5 遗传检测及其临床应用
目前尚没有基因检测应用在散发性胃癌的临床实践中,但是在一些遗传性肿瘤综合征的患者中,由于患胃癌风险较高,推荐在高危家系中进行遗传检测。理解基因检测对临床应用和预后的绝对价值非常重要。对高危家系进行遗传咨询是开展遗传检测必不可缺的部分。
5. 1 遗传性弥漫型胃癌 如前文所述, E2钙黏蛋白基因变异导致弥漫型胃癌的发生。该疾病的外显率是70% ,发生胃癌的平均年龄是38岁。存在该基因变异的风险包括以下几点:家属中至少有3例患该病而一级亲属有2例,后2代可能患病,有1例亲属50岁以前患病。此外,遗传性弥漫型胃癌常伴有乳腺癌、前列腺癌。目前应该在什么年龄段进行基因检测尚不清楚,目前没有循证医学证据支持这些患者应该定期进行内镜筛查。
5. 2 皮肤黏膜色素沉着2胃肠道多发性息肉综合征(普2杰二氏综合征) 胚系基因STK1 /LKB1变异导致皮肤色素沉着和胃肠道多发性息肉,称为普2杰二氏综合征。普2杰二氏综合征患胃癌的概率为29%。目前该基因变异测定已经比较可靠,筛查的方法包括10岁后每年行2次胃镜检查。
5. 3 遗传性非息肉性大肠癌 DNA错配修复基因MSH2或MLH1变异可以导致家族性大肠癌综合征,即HNPCC。胚系或者体细胞性错配基因变异可以导致微卫星不稳定,其发生率在散发性胃癌中占15%～50% , HNPCC患者一生中发展为胃癌的概率为11%。符合Bethesda指南标准的患者应该进行微卫星不稳定测定,诊断后应定期进行胃镜筛查[ 20 ] 。
5. 4 家族性腺瘤样息肉病 胚系APC基因变异可以导致经典家族性腺瘤样息肉病的发生。家族性腺瘤样息肉病绝不可少的是大肠癌,家族性腺瘤样息肉病患者中30% ～100%伴有胃底息肉。胃底的这些息肉很少发展为恶性肿瘤,但是家族性腺瘤样息肉病的患者有5%的危险发生胃腺瘤(胃窦部)和更小的危险发生胃癌。APC基因检测目前已经可靠,家族性腺瘤样息肉病的患者诊断后应在每1～3年行胃镜检查。
总之,在过去的20年里,胃癌的分子病理学有了长足的进步。将来采用基于遗传学研究的新型生物标记物将应用于临床筛查早期胃癌。此外,对胃癌癌变和转移分子机制的研究也有助于开发新药,尤其是靶向于异常基因的生物学治疗。
目前对胃癌癌变机制的理解仍不够全面,但深信未来新遗传学技术和药物治疗方案将逐步应用于临床实践。
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