查看“免疫治疗基因黑名单”的源代码

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            <strong>免疫治疗基因黑名单</strong> (Immunotherapy Gene Blacklist) 是指一组经临床研究证实，能够预测患者对<strong>[[免疫检查点抑制剂]]</strong> (ICI) 产生<strong>[[原发性耐药]]</strong>甚至诱发<strong>[[超进展]]</strong> (HPD) 的特定基因组改变。随着精准免疫治疗的发展，识别这些“负向预测因子”已成为治疗决策的关键环节。目前的“黑名单”主要包括三大类：1. 诱发超进展的高危基因（如 <strong>[[MDM2]]</strong>/<strong>[[MDM4]]</strong> 扩增）；2. 导致“冷肿瘤”表型和原发耐药的基因（如 <strong>[[STK11]]</strong>/<strong>[[KEAP1]]</strong> 突变、<strong>[[EGFR]]</strong> 驱动突变）；3. 破坏抗原呈递或干扰素信号通路的基因（如 <strong>[[B2M]]</strong> 缺失、<strong>[[JAK1]]/[[JAK2]]</strong> 突变）。对携带这些变异的患者，盲目使用免疫单药治疗可能导致病情恶化或延误治疗，需优先考虑<strong>[[靶向治疗]]</strong>或联合疗法。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">基因黑名单</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">ICI Negative Predictors (点击展开)</div>
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                    [[Image:Genomic_biomarkers_pie_chart.png|100px|负向基因占比示意图]]
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">HPD / 耐药 / 免疫逃逸</div>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">核心定义</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">ICI 疗效负向预测因子</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">HPD 风险</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong>MDM2</strong>, <strong>MDM4</strong>, <strong>EGFR</strong></td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">原发耐药</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0369a1;"><strong>STK11</strong>, <strong>KEAP1</strong>, <strong>PTEN</strong></td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">免疫逃逸</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;"><strong>B2M</strong>, <strong>JAK1/2</strong></td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">检测手段</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[NGS大Panel]]</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">临床价值</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">排除不获益人群</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">应对策略</th>
                    <td style="padding: 6px 12px; color: #15803d;">靶向 / 化疗 / 联合</td>
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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;">黑名单分类与风险分层</h2>
    
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        并非所有“黑名单”基因的临床表现都相同。根据其导致的不良后果严重程度，可分为三个风险等级。
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        <h3 style="margin-top: 0; color: #be123c; font-size: 1.1em;">🔴 一级风险：超进展 (Hyperprogression)</h3>
        <p style="font-size: 0.95em; color: #334155;">这类基因变异不仅导致治疗无效，反而会因免疫药物的使用加速肿瘤生长，缩短生存期。</p>
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            <li style="margin-bottom: 8px;"><strong>[[MDM2]] / [[MDM4]] 扩增：</strong> 
                <br>最强的 HPD 预测因子。IFN-γ 信号通路反常地促进 MDM2 表达，导致 p53 蛋白彻底降解，肿瘤爆发式生长。</li>
            <li style="margin-bottom: 8px;"><strong>[[EGFR]] 驱动突变：</strong>
                <br>约 20% 的 EGFR 突变患者发生 HPD。其机制涉及 Fc 受体介导的巨噬细胞重编程及本身属于“免疫荒漠”微环境。</li>
            <li><strong>[[CCND1]] / FGF3 / FGF4 / FGF19 (11q13 扩增)：</strong>
                <br>常与细胞周期调节失控相关，与 HPD 发生显著相关。</li>
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            🚫 临床建议：绝对/相对禁忌单药免疫治疗。
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        <h3 style="margin-top: 0; color: #0369a1; font-size: 1.1em;">🔵 二级风险：原发性耐药 (Primary Resistance)</h3>
        <p style="font-size: 0.95em; color: #334155;">这类肿瘤呈现典型的“冷肿瘤”特征，免疫细胞难以浸润，导致 ICI 无效。</p>
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            <li style="margin-bottom: 8px;"><strong>[[STK11]] (LKB1) / [[KEAP1]] 突变：</strong>
                <br>常见于 KRAS 突变的肺腺癌。这两个基因的功能丧失会导致严重的 CD8+ T 细胞排斥，形成<strong>[[免疫沙漠]]</strong>。即使 PD-L1 高表达，疗效也极差。</li>
            <li><strong>[[PTEN]] 缺失：</strong>
                <br>导致 PI3K-AKT 通路持续激活，抑制细胞自噬和抗原呈递，减少 T 细胞向肿瘤部位的募集。</li>
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            ⚠️ 临床建议：单药无效，需联合化疗或抗血管生成药物。
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        <h3 style="margin-top: 0; color: #854d0e; font-size: 1.1em;">🟠 三级风险：免疫逃逸 (Immune Escape)</h3>
        <p style="font-size: 0.95em; color: #334155;">这些变异破坏了免疫识别或杀伤的关键环节，常导致原发或治疗后的继发性耐药。</p>
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            <li style="margin-bottom: 8px;"><strong>[[B2M]] (β2-微球蛋白) 缺失：</strong>
                <br>B2M 是 MHC-I 类分子的关键亚基。缺失导致 MHC-I 无法组装，肿瘤细胞无法呈递抗原给 T 细胞，实现“隐身”。</li>
            <li><strong>[[JAK1]] / [[JAK2]] 失活突变：</strong>
                <br>肿瘤细胞对 IFN-γ 信号不敏感，无法上调 PD-L1 和 MHC 分子，使免疫系统无法识别或杀伤。</li>
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            🛡️ 临床建议：单药通常无效，需探索 NK 细胞疗法等新机制。
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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;">临床决策路径</h2>
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        在免疫治疗时代，“做减法”与“做加法”同样重要。通过 NGS 筛查排除不获益人群，是提高治疗成功率的关键。
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                <th style="padding: 10px; border: 1px solid #cbd5e1; width: 20%;">检出基因</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; width: 40%;">推荐策略</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; width: 40%;">替代方案示例</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: bold; color: #b91c1c;">MDM2 扩增</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;"><strong>回避 ICI</strong> (Avoid)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">化疗、针对性靶向药 (MDM2抑制剂研发中)</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: bold; color: #b91c1c;">EGFR 突变</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;"><strong>TKI 优先</strong> (Prioritize TKI)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">奥希替尼 → 铂类双药化疗 + 抗血管</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: bold; color: #0369a1;">STK11 突变</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;"><strong>联合治疗</strong> (Combine)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">PD-1 + CTLA-4 双免，或 PD-1 + 化疗</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: bold; color: #854d0e;">JAK1/2 突变</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;"><strong>另辟蹊径</strong> (Alternative)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">不依赖 MHC 的疗法 (如溶瘤病毒、NK细胞)</td>
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        <span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献与权威点评</span>
        
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            [1] <strong>Kato S, et al. (2017).</strong> <em>Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate.</em> <strong>[[Clinical Cancer Research]]</strong>. 2017;23(15):4242-4250.<br>
            <span style="color: #475569;">[HPD基石]：确立了 MDM2/MDM4 扩增和 EGFR 突变是超进展的核心基因组预测因子。</span>
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            [2] <strong>Skoulidis F, et al. (2018).</strong> <em>STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma.</em> <strong>[[Cancer Discovery]]</strong>. 2018;8(7):822-835.<br>
            <span style="color: #475569;">[原发耐药]：定义了 STK11/KEAP1 突变型肺癌为“冷肿瘤”，揭示了其对 PD-1 抑制剂原发性耐药的机制。</span>
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            [3] <strong>Zaretsky JM, et al. (2016).</strong> <em>Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.</em> <strong>[[New England Journal of Medicine]]</strong>. 2016;375(9):819-829.<br>
            <span style="color: #475569;">[获得性耐药]：首次通过配对样本测序，发现 JAK1/2 和 B2M 的功能缺失突变是导致免疫治疗继发性耐药的关键。</span>
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        <p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;">
            [4] <strong>Mazieres J, et al. (2019).</strong> <em>Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.</em> <strong>[[Annals of Oncology]]</strong>. 2019;30(8):1321-1328.<br>
            <span style="color: #475569;">[驱动基因]：系统性证实了 EGFR、ALK、ROS1 等驱动基因阳性患者使用免疫单药疗效极差，支持了 TKI 优先的原则。</span>
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            免疫治疗基因黑名单 · 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; vertical-align: middle; white-space: nowrap;">HPD 基因</td>
                <td style="padding: 10px 15px; color: #334155;">[[MDM2]] (扩增) • [[EGFR]] • [[MDM4]] • [[11q13]] (CCND1)</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">耐药基因</td>
                <td style="padding: 10px 15px; color: #334155;">[[STK11]] (LKB1) • [[KEAP1]] • [[PTEN]] • [[JAK1]]/[[JAK2]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">关键机制</td>
                <td style="padding: 10px 15px; color: #334155;">[[超进展]] (HPD) • [[原发性耐药]] • [[冷肿瘤]] • [[抗原呈递缺失]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">临床对策</td>
                <td style="padding: 10px 15px; color: #334155;">[[NGS筛查]] • [[避免单药]] • [[靶向优先]] • [[联合化疗]]</td>
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