Eur J Hum Genet:丁培荣教授解说林奇综合征初筛结果为MSI-H/dMMR,下一步该做什么检测?

2020-07-24 丁培荣、肖斌毅 肿瘤资讯

dMLH1基因甲基化检测是林奇综合征的重要筛查方式。一般认为,MLH1甲基化的结直肠癌为散发起源,可免于胚系检测,节省社会经济资源。然而,并不适用于中国人群林奇综合征的筛查,直接胚系检测或是最佳方案。

dMLH1基因甲基化检测是林奇综合征的重要筛查方式。一般认为,MLH1甲基化的结直肠癌为散发起源,可免于胚系检测,节省社会经济资源。然而,日前中山大学肿瘤医院丁培荣教授团队的研究发现,这一检测方式并不适用于中国人群林奇综合征的筛查,直接胚系检测或是最佳方案。该研究发表在欧洲著名遗传学杂志《European Journal of Human Genetics》。


丁培荣,中山大学肿瘤医院结直肠科副主任、教授、主任医师、博士生导师、FACS,广东省杰出青年医学人才(首批),美国外科学院院士(FACS)、美国纪念斯隆凯特林癌症中心(MSKCC)访问学者,中国抗癌协会家族遗传性肿瘤专业委员会 副主任委员,中国临床肿瘤学会(CSCO)青年专家委员会 副主任委员,广东省抗癌协会遗传性肿瘤专业委员会 主任委员,广东省医学会胃肠外科学分会 副主任委员,中国医师协会结直肠遗传专委会 副主任委员,中国医师学会外科医师分会MDT专业委员会青委会 副主任委员,遗传性结直肠癌临床诊治和家系管理中国专家共识、中国直肠癌侧方淋巴结转移诊疗专家共识(2019版)、直肠癌新辅助治疗后等待观察策略专家共识、结直肠癌肝转移MDT临床操作共识专家组成员.


研究背景


林奇(Lynch)综合征是最常见的遗传性肠癌综合征,约占所有结直肠癌的3%。林奇综合征患者不仅能将突变基因遗传给下一代,其自身肿瘤再发的风险也远高于普通肠癌患者。因此,在肠癌患者中识别这部分患者具有重要的临床意义。


一种普遍使用的筛查方式是分“两步走”,即在MMR免疫组化的结果上,对MLH1(-)的患者进行甲基化检测以排除散发型患者。由于MLH1甲基化和胚系MMR突变具有“互斥性”,这一筛查策略不仅能够剔除散发型肠癌,而且很少出现“误踢”林奇综合征的情况,目前已广泛应用于西方国家。然而,在中国人群中,这一筛查策略的效能尚未得到证实。


我们前期的研究发现,中国人群MLH1/PMS2缺失的患者BRAF突变发生率显着低于西方人群,提示甲基化检测对富集高危人群效能低下。为此,丁培荣教授团队设计了一个研究方案,比较甲基化检测和其他筛查策略的效能及经济效益,并探索最适合中国人群林奇综合征的筛查策略。


方法和结果


研究者回顾了2011年11月1日至2015年12月31日在中山大学肿瘤防治中心诊断、且有MMR蛋白检测结果的3250例结直肠癌病例,筛选出170例MLH1(-)肠癌患者,最终纳入109例已行胚系检测且有肿瘤组织标本的患者,行MLH1甲基化和BRAF突变检测。


研究者首先评估MLH1甲基化策略的有效性。在109例MLH1(-)的结直肠癌中,MLH1甲基化有40(36.7%)例,其中39(97.5%)例为散发型。该筛查策略的敏感性和特异性分别为95.7%和45.3%。在经济效益分析中,与直接测序相比,MLH1甲基化检测能够通过减少测序人数降低筛查成本,使得检出一例林奇综合征的成本从15260元降至13607元。


光从数据上看,甲基化检测似乎降低了筛查成本,但需要注意的是,该研究所计的测序成本包含了一个14基因的panel。当该panel缩减至5个基因甚至2个基因时(MLH1和PMS2),或随着测序技术的成熟、测序成本下降时,甲基化检测的筛查成本和直接测序将所差无几。况且,这种检测方法存在漏诊的风险。在所检测人群中的23例林奇综合征,有1(4.3%)例被遗漏。


由于MLH1甲基化常伴有BRAF突变,研究者随后评估了BRAF检测的筛查效率。他们发现,中国MLH1(-)结直肠癌患者中BRAF突变率仅有5.5%,远低于西方国家的患者。虽然这种检测有很高的敏感性(100%),但其特异性只有7%,所能剔除的散发型肠癌数量太少,难以起到筛查的作用。因此,在经济效益分析中,这种检测方式反而增加了筛查成本。


除此之外,研究者还分析了MLH1甲基化检测和BRAF突变检测、Besthesda标准相结合的筛查策略,但它们都不能显着降低筛查成本。


结论


MLH1甲基化和BRAF突变在中国结直肠癌患者中的发生率低于西方国家患者。在MLH1(-)的结直肠癌患者中筛查林奇综合征时,这两种检测方式不能有效降低筛查成本,直接胚系测序或是最佳选择。


原始出处:
Binyi Xiao 1, Jun Luo 2, E Xie 3,et al.Comparisons of screening strategies for identifying Lynch syndrome among patients with MLH1-deficient colorectal cancer.Eur J Hum Genet. 2020 Jul 13. doi: 10.1038/s41431-020-0687-8.

 

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    2021-03-28 canlab
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    2021-05-26 d830372
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    2020-07-26 vividelife
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    2020-07-26 小几洁
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    2020-07-24 1379a13dm02暂无昵称

    学习了,谢谢!

    0

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