后GWAS时代结直肠癌致病SNP功能机制的研究进展

doi:10.16288/j.yczz.20-320

遗传 ›› 2021, Vol. 43 ›› Issue (3): 203-214.doi: 10.16288/j.yczz.20-320

后GWAS时代结直肠癌致病SNP功能机制的研究进展

李以格^1,^2,³(), 张丹丹^1,^2,³()

¹ 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;

收稿日期:2020-12-01 出版日期:2021-03-16 发布日期:2021-01-14
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

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

Yige Li^1,^2,³(), Dandan Zhang^1,^2,³()

¹ 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;

Received:2020-12-01 Online:2021-03-16 Published:2021-01-14
Supported by:
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/Abstract

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:

Colorectal cancer (CRC) is caused by genetic and environmental factors, and the genetic component plays a significant role in CRC development. Currently, genome-wide association studies (GWAS) have identified a large number of genetic loci associated with CRC risk. In the post-GWAS era, more and more efforts focus on deciphering the biological mechanisms behind these potential causal variants by using multi-omics data and functional experiments. Many analyses have revealed that most risk single nucleotide polymorphisms (SNPs) are located in non-coding regions and these variants may regulate the expression of target genes by altering the transcription factor-binding motif, epigenetic modification, chromatin accessibility or 3D genome conformation. Results obtained from post-GWAS era have highlighted the possibility of moving from association to function. In this review, we summarize the current status of CRC post-GWAS studies and discusses the clinical application as well as future directions of CRC GWAS, in order to better gain insight into the molecular basis of CRC and provide evidence for prevention.

Key words: colorectal cancer, post-GWAS, SNP, casual variant

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[J]. 遗传, 2021, 43(3): 203-214.

Yige Li, Dandan Zhang. Progress on functional mechanisms of colorectal cancer causal SNPs in post-GWAS[J]. Hereditas(Beijing), 2021, 43(3): 203-214.

图/表 4

图1

表1

表2

后GWAS实验性研究阐明的非编码SNP作用机制"

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	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]
	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]

表2

图2

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后GWAS时代结直肠癌致病SNP功能机制的研究进展

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

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