摘要
Lynch综合征(LS)是由于错配修复(MMR)基因突变,继而引发肿瘤的一种常染色体显性遗传性疾病,在临床上主要表现为微卫星不稳定性(MSI)。遗传性结直肠癌最常见的病因就是LS。随着分子诊断技术地不断提高,通过对LS分子检测实现LS相关结直肠癌的精准诊疗,逐渐成为临床关注的焦点。在我国,LS相关结直肠癌虽有较好的预后,但进一步提高LS家族史患者的筛查和随访策略仍是重要任务。此外,利用LS的免疫学特性来指导其治疗和预防是许多学者面临的一项新挑战。笔者就LS相关结直肠癌的流行病学、临床病理特征、筛查诊断和治疗及预防等新进展进行综述。
结直肠癌是消化道最常见的恶性肿瘤之一,2015年我国有38.7万例新确诊的结直肠癌患者,其中2%~5%可归因于Lynch综合征(Lynch syndrome,LS
LS相关结直肠癌的发病率居所有LS相关癌症之首,中国等亚洲国家与美国、英国等西方国家LS相关结直肠癌的发生风险相
LS相关结直肠癌的发病风险和MMR基因的类型相关。MMR基因MLH1、MSH2、MSH6和PMS2致病变异的外显率和表达存在差异,并且在每一组MMR基因的携带者中,LS相关结直肠癌的发病率与年龄有
腺瘤是LS相关结直肠癌患者的主要癌前病变。研
由于部分临床医生对LS认识不足,临床上很难获得1份LS患者完整的家族史资料,如一级亲属和二级亲属的癌症类型和诊断年龄等。当1例患者和家族的病史符合阿姆斯特丹I/II标
MMR蛋白表达的免疫组织化学检测是一种快速、简便和廉价的方
MSI是指肿瘤中重复DNA序列的长度与正常组织中相同微卫星位点长度的变化,这种变化是MMR缺陷的结果,是LS的特征。通过聚合酶链式反应进行MSI检测,若在微卫星标记中发现超过30%的MSI,则肿瘤被定义为微卫星不稳定的高频率,表明MMR缺
在LS筛查中,MLH1启动子甲基化和BRAF突变的检测被广泛用于区分散发dMMR患者和MLH1缺失的结直肠癌患
现阶段二代测序(next-generation sequencing,NGS)技术是胚系检测的主要手段,它的优势不仅在于揭示了MMR基因的缺陷,而且还揭示了致病性突变体的特异度,这有助于对MMR基因进行定向鉴定。研
随着深度学习算法的出现和计算机性能的显著提高,人工智能检测正逐步在结肠镜检查中实现。通过人工智能结肠镜不仅可实时显示息肉的存在和位置,并可对息肉的表征进行模拟分析。Urban
手术治疗是LS相关结直肠癌的主要治疗方式,切除方式主要为局部切除和全结肠切除。对于疑似LS相关结直肠癌患者可在术前行结肠镜检查并取肿瘤组织,分析其MMR蛋白的表达。LS结直肠癌患者行节段性切除和全结肠切除术后异位性结直肠癌发生率分别为25%和8%,且节段性切除术后10年、20年和30年异位结直肠癌发生率分别为16%、41%和62
LS相关结直肠癌的化学治疗与一般人群的结直肠癌基本一致。Ribic
免疫抑制剂的应用可进一步提高晚期LS相关结直肠癌患者的生存期。目前,PD-L1抑制剂(派姆单抗和纳武单抗)已广泛应用于晚期LS相关结直肠癌患
我国遗传性结直肠癌专家共
综上所述,相比于其它癌症(胃癌、子宫内膜癌和卵巢癌),我国LS相关结直肠癌患者的预后较好,5年和10年生存率分别为85%和79%。为了进一步提高LS相关结直肠癌的监测率,医务人员应该特别重视LS家族史患者、年轻患者和女性患者,并向他们及其家庭成员宣传筛查和随访的重要性。并且,人工智能辅助结肠镜在LS中的发展可能会极大的提高LS筛查质量。对于所有结直肠癌患者,无论分期,都应该进行MSI测试,这不仅具有诊断意义,还可指导治疗以获得良好的预后。虽然分子生物学和NGS技术在LS相关疾病中取得了快速发展,但考虑到技术水平和服务费用,近年LS相关结直肠癌的筛查和诊断的主要方式仍将会局限于免疫组化和MSI检测。与此同时,MLH1启动子甲基化水平对LS相关结直肠癌基因突变的临床指导意义值得进一步探索和应用。在临床和分子水平研究的指导下,根据LS相关结直肠癌基因突变的类型建立不同的监测方案,这可能会进一步改善患者预后。在治疗上,对于年轻的LS相关结直肠癌患者,应首选全结肠切除回肠直肠吻合术;对于II期或III期LS相关结直肠癌患者,在化疗失败的情况下免疫靶点抑制剂的选择可能会起到作用。现阶段,如何利用LS的免疫学特性来指导其治疗和预防是许多学者面临的一项新挑战。当前,我国虽已建立完善的LS患者筛查标准,但未来仍需进一步加强筛查策略的实施,深入探究LS相关结直肠癌基因亚型在临床诊断、治疗等,以提高LS相关结直肠癌的诊断、治疗和预防水平。
利益冲突
所有作者均声明不存在利益冲突。
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