哪些人易患恶性肿瘤?《科学》科研提出全新方向,揭示影响癌症显现的遗传原由
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;">▎药明康德内容团队编辑</strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">同一类型的肿瘤,不同<span style="color: black;">病人</span>的治疗难度和预后有巨大差异,<span style="color: black;">因为</span>肿瘤的分子特征不<span style="color: black;">同样</span>,<span style="color: black;">每一个</span><span style="color: black;">病人</span>适合的治疗<span style="color: black;">办法</span>、复发转移的<span style="color: black;">危害</span>都不相同。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">以<strong style="color: blue;">女性中最高发的癌症——乳腺癌</strong>为例,人表皮生长因子受体2(HER2)阳性乳腺癌相比于HER2阴性乳腺癌就更具侵袭性,<span style="color: black;">病人</span>预后更差;而常被<span style="color: black;">叫作</span>为“最毒”乳腺癌的三阴性乳腺癌,即HER2阴性、雌激素受体(ER)阴性、孕激素受体(PR)阴性的乳腺癌亚型,对内分泌治疗不<span style="color: black;">敏锐</span>,术后易复发转移,缺乏有效治疗靶点,是公认的最难治疗的乳腺癌亚型。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://q1.itc.cn/q_70/images03/20240531/6ecb23b755a74351a55cd27dd8102f21.png" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">在过去几十年的<span style="color: black;">科研</span>中,肿瘤学<span style="color: black;">专家</span>找到了几个<span style="color: black;">重要</span>基因,当检测到这几个基因<span style="color: black;">拥有</span>特定突变时,预示着<span style="color: black;">将来</span>会有较高的可能性<span style="color: black;">出现</span>癌症。最为人熟知的一个例子<span style="color: black;">便是</span>乳腺癌易感基因BRCA,该基因的两个成员(BRCA1和BRCA2)有缺陷时,个体患乳腺癌的可能性大大<span style="color: black;">增多</span>。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">但除了<span style="color: black;">少许</span>几个像BRCA、TP53<span style="color: black;">这般</span>的重大癌症<span style="color: black;">危害</span>基因外,遗传<span style="color: black;">原因</span><span style="color: black;">怎样</span>决定癌症的<span style="color: black;">出现</span>和发展依然是未知数,<strong style="color: blue;">要<span style="color: black;">经过</span>一个健康人的遗传信息来预测其<span style="color: black;">将来</span>十年、二十年内<span style="color: black;">是不是</span>会患癌、癌症的恶性程度高低</strong>,几乎是不可能的。相反,</span><span style="color: black;">大<span style="color: black;">都数</span>恶性肿瘤被认为是细胞分裂过程中<span style="color: black;">显现</span>随机错误<span style="color: black;">持续</span>累积而<span style="color: black;">引起</span></span><span style="color: black;">,<span style="color: black;">或</span>说是纯粹的“运气<span style="color: black;">欠好</span>”。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">然而在《科学》期刊的最新一期中,来自斯坦福大学医学院的<span style="color: black;">研究</span>人员对<span style="color: black;"><strong style="color: blue;">决定癌症的遗传<span style="color: black;">原因</span></strong></span>有了全新的认识。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">这篇论文<span style="color: black;">发掘</span>,从出生时的基因序列中就<span style="color: black;">能够</span>“预测”几十年后的体细胞是否可能演变为新的癌细胞,<span style="color: black;">由于</span><strong style="color: blue;">有<span style="color: black;">有些</span>序列决定了<span style="color: black;">拥有</span>潜在致癌突变的细胞日后的命运:是会被免疫系统识别并清除,还是能避开免疫系统的<span style="color: black;">监测</span><span style="color: black;">出现</span>癌变</strong>。这一<span style="color: black;">发掘</span>挑战了<span style="color: black;">长时间</span><span style="color: black;">败兴</span>对癌症起源的观点,即认为大<span style="color: black;">都数</span>癌症是体细胞在数千万次分裂过程中<span style="color: black;">持续</span>累积随机<span style="color: black;">出现</span>的突变而产生的结果。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">专家</span>们<span style="color: black;">在这项<span style="color: black;">科研</span>中</span>提出了一个新的概念:<span style="color: black;"><strong style="color: blue;">种系表位<span style="color: black;">包袱</span></strong></span>(germline epitope burden,简<span style="color: black;">叫作</span>GEB)。种系基因组<span style="color: black;">便是</span>从父母那里遗传到的基因序列。表位是人类白细胞抗原(HLA)分子上呈现给T细胞受体识别的特定部位,它们会<span style="color: black;">导致</span>免疫应答反应,由多个不同的HLA等位基因编码。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">为了易于理解,<span style="color: black;">科研</span>人员用首饰打了一个比方:<strong style="color: blue;">高GEB的</strong><strong style="color: blue;">细胞<span style="color: black;">拥有</span><span style="color: black;">海量</span>高识别度的HLA抗原表位,就<span style="color: black;">好似</span>带了好几副招摇的宝石耳环</strong><strong style="color: blue;">,很容易吸引T细胞的<span style="color: black;">重视</span></strong>;相反,低GEB细胞<span style="color: black;">拥有</span>低调的表位,就<span style="color: black;">好似</span>只带了一对<span style="color: black;">基本</span>款的银耳钉。<span style="color: black;">科研</span>人员推测,在这两种<span style="color: black;">状况</span>下,<span style="color: black;">因为</span>免疫系统对它们的警觉性不同,细胞内的癌基因<span style="color: black;">倘若</span>要做<span style="color: black;">有些</span>出格的事,难度<span style="color: black;">亦</span>是不同的。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">癌基因在正常状态下是刺激细胞正常生长所必需的,<span style="color: black;">仅有</span><span style="color: black;">出现</span>突变时才会使细胞不受<span style="color: black;">掌控</span>地增殖,最后<span style="color: black;">引起</span>癌变。而突变的癌基因<span style="color: black;">常常</span>以正常基因的多个拷贝的形式<span style="color: black;">显现</span>,<span style="color: black;">出现</span><span style="color: black;">所说</span>的<strong style="color: blue;">癌基因扩增</strong>现象,<span style="color: black;">亦</span><span style="color: black;">便是</span>前面所指的“出格的事”。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://q5.itc.cn/q_70/images03/20240531/9b9446ecb556458aaf41471681ccc91b.jpeg" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;">▲<span style="color: black;">因为</span>种系基因组和HLA等位基因的不同,同一个<span style="color: black;">目的</span>癌基因<span style="color: black;">出现</span>基因扩增时被免疫系统识别的可能性不同</span></strong></span><strong style="color: blue;"><span style="color: black;">(<span style="color: black;">照片</span><span style="color: black;">源自</span>:参考资料)</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">为了验证这一推测,<span style="color: black;">科研</span>人员以乳腺癌为例,对近6000例<span style="color: black;">病人</span>的病变样本和正常组织的测序数据展开了分析,<span style="color: black;">检测</span>肿瘤亚型与<span style="color: black;">病人</span>的种系癌基因序列的关系。在<span style="color: black;">设备</span>学习的辅助下,<span style="color: black;">科研</span>人员深入分析了病变中<span style="color: black;">显现</span>的体细胞突变类型,并据此将乳腺癌分<span style="color: black;">成为了</span>预后和复发<span style="color: black;">危害</span>各不相同的11个亚型,其中4个亚型(如三阴性乳腺癌)的转移复发可能性<span style="color: black;">明显</span>大于其他亚型。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">和猜测一致,<span style="color: black;">她们</span><span style="color: black;">发掘</span>,遗传了突变癌基因且GEB高的人,<span style="color: black;">病患</span>与该癌基因扩增<span style="color: black;">关联</span>的乳腺癌亚型的可能性要<span style="color: black;">小于</span>GEB低的人。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">不外</span>,<span style="color: black;">科研</span>人员还有意外的<span style="color: black;">发掘</span>:尽管<span style="color: black;">拥有</span>高GEB的肿瘤<span style="color: black;">更易</span>在发展<span style="color: black;">初期</span>被识别和消灭,可一旦侥幸躲过免疫细胞的攻击,它们<span style="color: black;">常常</span>发展得更具侵袭性,预后<span style="color: black;">亦</span>比<span style="color: black;">哪些</span>低GEB的同类癌症要更差,<span style="color: black;">更易</span>转移,并且表现出淋巴细胞耗竭的微环境。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">换句话说,<strong style="color: blue;">在浸润前乳腺肿瘤中,高GEB<span style="color: black;">拥有</span><span style="color: black;">守护</span><span style="color: black;">功效</span>;但<span style="color: black;">已然</span><span style="color: black;">得到</span>体细胞扩增的肿瘤在<span style="color: black;">发展</span>过程中,高GEB肿瘤更难消灭</strong>。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://q8.itc.cn/q_70/images03/20240531/c01a2442f7ce4d4da7cdd5dc033cba2e.jpeg" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;">▲</span></strong></span><strong style="color: blue;"><span style="color: black;">种系基因介导的免疫编辑塑造了癌症亚型和转移倾向(<span style="color: black;">照片</span><span style="color: black;">源自</span>:参考资料)</span></strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><span style="color: black;">科研</span>人员总结说:“<span style="color: black;">咱们</span><span style="color: black;">发掘</span>,肿瘤的<span style="color: black;">出现</span>路径受到遗传<span style="color: black;">原因</span>和免疫性的制约。”<span style="color: black;">按照</span>肿瘤起源的新<span style="color: black;">发掘</span>,<span style="color: black;">科研</span>人员提出,<strong style="color: blue;">将来<span style="color: black;">能够</span><span style="color: black;">经过</span>简单的血液样本检测一个人的种系基因组特征,来预测一个健康人的患癌<span style="color: black;">危害</span></strong>,以及识别治疗<span style="color: black;">干涉</span>的最佳<span style="color: black;">机会</span>,并基于细分的亚型来<span style="color: black;">指点</span>癌症<span style="color: black;">病人</span>采用什么样的治疗决策和监测复发。</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">参考资料:</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"> Kathleen E. Houlahan et al., (2024) Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity. Science Doi: https://doi.org/10.1126/science.adh8697</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"> Nicola Waddell & Venkateswar Addala (2024) Germline variants alter immune surveillance. Science Doi: 10.1126/science.adp7370</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"> Gene variants foretell the biology of future breast cancers in Stanford Medicine study. Retrieved May 30, 2024 from https://www.eurekalert.org/news-releases/1045675</span></p>
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