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19del - 版本历史
2026-04-21T08:38:29Z
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2026年1月24日 (六) 12:08 77921020
2026-01-24T12:08:20Z
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<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <p style="margin: 15px 0; text-align: justify;"></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <p style="margin: 15px 0; text-align: justify;"></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> 19号外显子编码 EGFR 激酶结构域中的 <strong><del class="diffchange diffchange-inline">$\</del>beta<del class="diffchange diffchange-inline">$</del>3-<del class="diffchange diffchange-inline">$\</del>alpha<del class="diffchange diffchange-inline">$</del>C 环</strong><del class="diffchange diffchange-inline">。这一区域对于调节激酶的活性至关重要。</del></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> 19号外显子编码 EGFR 激酶结构域中的 <strong><ins class="diffchange diffchange-inline">&</ins>beta<ins class="diffchange diffchange-inline">;</ins>3-<ins class="diffchange diffchange-inline">&</ins>alpha<ins class="diffchange diffchange-inline">;</ins>C 环</strong><ins class="diffchange diffchange-inline">（Beta3-AlphaC loop）。这一区域对于调节激酶的活性至关重要。</ins></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </p></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </p></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <ul style="padding-left: 25px; color: #334155;"></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <ul style="padding-left: 25px; color: #334155;"></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <li style="margin-bottom: 12px;"><strong>结构改变：</strong></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <li style="margin-bottom: 12px;"><strong>结构改变：</strong></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <br>最典型的缺失是去除了高度保守的 <strong>LREA</strong> 序列（亮氨酸-精氨酸-谷氨酸-丙氨酸，残基 747-750）。这种缺失缩短了 <del class="diffchange diffchange-inline">$\</del>beta<del class="diffchange diffchange-inline">$</del>3-<del class="diffchange diffchange-inline">$\</del>alpha<del class="diffchange diffchange-inline">$</del>C <del class="diffchange diffchange-inline">环，拉近了 $\</del>alpha<del class="diffchange diffchange-inline">$</del>C <del class="diffchange diffchange-inline">螺旋的方向，将激酶“锁定”在一种不需要配体（EGF）结合就能自动激活的构象。</del></li></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <br>最典型的缺失是去除了高度保守的 <strong>LREA</strong> 序列（亮氨酸-精氨酸-谷氨酸-丙氨酸，残基 747-750）。这种缺失缩短了 <ins class="diffchange diffchange-inline"><strong>&</ins>beta<ins class="diffchange diffchange-inline">;</ins>3-<ins class="diffchange diffchange-inline">&</ins>alpha<ins class="diffchange diffchange-inline">;</ins>C <ins class="diffchange diffchange-inline">环</strong>，拉近了 <strong>&</ins>alpha<ins class="diffchange diffchange-inline">;</ins>C <ins class="diffchange diffchange-inline">螺旋</strong>（AlphaC-helix）的方向，将激酶“锁定”在一种不需要配体（EGF）结合就能自动激活的构象。</ins></li></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <li style="margin-bottom: 12px;"><strong>药物亲和力：</strong></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <li style="margin-bottom: 12px;"><strong>药物亲和力：</strong></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <br>这种构象改变不仅增加了 ATP 结合口袋对 TKI 药物的亲和力，还降低了其对 ATP 的亲和力。相比 L858R，19del 与 TKI 的结合更为紧密，这也是其疗效通常优于 L858R 的分子基础。</li></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <br>这种构象改变不仅增加了 ATP 结合口袋对 TKI 药物的亲和力，还降低了其对 ATP 的亲和力。相比 L858R，19del 与 TKI 的结合更为紧密，这也是其疗效通常优于 L858R 的分子基础。</li></div></td></tr>
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77921020
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2026-01-24T12:04:55Z
<p>建立内容为“<div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff…”的新页面</p>
<p><b>新页面</b></p><div><div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff; max-width: 1200px; margin: auto;"><br />
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<strong>19号外显子缺失</strong>（Exon 19 Deletion），常简写为 <strong>19del</strong> 或 E19del，是非小细胞肺癌（NSCLC）中最常见的 <strong>[[EGFR]]</strong> 敏感突变类型，约占所有 EGFR 突变病例的 45%-50%。该突变涉及 EGFR 酪氨酸激酶结构域中第 746-750 位密码子区域的氨基酸缺失（最常见的是 <strong>delE746-A750</strong>）。从分子生物学角度看，这一缺失改变了激酶的 ATP 结合口袋构象，使其处于持续激活状态。临床数据一致表明，相比于另一种常见的 [[L858R]] 突变，携带 19del 的患者对 <strong>[[EGFR-TKI]]</strong>（尤其是奥希替尼和阿法替尼）更敏感，无进展生存期（PFS）和总生存期（OS）更长，因此常被称为“<strong>黄金突变</strong>”。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">EGFR 19del</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">Exon 19 Deletion (点击展开)</div><br />
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[[Image:EGFR_19del_vs_L858R_structure_comparison.png|100px|19del 导致的激酶构象改变]]<br />
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<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">最常见的敏感突变</div><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">基因位点</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">EGFR Exon 19</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">典型变异</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;"><strong>delE746-A750</strong><br>(最常见亚型)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">发生频率</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">~45% (EGFR+ NSCLC)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">药物敏感性</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #166534;"><strong>极高</strong> (High Sensitivity)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">首选药物</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;"><strong>[[奥希替尼]]</strong><br><strong>[[阿美替尼]]</strong>, [[伏美替尼]]</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">其他选择</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[阿法替尼]] (OS获益明确)<br>[[吉非替尼]]</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">预后对比</th><br />
<td style="padding: 6px 12px; color: #b91c1c;">优于 [[L858R]]</td><br />
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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;">分子机制：LREA 缺失锁定活性态</h2><br />
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<p style="margin: 15px 0; text-align: justify;"><br />
19号外显子编码 EGFR 激酶结构域中的 <strong>$\beta$3-$\alpha$C 环</strong>。这一区域对于调节激酶的活性至关重要。<br />
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<li style="margin-bottom: 12px;"><strong>结构改变：</strong><br />
<br>最典型的缺失是去除了高度保守的 <strong>LREA</strong> 序列（亮氨酸-精氨酸-谷氨酸-丙氨酸，残基 747-750）。这种缺失缩短了 $\beta$3-$\alpha$C 环，拉近了 $\alpha$C 螺旋的方向，将激酶“锁定”在一种不需要配体（EGF）结合就能自动激活的构象。</li><br />
<li style="margin-bottom: 12px;"><strong>药物亲和力：</strong><br />
<br>这种构象改变不仅增加了 ATP 结合口袋对 TKI 药物的亲和力，还降低了其对 ATP 的亲和力。相比 L858R，19del 与 TKI 的结合更为紧密，这也是其疗效通常优于 L858R 的分子基础。</li><br />
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<h2 style="background: #fff1f2; color: #9f1239; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #9f1239; font-weight: bold;">临床景观：19del vs L858R</h2><br />
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<h3 style="margin-top: 0; color: #be123c; font-size: 1.1em;">为什么被称为“黄金突变”？</h3><br />
<p style="margin-bottom: 0; text-align: justify; font-size: 0.95em; color: #334155;"><br />
在几乎所有的大型 EGFR-TKI 临床试验中（从一代到三代），19del 亚组的获益幅度都一致地优于 21-L858R 亚组。<br />
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<th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">研究 (药物)</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af; width: 35%;">19del 亚组表现</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569; width: 40%;">L858R 亚组表现</th><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;"><strong>FLAURA</strong><br>(奥希替尼 vs 一代)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; color: #b91c1c; font-weight: 700;">mPFS 21.4 个月<br>HR 0.43 (显著获益)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">mPFS 14.4 个月<br>HR 0.51</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;"><strong>LUX-Lung 3/6</strong><br>(阿法替尼 vs 化疗)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; color: #166534; font-weight: 700;">总生存期 (OS) 显著延长<br>(增加约 1 年)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">未观察到显著 OS 获益</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;"><strong>AENEAS</strong><br>(阿美替尼 vs 吉非替尼)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">mPFS 20.8 个月</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">mPFS 13.4 个月</td><br />
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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;">治疗建议：首选三代</h2><br />
<p style="margin: 15px 0; text-align: justify;"><br />
鉴于 19del 的高敏感性，治疗目标是尽可能延长无化疗生存期。<br />
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<ul style="padding-left: 25px; color: #334155;"><br />
<li style="margin-bottom: 12px;"><strong>一线首选 (Preferred)：</strong><br />
<br>第三代 TKI（<strong>[[奥希替尼]]</strong>、<strong>[[阿美替尼]]</strong>、<strong>[[伏美替尼]]</strong>）。<br />
<br><em>理由：</em> 相比一代药，三代药不仅 PFS 更长，更能有效穿透血脑屏障（19del 患者生存期长，后期脑转移风险累积），且耐受性更好。</li><br />
<li style="margin-bottom: 12px;"><strong>可选方案 (Alternative)：</strong><br />
<br>第二代 TKI（<strong>[[阿法替尼]]</strong>）。<br />
<br><em>理由：</em> 尽管副作用较大，但阿法替尼在 19del 患者中具有确切的总生存期（OS）获益数据，是经济条件受限时的有力选择。</li><br />
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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><br />
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[1] <strong>Rosell R, Moran T, Queralt C, et al. (2009).</strong> <em>Screening for epidermal growth factor receptor mutations in lung cancer.</em> <strong>[[New England Journal of Medicine]]</strong>. 2009;361(10):958-967.<br><br />
<span style="color: #475569;">[早期发现]：该研究奠定了大规模筛查 EGFR 突变的基础，并早期指出了 19del 与 L858R 在药物响应上的潜在差异。</span><br />
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[2] <strong>Yang JC, Wu YL, Schuler M, et al. (2015).</strong> <em>Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.</em> <strong>[[The Lancet Oncology]]</strong>. 2015;16(2):141-151.<br><br />
<span style="color: #475569;">[生存获益]：这是区分 19del 和 L858R 临床价值的关键文献。研究显示阿法替尼能显著延长 19del 患者的总生存期，而 L858R 亚组则无统计学差异。</span><br />
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[3] <strong>Soria JC, Ohe Y, Vansteenkiste J, et al. (2018).</strong> <em>Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer.</em> <strong>[[New England Journal of Medicine]]</strong>. 2018;378(2):113-125.<br><br />
<span style="color: #475569;">[FLAURA 研究]：奥希替尼的一线基石研究。亚组分析进一步证实了 19del 患者的获益幅度最大，确立了三代 TKI 作为该亚型首选治疗的地位。</span><br />
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EGFR 19del · 知识图谱<br />
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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;">同一基因</td><br />
<td style="padding: 10px 15px; color: #334155;"><strong>[[L858R]]</strong> (Exon 21) • <strong>[[Exon 20ins]]</strong> (耐药)</td><br />
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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;">耐药演变</td><br />
<td style="padding: 10px 15px; color: #334155;">继发 <strong>[[T790M]]</strong> (一代耐药后) • 继发 <strong>[[C797S]]</strong> (三代耐药后)</td><br />
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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;">特效药物</td><br />
<td style="padding: 10px 15px; color: #334155;">[[奥希替尼]] (优选) • [[阿法替尼]] (生存获益) • [[阿美替尼]]</td><br />
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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;">别名</td><br />
<td style="padding: 10px 15px; color: #334155;">E19del • delE746-A750 • 黄金突变</td><br />
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