <strong>[[TRIM24]]</strong> 的 N 端卷曲螺旋结构域与 <strong>[[BRAF]]</strong> 的 C 端激酶结构域（通常自第 10 或 11 外显子断裂）相连。作为 <strong>[[II 类 BRAF 变异]]</strong> 的典型代表，该蛋白通过强效的自发二聚化实现 RAS 非依赖性的激酶激活。在 2026 年的精准诊疗共识中，它被视为儿童胶质瘤及某些“全阴性”实体瘤的关键靶点。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">TRIM24-BRAF 档案</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">Targeted Fusion Profile</div>
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                <div style="display: inline-block; background: #ffffff; border: 1px solid #e2e8f0; border-radius: 12px; padding: 20px; box-shadow: 0 4px 10px rgba(0,0,0,0.04);">
                    <div style="width: 120px; height: 70px; background-color: #f1f5f9; display: flex; align-items: center; justify-content: center; border-radius: 4px; color: #94a3b8; font-size: 0.65em; text-align: center;">Protein Structure:<br>TRIM24-CC + BRAF-KD</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">功能：MAPK 通路持续激活</div>
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                <tr><th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; background-color: #f8fafc;">[[Entrez]] ID</th><td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9;">8805 / 673</td></tr>
                <tr><th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; background-color: #f8fafc;">[[HGNC]] 符号</th><td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9;">TRIM24 / BRAF</td></tr>
                <tr><th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; background-color: #f8fafc;">[[UniProt]]</th><td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #1e40af;">O15164 / P15056</td></tr>
                <tr><th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; background-color: #f8fafc;">分子量</th><td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9;">~138.5 kDa</td></tr>
                <tr><th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; background-color: #f8fafc;">变异类型</th><td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9;">基因融合 (Fusion)</td></tr>
                <tr><th style="text-align: left; padding: 8px 12px; background-color: #f8fafc;">首选药物</th><td style="padding: 8px 12px; color: #1e40af; font-weight: bold;">[[二代 RAFi]]</td></tr>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">分子致病机制：结构重排与信号逃逸</h2>
    
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        TRIM24-BRAF 融合蛋白通过物理结构的变化，绕过了细胞正常的增殖调控：
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        <li style="margin-bottom: 12px;"><strong>组成型二聚化 (Constitutive Dimerization)：</strong>TRIM24 的卷曲螺旋（Coiled-coil）结构域提供了一个强力的支架，迫使两个 BRAF 激酶结构域结合。由于 BRAF 必须以二聚体形式激活，这种重组使激酶处于永久开启状态。</li>
        <li style="margin-bottom: 12px;"><strong>自抑制结构域缺失：</strong>融合通常丢失了 BRAF N 端的调节区（CR1、CR2），该区域原本负责在无上游信号时抑制激酶活性。</li>
        <li style="margin-bottom: 12px;"><strong>信号级联级联：</strong>持续激活的融合蛋白通过磷酸化下层的 <strong>[[MEK]]</strong> 和 <strong>[[ERK]]</strong>，推动细胞周期从 G1 期向 S 期转化。</li>
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    <h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">临床景观：跨瘤种分布与发生率</h2>
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                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a;">主要癌种</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">突变频率</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">2026 临床意义</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">儿童胶质瘤 (pLGG)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">2% - 5%</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">WHO 2021 分类中的关键分子亚型。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">黑色素瘤</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">< 0.5%</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">多见于肢端或粘膜型，需与 V600 突变区分。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">肺腺癌</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">极罕见</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">与吸烟史无关，一代药耐药，建议入组二代药临床。</td>
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        <li style="margin-bottom: 12px;"><strong>规避一代抑制剂：</strong> 维罗非尼（Vemurafenib）等单体抑制剂对融合诱导的二聚体可能产生<strong>矛盾激活</strong>，临床应慎用。</li>
        <li style="margin-bottom: 12px;"><strong>垂直联合封锁：</strong> 2026 NCCN 指南推荐使用 <strong>[[Belvarafenib]]</strong> 或 <strong>[[Tovorafenib]]</strong>。此类药物可同时稳定抑制 RAF 二聚体，联合 MEK 抑制剂（如曲美替尼）疗效更佳。</li>
        <li style="margin-bottom: 12px;"><strong>液体活检监控：</strong> 推荐定期通过 ctDNA 监测是否出现 <strong>[[MEK1/2]]</strong> 或 <strong>[[NRAS]]</strong> 等继发性耐药突变。</li>
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            [[KIAA1549-BRAF]] • [[二聚体抑制剂]] • [[矛盾激活]] • [[Type II BRAF]] • [[RNA-Seq 检测]]
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        <span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献 [Academic Review]</span>
        
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            [1] <strong>Stransky N, et al. (2014).</strong> <em>The landscape of kinase fusions in cancer.</em> <strong>Nature Communications</strong>. 5:4843.<br>
            <span style="color: #475569;">[点评]：大规模测序研究，首次在系统层面确定了实体瘤中 TRIM24-BRAF 的融合特征。</span>
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            [2] <strong>Ross JS, et al. (2016).</strong> <em>Comprehensive Genomic Profiling of BRAF Fusions in Cancer.</em> <strong>The Oncologist</strong>. 21(11):1316-1325.<br>
            <span style="color: #475569;">[点评]：全面论述了 BRAF 融合从分子基础到临床靶向治疗的演进。</span>
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            [3] <strong>Schrock AB, et al. (2016).</strong> <em>Clinical Response to Vemurafenib and Cobimetinib in a Patient with a TRIM24-BRAF Fusion-Positive Lung Adenocarcinoma.</em> <strong>J Thorac Oncol</strong>. 11(9):e101-3.<br>
            <span style="color: #475569;">[点评]：首次报告肺癌中该融合的临床获益案例，验证了 MAPK 联合封锁策略。</span>
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            [4] <strong>Botton T, et al. (2013).</strong> <em>Recurrent BRAF kinase domain fusions in melanocytic tumors.</em> <strong>Nature Communications</strong>. 4:1449.<br>
            <span style="color: #475569;">[点评]：阐明了 BRAF 融合在黑色素瘤中作为独立驱动因子的生物学地位。</span>
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            TRIM24-BRAF · 知识图谱
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">核心靶点</td>
                <td style="padding: 10px 15px; color: #334155;">[[BRAF]] • [[MEK1/2]] • [[TRIM24]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">前沿药物</td>
                <td style="padding: 10px 15px; color: #334155;">[[Belvarafenib]] • [[Lifirafenib]] • [[曲美替尼]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">检测技术</td>
                <td style="padding: 10px 15px; color: #334155;">[[RNA-Seq]] • [[FISH]] • [[NGS大面板]]</td>
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