李以格^,1,2,3, 张丹丹^,1,2,31 浙江大学医学院病理学与病理生理学系,杭州 310058
2 浙江大学医学院附属第二医院肿瘤内科,杭州 310058
3 浙江省疾病蛋白质组学重点实验室,杭州 310058;

Progress on functional mechanisms of colorectal cancer causal SNPs in post-GWAS

Li Yige^,1,2,3, Zhang Dandan^,1,2,31 Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, China
2 Department of Medical Oncology of The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
3 Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou 310058, China;

通讯作者: 张丹丹,博士,副教授,研究方向：复杂疾病遗传学及分子机制。E-mail:dandanz@zju.edu.cn

第一联系人: 作者简介: 李以格,在读硕士研究生,专业方向：病理学与病理生理学。E-mail: yigelee@zju.edu.cn
收稿日期:2020-12-1

基金资助:

国家自然科学基金项目.81773027 国家自然科学基金项目.81101640 浙江省自然科学基金项目.LY21H160027 中央高校基本科研业务费专项资金资助

Received:2020-12-1

Fund supported:

the National Natural Science Foundation of China.81773027 the National Natural Science Foundation of China.81101640 Natural Science Foundation of Zhejiang Province of China.LY21H160027 Fundamental Research Funds for the Central Universities

摘要
结直肠癌(colorectal cancer, CRC)是受遗传与环境因素共同影响的复杂疾病,其中遗传因素发挥重要作用。至今,全基因组关联研究(genome-wide association studies, GWAS)已经发现了大量与结直肠癌风险相关的遗传变异。随之而来的后GWAS时代,越来越多的研究侧重于利用多组学数据和功能实验对潜在的致病位点进行解析。分析表明绝大多数风险单核苷酸多态性(single nucleotide polymorphism, SNP)位于非编码区,可能通过影响转录因子结合、表观遗传修饰、染色质可及性、基因组高级结构等,调控靶基因表达。本文对后GWAS时代结直肠癌致病位点的机制研究进行综述,阐述了后GWAS对于理解结直肠癌分子机制的重要意义,并探讨了结直肠癌GWAS的应用和前景,为实现GWAS成果转化提供参考。
关键词： 结直肠癌;后全基因组关联研究;单核苷酸多态性;致病变异

Abstract
Keywords：colorectal cancer;post-GWAS;SNP;casual variant


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本文引用格式
李以格, 张丹丹. 后GWAS时代结直肠癌致病SNP功能机制的研究进展. 遗传[J], 2021, 43(3): 203-214 doi:10.16288/j.yczz.20-320
Li Yige. Progress on functional mechanisms of colorectal cancer causal SNPs in post-GWAS. Hereditas(Beijing)[J], 2021, 43(3): 203-214 doi:10.16288/j.yczz.20-320


结直肠癌(colorectal cancer, CRC)是常见的恶性肿瘤之一,严重威胁人类健康。据统计,2018年全球CRC新发病例超过180万,死亡病例约86万;位居发病瘤谱第3位,死亡瘤谱第2位^[1]。在我国,2015年CRC新发病例估计有38.76万例,死亡病例18.71万例;位列发病瘤谱第4位,死亡瘤谱第5位^[2,3]。吸烟、缺乏锻炼、不健康的饮食习惯等环境因素均会增加CRC患病风险^[3];此外,遗传因素也影响着CRC的发生,大型双生子研究表明CRC的遗传力约占35%^[4]。可见,CRC受遗传与环境因素共同作用。随着人类基因组计划等大型项目的开展以及测序技术的进步,利用全基因组关联研究(genome-wide association studies, GWAS)发现了大量结直肠癌易感位点,为了解和防治结直肠癌提供信息。

GWAS被认为是探索常见遗传变异主要是单核苷酸多态性(single nucleotide polymorphism, SNP)与复杂疾病相关性的“万能钥匙”^[5],广泛应用于癌症、糖尿病和精神分裂症等疾病^[6,7]。自2007年GWAS研究发现8q24.2, 18q21.1区域上的多态位点与结直肠癌风险显著相关^[8⇓~10]后,越来越多的位点被鉴定,然而由于连锁不平衡的存在以及基因与环境之间复杂的相互作用,GWAS识别的标签SNP不一定是真正的致病变异,因此迫切需要对GWAS结果进行深入解读。早前,Freedman等^[11]和Edwards等^[12]提出后GWAS(post-GWAS)研究策略,旨在筛选功能位点并阐明其潜在的分子机制(图1)。至今已有相当数量的研究对结直肠癌风险SNP进行功能解析。为了更好地理解功能SNP在结直肠癌发生发展过程中的作用,本文总结了致病位点的功能机制,并期望促进GWAS成果的临床转化,为疾病的预防、诊断寻找可靠的生物标志物和高效的治疗方法。

1 结直肠癌风险位点

截至到2020年11月,GWAS Catalog (http://www.genome.gov/gwastudies/ )数据库收录了70多篇结直肠癌GWAS研究,共鉴定到821个相关位点,其中584个为非重复位点,241个SNP与结直肠癌风险显著相关(P<5×10^-8),绝大部分位于内含子、基因间等非编码区(表1)。从人群上看,影响东亚人群患病风险的SNP约有38个,与欧洲人群相关的SNP超过100个^[14]。组学数据的累积、样本数量的增加和分析方法的改善,促进了新的风险位点不断被发现,这些位点包括位于已知风险位点上的新变异(rs6584283, 10q24.2^[15]),甚至是一些稀有、低频变异(rs145364999, 频率为0.3%^[16])。然而,这些变异的风险预测效应较弱(OR<1.5),但大部分SNP所在或邻近基因参与TGF-β/BMP (如BMP2、SMAD7、CCND2)、Wnt (如CTNNB1、TCF7L2)等信号通路以及维持端粒生物功能(如TERC、TERT),暗示这些变异的功能效应赋予疾病易感性^[17,18]。因此,有必要对风险变异进行进一步的功能分析。

图1

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图1后GWAS研究策略

GWAS-SNP功能研究的一般策略是：(1)对结直肠癌相关位点进行基因型填补,获得连锁不平衡区域内的所有位点;(2)整合转录组、表观遗传等多组学数据对相关位点进行注释,筛选潜在功能位点并对候选位点做进一步的功能注释。如ENCODE、Roadmap等数据库提供了甲基化、组蛋白修饰、染色质开放程度等信息;表达数量性状基因座(expression quantitative trait loci, eQTL)数据有助于识别SNP可能影响的靶基因;Cistrome、JASPAR等数据库可用于预测SNP是否影响转录因子结合等;(3)利用体内外实验阐明风险位点的致病机制。常见的实验方法有：荧光素酶报告基因实验、ChIP-seq、染色体构象捕获技术、基因敲除等。参考文献[5]绘制。
Fig. 1Post-GWAS approach

2 结直肠癌后GWAS研究

2.1 功能注释

2.1.1 编码区SNP

位于编码区的SNP可分为同义和非同义突变,同义突变虽然不影响蛋白质的氨基酸序列,但可能通过影响转录后修饰、翻译速率等过程,改变蛋白的表达;而非同义SNP (non-synonymous SNP, nsSNP)会引起氨基酸的替换,造成蛋白结构、理化性质(稳定性、溶解性等)和功能发生改变。那些对蛋白结构和功能影响较大的非同义突变往往会在自然选择中被淘汰,推测剩下的非同义突变功能效应可能较小,这给nsSNP的研究带来一定的挑战。目前,已有大量的生物软件(如MUpro、INPS-MD、ModPred等)可用于预测nsSNP对蛋白结构和功能的影响,相较而言,nsSNP的功能机制相对简单,因此相关的研究也较多^{[19⇓⇓~22]}。结合全外显子分析发现多个与结直肠癌发展相关的编码区SNP,如位于SH2B3重要结构域上的错义突变rs3184504 (p.Trp263Arg)可能改变该蛋白对细胞分裂的调节功能;还有些编码变异可能影响可变剪切(rs16888728, UTP23)^[23]。

Table 1
表1
表1GWAS鉴定的SNP的类型
Table 1The genomic context of identified SNPs

变异类型	数量	比例(%)
内含子	137	57
基因间	85	35
3ʹ非翻译区	4	~1
5ʹ非翻译区	2	~1
同义编码	3	~1
错义变异	4	~2
非编码RNA	4	~2
剪接受体	1	~0.5
获得性终止子	1	~0.5

新窗口打开|下载CSV

2.1.2 非编码区SNP

目前GWAS发现的结直肠癌风险相关位点主要位于非编码区,这些位点可能参与基因转录、转录后加工、翻译和翻译后修饰等过程调控基因表达。在研究非编码区SNP时,首先需要明确这类SNP的靶基因,常用的方法是利用表达数量性状基因座(expression quantitative trait loci, eQTL)检测SNP与基因表达的关系,基于此策略,已发现大量非编码SNP可能影响的靶基因,包括CTNNB1、GREM1、ATF1等以及一些与结直肠癌关系尚不明确的基因(如TNS3、FUT2)。非编码SNP可以通过近距离顺式或远距离反式作用调控靶基因的转录,研究发现这类风险SNP所在区域的组蛋白修饰特别丰富,尤其是与启动子、增强子活性相关的修饰(H3K4me3、H3K4me1、H3K27ac);并预测大部分SNP会破坏特定转录因子的结合基序,如rs6983267可能会改变与MYC、CTCF、TCF7L2等转录因子的结合^[18]。有些非编码SNP可能影响增强子活性,通过远距离增强子与启动子相互作用改变靶基因的表达^[14]。此外,基因组的3D结构在基因表达调控等过程中发挥重要作用^[24,25],整合Hi-C等数据发现,一些非编码SNP所在区域与靶基因启动子区存在显著的染色质环相互作用^[14,18,26],因此在对非编码SNP进行功能解析时,常常需要考虑染色质相互作用等。

非编码SNP功能多样,可参与到基因表达调控的各个进程中,可能位于不同的调控区,如miRNA种子序列结合位点区、可变剪切位点区等,还可以出现在非编码RNA上,包括长链非编码RNA和miRNA等。功能注释发现位于DOK3非翻译区的rs2279398可能改变与miRNA的结合效率^[27];目前也识别到大量非编码RNA上的SNP,如rs2632159 (lncRNA-PCAT1)、rs6505162 (miR-423)等^{[28⇓⇓~31]};位于hsa-mir-146a的 rs1052918可能会引起Wnt信号通路的持续激活,导致细胞增殖失控和肿瘤发生^[32]。可见,非编码SNP功能机制十分复杂,有待系统、深入的研究。

2.2 功能SNP机制的实验证据

2.2.1 编码区SNP的潜在功能机制

编码区SNP影响患病风险的机制离不开其所在基因编码蛋白的功能。由于这类SNP发生的频率相对较低,研究者往往聚焦在特定信号通路/基因或某种感兴趣的修饰方式,如N⁶-甲基腺嘌呤(N⁶-Methyladenosine, m⁶A)修饰,进行全外显子关联分析以发现效应较大的编码SNP。对参与TGFβ信号通路的12个基因进行外显子测序和关联性分析,筛选到SMAD7上的低频错义变异rs3764482与中国汉族人群的结直肠癌风险显著相关,SMAD7能够抑制R-SMAD的磷酸化并在该通路中发挥负调控作用,鉴于此功能而设计的体外实验表明,该SNP通过影响R-SMAD磷酸化,改变TGFβ信号活性^[33]。类似地,rs3750050 (PTPN12, p.Thr573Ala)、rs149418249 (TPP1, p.Pro507Leu)通过破坏蛋白功能、蛋白与蛋白的相互作用,分别引起Ras/MEK/ERK通路和端粒功能异常,导致结直肠患病风险升高^[34,35]。

编码区SNP还可能影响基因或蛋白的修饰。如m⁶A修饰主要发生在RNA上,参与mRNA稳定性的维持、mRNA前体剪切、翻译调控等过程,是近些年的研究热点。通过分析m⁶A相关SNP与结直肠癌风险的关系,发现在m⁶A编辑器的参与下,发生在ANKLE1外显子区的rs8100241[A]等位基因能够增加ANKLE1的m⁶A修饰水平和转录效率,促进该潜在抑癌蛋白的表达^[36]。

值得注意的是,编码区SNP可能与其他SNP存在相互作用^[23,37],发挥更强的功能效应。如：位于转录因子TCF7L2外显子区的rs138649767[A]等位基因,能激活含有rs6983267[G]的MYC增强子,促进MYC的表达^[38];发生在SMAD7外显子和内含子上的SNP可能存在调控与被调控的关系,也可能共同影响SMAD7的功能和TGFβ信号通路^[33]。因此,在研究编码区SNP时,可以考虑SNP之间的相互作用,以更好的解析其功能机制。

2.2.2 非编码区SNP调控基因表达

结直肠癌风险SNP主要位于非编码区^[39],根据所处位置发挥不同的机制,其所在区域可以是近端(启动子、增强子或超级增强子)或远端(基因间或基因内)应答元件。非编码SNP往往通过改变转录因子结合位点(transcription factor-binding site, TFBS)、表观遗传修饰和/或染色质结构,影响基因转录水平(表2,图2)。SNP造成的序列变化可能会产生新的TFBS或破坏已存在的TFBS,影响与转录因子(如SP1, NF1, GATA3; MYC, NFATC2, YY1等^{[40⇓⇓⇓~44]})的结合,调控靶基因的转录,参与细胞增殖、凋亡、迁移侵袭等过程。

(1)影响启动子活性。启动子区上的SNP一般通过影响与转录因子的结合,发挥调控作用。如：rs13278062和rs2243828分别位于DR4和MPO启动子区,体内体外实验表明,这两个SNP的[T]等位基因在结直肠癌发展中有着不同的作用,前者抑制克隆形成,后者促进细胞增殖,但它们的分子机制相似,都是通过增加与转录因子(Sp1/NF1、AP-2α)的结合亲和力,使DR4和MPO表达增加^[40,47]。

(2)影响增强子活性。内含子区的SNP常位于增强子元件,也会改变与转录因子的结合,主要发挥远距离调控作用。发生在CDH1内含子区的rs7198799能够靶向转录因子NFATC2,远距离增强ZFP90(距离致病位点超过200 kb)的表达,通过NFATC2- ZFP90-BMP4通路促进癌症发生^[43];类似地,rs174575可以在转录因子E2F1的参与下,作为FADS2和lncRNA-AP002754.2位点特异的远距离增强子^[50],有趣的是后者又能够促进FADS2的表达,形成环路,影响结直肠癌发生^[50]。

单个SNP的效应可能较小,但是多个致病SNP对TFBS产生的累积效应可能对靶基因表达的影响很大。例如,rs61926301和rs7959129是分别发生在ATF1启动子区和内含子区上的SNP,这两个SNP的[T]风险等位基因能够分别增加与转录因子SP1和GATA3的结合能力,通过启动子与增强子相互作用的方式促进潜在癌基因ATF1的转录,影响细胞增殖、抑制细胞凋亡;基因表达的调控与染色质的高级结构密切相关,分析发现这两个SNP所在的区域富集活跃的组蛋白修饰峰和开放的染色质可及性^[41]。

(3)其他。miRNA能够靶向基因3ʹ非翻译区(untranslated region, UTR),沉默基因表达。如,发生在IGF2BP1 3ʹUTR区的rs6504593突变位点减弱了miR-21与该区域的结合,使IGF2BP1表达上调,引起结直肠癌发生^[56]。发挥类似机制的还有位于GREM1、LAMC1、ATF1等基因3ʹUTR区的SNP^[38,53,54],此外,长链非编码RNA上的一些SNP也能通过改变与miRNA的结合发挥作用,如rs1317082、rs664589、rs12982687^[58⇓~60]等。若SNP发生在miRNA上,同样会影响其与靶基因的结合亲和力^[61]。

Table 2
表2
表2后GWAS实验性研究阐明的非编码SNP作用机制
Table 2Mechanisms of non-coding SNPs based on post-GWAS experimental reports

功能	SNP	位置	靶基因	实验	参考文献
影响与转录因子的 结合	rs13278062	DR4启动子区	DR4	CRISPR/Cas9、ChIP、流式分析等实验	[40]
	rs11777210	KBTBD11内含子区	KBTBD11	凝胶迁移、荧光素酶报告基因等实验	[42]
	rs55829688	lncRNA-GAS5	GAS5	荧光素酶报告基因、凝胶迁移、流式分析、迁移侵袭等实验	[44]
	rs2238126	ETV6内含子区	ETV6	荧光素酶报告基因、凝胶迁移实验、ChIP	[45]
	rs27437	SLC22A5上游	SLC22A5	荧光素酶报告基因实验	[46]
	rs2333227	MPO启动子区	MPO	ChIP、CRISPR/Cas9、克隆形成、侵袭迁移、裸鼠体内成瘤等实验	[47]
	rs420038	SLC22A3内含子区	SLC22A3	荧光素酶报告基因、流式分析、细胞增殖等实验	[48]
影响启动子增强子 相互作用	rs61926301	ATF1启动子区	ATF1	荧光素酶报告基因、凝胶迁移、ChIP、3C、裸鼠异种移植体外等实验	[41]
	rs7959129	ATF1内含子区
	rs7198799	CDH1内含子区	ZFP90	荧光素酶报告基因、凝胶迁移、ChIP、4C测序、3C-qPCR、小鼠实验等	[43]
	rs12263636	ZMIZ1内含子区	RPS24	荧光素酶报告基因实验	[49]
	rs174575	FADS2内含子区	FADS2, AP002754.2	荧光素酶报告基因、凝胶迁移、3C、裸鼠体内异种移植等实验	[50]
作为绝缘子发挥远 距离调控作用	rs6702619	LPPR4与PALMD 基因间	GNAS等	ChIP、增强子阻断、3C测序等实验	[51]
影响与miRNA的 结合	rs11169571	ATF1 3ʹUTR	ATF1	荧光素酶报告基因实验	[38]
	rs3814058	PXR 3ʹUTR	PXR	荧光素酶报告基因实验	[52]
	rs12915554	GREM1 3ʹUTR	GREM1	荧光素酶报告基因实验	[53]
	rs1062044	LAMC1 3ʹUTR	LAMC1	荧光素酶报告基因实验	[54]
	rs5030740	RPA1 3ʹUTR	RPA1	荧光素酶报告基因、细胞增殖、流式分析等实验	[55]
	rs6504593	IGF2BP1 3ʹUTR	IGF2BP1	荧光素酶报告基因、细胞增殖、流式分析等实验	[56]
	rs1590	TGFBR1 3ʹUTR	TGFBR1	荧光素酶报告基因	[57]
	rs1317082	CCSlnc362	CCSlnc362	荧光素酶报告基因、细胞增殖、流式分析等实验	[58]
	rs664589	lncRNA-MALAT1	MALAT1	荧光素酶报告基因实验	[59]
	rs12982687	lncRNA-UCA1	UCA1	荧光素酶报告基因、细胞增殖、侵袭迁移等实验	[60]
影响与靶基因的结合	rs35301225	miR-34	E2F1	荧光素酶报告基因、细胞增殖等实验	[61]

ChIP (chromatin immunoprecipitation)：染色质免疫沉淀;3C (chromosome conformation capture)：染色体构象捕获;4C (circular chromosome conformation capture)：环形染色体构象捕获; UTR (untranslated region)：非翻译区。

新窗口打开|下载CSV

图2

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图2致病SNP潜在功能机制总结

A：启动子区SNP的潜在功能机制。通过影响与转录因子的结合,调控靶基因的表达,影响结直肠癌发生;B：内含子区SNP的潜在功能机制。常在转录因子的参与下,通过远距离启动子增强子相互作用,影响靶基因表达;C：3ʹUTR区SNP的潜在功能机制。往往通过改变与miRNA的结合,影响靶基因转录后水平;D：外显子区SNP的潜在功能机制。可能通过改变氨基酸序列,影响蛋白与蛋白之间的相互作用。
Fig. 2Summary of the potential functional mechanisms of causal SNPs

3 结直肠癌GWAS的应用

GWAS和后GWAS研究不仅可以帮助人们更好地在遗传水平上理解结直肠癌的发病机制,也有助于筛查预防、风险分层和临床治疗等。

3.1 风险预测

通过组合已发现的结直肠癌风险位点计算遗传风险评分(genetic risk score, GRS)是GWAS-SNP重要的公共卫生价值之一^[62],该方法对每个SNP的微弱效应进行叠加,大大提高了对疾病风险的预测能力,有潜力成为药物治疗、行为矫正的基础。基于37个已知CRC风险变异的GRS表明,与人群中位数相比,得分排在前1%的个体患CRC的风险增加了2.9倍^[63];在中国南方汉族人群中,GRS结合传统风险因素构建的风险模型预测能力优于传统风险因素模型^[64]。随着风险位点的数量不断增加,基于此建立的GRS风险模型的预测效能也将不断提高,有望实现肿瘤精准预防。

3.2 预后分析

rs5030740、rs9939049、rs11196172等结直肠癌风险SNP与患者的生存期显著相关,有可能发展成为可靠的预后标志物^{[55,65⇓~67]}。其中,rs5030740能够调控RPA1的表达,而RPA1低表达增加了结直肠癌细胞对奥沙利铂的敏感性,抑制了奥沙利铂治疗后的细胞增殖^[55];另外,在接受贝伐单抗一线化疗的结直肠癌患者中开展的试验表明,携带rs699947-AA(VEGF-A)和rs1799969-GA (ICAM-1)基因型的患者总生存期比其他患者更长^[68]。上述研究表明风险SNP可用于分析预后、指导用药,实现个体化治疗。

4 结语与展望

尽管GWAS研究已经发现了大量结直肠癌风险相关位点，但大部分SNP的功能效应较小，更多高效力的位点有待发掘。相信随着测序技术的进步、人群研究规模的扩大、分析水平的提高，新的结直肠癌易感位点(包括一些低频、稀有变异)将会不断被发现^[15,69~71]。目前，对结直肠癌潜在功能变异的筛选稍显不足，对其进行机制探索的实验更是屈指可数。各种组学、基因组结构等数据的涌现，以及孟德尔随机化的应用，为筛选潜在致病变异提供了可靠信息^{[72, 73]}；实验技术的发展为阐明致病变异的生物学功能提供更可靠的证据，如：CRISPR/Cas9使单碱基编辑成为可能，染色体构象捕获及其衍生技术可探究SNP的远距离调控机制等等，相信未来将会有更多致病变异的分子机制被阐明。此外，已有研究表明几个不同区域的SNP同时突变时，结直肠癌的患病风险大大增加^{[38, 49]}；SNP还与多种因素(如阿司匹林的服用、吸烟等)存在交互作用，影响结直肠癌风险^{[74, 75]}。可见癌症作为复杂疾病，遗传与遗传、遗传与环境之间的相互作用不可忽视^[76]。因此在研究风险SNP的功能时，需要更多的关注SNP与SNP以及SNP与环境之间的作用。相信随着后GWAS研究的开展和深入，将会帮助我们更好地认识变异与结直肠癌发生发展之间的关系，推动个体化预防和精准治疗的发展。

(责任编委: 周钢桥)

The authors have declared that no competing interests exist.

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