后GWAS時代結直腸癌致病SNP功能機制的研究進展

李以格，張丹丹

綜 述

后GWAS時代結直腸癌致病SNP功能機制的研究進展

李以格1,2,3，張丹丹1,2,3

1. 浙江大學醫學院病理學與病理生理學系，杭州 310058 2. 浙江大學醫學院附屬第二醫院腫瘤內科，杭州 310058 3. 浙江省疾病蛋白質組學重點實驗室，杭州 310058

結直腸癌(colorectal cancer, CRC)是受遺傳與環境因素共同影響的復雜疾病，其中遺傳因素發揮重要作用。至今，全基因組關聯研究(genome-wide association studies, GWAS)已經發現了大量與結直腸癌風險相關的遺傳變異。隨之而來的后GWAS時代，越來越多的研究側重于利用多組學數據和功能實驗對潛在的致病位點進行解析。分析表明絕大多數風險單核苷酸多態性(single nucleotide polymorphism, SNP)位于非編碼區，可能通過影響轉錄因子結合、表觀遺傳修飾、染色質可及性、基因組高級結構等，調控靶基因表達。本文對后GWAS時代結直腸癌致病位點的機制研究進行綜述，闡述了后GWAS對于理解結直腸癌分子機制的重要意義，并探討了結直腸癌GWAS的應用和前景，為實現GWAS成果轉化提供參考。

結直腸癌；后全基因組關聯研究；單核苷酸多態性；致病變異

結直腸癌(colorectal cancer, CRC)是常見的惡性腫瘤之一，嚴重威脅人類健康。據統計，2018年全球CRC新發病例超過180萬，死亡病例約86萬；位居發病瘤譜第3位，死亡瘤譜第2位[1]。在我國，2015年CRC新發病例估計有38.76萬例，死亡病例18.71萬例；位列發病瘤譜第4位，死亡瘤譜第5位[2,3]。吸煙、缺乏鍛煉、不健康的飲食習慣等環境因素均會增加CRC患病風險[3]；此外，遺傳因素也影響著CRC的發生，大型雙生子研究表明CRC的遺傳力約占35%[4]。可見，CRC受遺傳與環境因素共同作用。隨著人類基因組計劃等大型項目的開展以及測序技術的進步，利用全基因組關聯研究(genome-wide association studies, GWAS)發現了大量結直腸癌易感位點，為了解和防治結直腸癌提供信息。

GWAS被認為是探索常見遺傳變異主要是單核苷酸多態性(single nucleotide polymorphism, SNP)與復雜疾病相關性的“萬能鑰匙”[5]，廣泛應用于癌癥、糖尿病和精神分裂癥等疾病[6,7]。自2007年GWAS研究發現8q24.2, 18q21.1區域上的多態位點與結直腸癌風險顯著相關[8~10]后，越來越多的位點被鑒定，然而由于連鎖不平衡的存在以及基因與環境之間復雜的相互作用，GWAS識別的標簽SNP不一定是真正的致病變異，因此迫切需要對GWAS結果進行深入解讀。早前，Freedman等[11]和Edwards等[12]提出后GWAS(post-GWAS)研究策略，旨在篩選功能位點并闡明其潛在的分子機制(圖1)。至今已有相當數量的研究對結直腸癌風險SNP進行功能解析。為了更好地理解功能SNP在結直腸癌發生發展過程中的作用，本文總結了致病位點的功能機制，并期望促進GWAS成果的臨床轉化，為疾病的預防、診斷尋找可靠的生物標志物和高效的治療方法。

1 結直腸癌風險位點

截至到2020年11月，GWAS Catalog (http://www. genome.gov/gwastudies/)數據庫收錄了70多篇結直腸癌GWAS研究，共鑒定到821個相關位點，其中584個為非重復位點，241個SNP與結直腸癌風險顯著相關(<5×10–8)，絕大部分位于內含子、基因間等非編碼區(表1)。從人群上看，影響東亞人群患病風險的SNP約有38個，與歐洲人群相關的SNP超過100個[14]。組學數據的累積、樣本數量的增加和分析方法的改善，促進了新的風險位點不斷被發現，這些位點包括位于已知風險位點上的新變異(rs6584283, 10q24.2[15])，甚至是一些稀有、低頻變異(rs145364999, 頻率為0.3%[16])。然而，這些變異的風險預測效應較弱(OR<1.5)，但大部分SNP所在或鄰近基因參與TGF-β/BMP (如、、)、Wnt (如、)等信號通路以及維持端粒生物功能(如、)，暗示這些變異的功能效應賦予疾病易感性[17,18]。因此，有必要對風險變異進行進一步的功能分析。

圖1 后GWAS研究策略

GWAS-SNP功能研究的一般策略是：(1)對結直腸癌相關位點進行基因型填補，獲得連鎖不平衡區域內的所有位點；(2)整合轉錄組、表觀遺傳等多組學數據對相關位點進行注釋，篩選潛在功能位點并對候選位點做進一步的功能注釋。如ENCODE、Roadmap等數據庫提供了甲基化、組蛋白修飾、染色質開放程度等信息；表達數量性狀基因座(expression quantitative trait loci, eQTL)數據有助于識別SNP可能影響的靶基因；Cistrome、JASPAR等數據庫可用于預測SNP是否影響轉錄因子結合等；(3)利用體內外實驗闡明風險位點的致病機制。常見的實驗方法有：熒光素酶報告基因實驗、ChIP-seq、染色體構象捕獲技術、基因敲除等。參考文獻[5]繪制。

2 結直腸癌后GWAS研究

2.1 功能注釋

2.1.1 編碼區SNP

位于編碼區的SNP可分為同義和非同義突變，同義突變雖然不影響蛋白質的氨基酸序列，但可能通過影響轉錄后修飾、翻譯速率等過程，改變蛋白的表達；而非同義SNP (non-synonymous SNP, nsSNP)會引起氨基酸的替換，造成蛋白結構、理化性質(穩定性、溶解性等)和功能發生改變。那些對蛋白結構和功能影響較大的非同義突變往往會在自然選擇中被淘汰，推測剩下的非同義突變功能效應可能較小，這給nsSNP的研究帶來一定的挑戰。目前，已有大量的生物軟件(如MUpro、INPS-MD、ModPred等)可用于預測nsSNP對蛋白結構和功能的影響，相較而言，nsSNP的功能機制相對簡單，因此相關的研究也較多[19~22]。結合全外顯子分析發現多個與結直腸癌發展相關的編碼區SNP，如位于重要結構域上的錯義突變rs3184504 (p.Trp263Arg)可能改變該蛋白對細胞分裂的調節功能；還有些編碼變異可能影響可變剪切(rs16888728,)[23]。

表1 GWAS鑒定的SNP的類型

2.1.2 非編碼區SNP

目前GWAS發現的結直腸癌風險相關位點主要位于非編碼區，這些位點可能參與基因轉錄、轉錄后加工、翻譯和翻譯后修飾等過程調控基因表達。在研究非編碼區SNP時，首先需要明確這類SNP的靶基因，常用的方法是利用表達數量性狀基因座(expression quantitative trait loci, eQTL)檢測SNP與基因表達的關系，基于此策略，已發現大量非編碼SNP可能影響的靶基因，包括、等以及一些與結直腸癌關系尚不明確的基因(如、)。非編碼SNP可以通過近距離順式或遠距離反式作用調控靶基因的轉錄，研究發現這類風險SNP所在區域的組蛋白修飾特別豐富，尤其是與啟動子、增強子活性相關的修飾(H3K4me3、H3K4me1、H3K27ac)；并預測大部分SNP會破壞特定轉錄因子的結合基序，如rs6983267可能會改變與MYC、CTCF、TCF7L2等轉錄因子的結合[18]。有些非編碼SNP可能影響增強子活性，通過遠距離增強子與啟動子相互作用改變靶基因的表達[14]。此外，基因組的3D結構在基因表達調控等過程中發揮重要作用[24,25]，整合Hi-C等數據發現，一些非編碼SNP所在區域與靶基因啟動子區存在顯著的染色質環相互作用[14,18,26]，因此在對非編碼SNP進行功能解析時，常常需要考慮染色質相互作用等。

非編碼SNP功能多樣，可參與到基因表達調控的各個進程中，可能位于不同的調控區，如miRNA種子序列結合位點區、可變剪切位點區等，還可以出現在非編碼RNA上，包括長鏈非編碼RNA和miRNA等。功能注釋發現位于非翻譯區的rs2279398可能改變與miRNA的結合效率[27]；目前也識別到大量非編碼RNA上的SNP，如rs2632159 (-)、rs6505162 ()等[28~31]；位于的 rs1052918可能會引起Wnt信號通路的持續激活，導致細胞增殖失控和腫瘤發生[32]。可見，非編碼SNP功能機制十分復雜，有待系統、深入的研究。

2.2 功能SNP機制的實驗證據

2.2.1 編碼區SNP的潛在功能機制

編碼區SNP影響患病風險的機制離不開其所在基因編碼蛋白的功能。由于這類SNP發生的頻率相對較低，研究者往往聚焦在特定信號通路/基因或某種感興趣的修飾方式，如6-甲基腺嘌呤(6-Methy-ladenosine, m6A)修飾，進行全外顯子關聯分析以發現效應較大的編碼SNP。對參與TGFβ信號通路的12個基因進行外顯子測序和關聯性分析，篩選到上的低頻錯義變異rs3764482與中國漢族人群的結直腸癌風險顯著相關，SMAD7能夠抑制R-SMAD的磷酸化并在該通路中發揮負調控作用，鑒于此功能而設計的體外實驗表明，該SNP通過影響R-SMAD磷酸化，改變TGFβ信號活性[33]。類似地，rs3750050 (, p.Thr573Ala)、rs149418249 (, p.Pro507Leu)通過破壞蛋白功能、蛋白與蛋白的相互作用，分別引起Ras/MEK/ERK通路和端粒功能異常，導致結直腸患病風險升高[34,35]。

編碼區SNP還可能影響基因或蛋白的修飾。如m6A修飾主要發生在RNA上，參與mRNA穩定性的維持、mRNA前體剪切、翻譯調控等過程，是近些年的研究熱點。通過分析m6A相關SNP與結直腸癌風險的關系，發現在m6A編輯器的參與下，發生在外顯子區的rs8100241[A]等位基因能夠增加的m6A修飾水平和轉錄效率，促進該潛在抑癌蛋白的表達[36]。

值得注意的是，編碼區SNP可能與其他SNP存在相互作用[23,37]，發揮更強的功能效應。如：位于轉錄因子外顯子區的rs138649767[A]等位基因，能激活含有rs6983267[G]的增強子，促進的表達[38]；發生在外顯子和內含子上的SNP可能存在調控與被調控的關系，也可能共同影響SMAD7的功能和TGFβ信號通路[33]。因此，在研究編碼區SNP時，可以考慮SNP之間的相互作用，以更好的解析其功能機制。

2.2.2 非編碼區SNP調控基因表達

結直腸癌風險SNP主要位于非編碼區[39]，根據所處位置發揮不同的機制，其所在區域可以是近端(啟動子、增強子或超級增強子)或遠端(基因間或基因內)應答元件。非編碼SNP往往通過改變轉錄因子結合位點(transcription factor-binding site, TFBS)、表觀遺傳修飾和/或染色質結構，影響基因轉錄水平(表2，圖2)。SNP造成的序列變化可能會產生新的TFBS或破壞已存在的TFBS，影響與轉錄因子(如SP1, NF1, GATA3; MYC, NFATC2, YY1等[40~44])的結合，調控靶基因的轉錄，參與細胞增殖、凋亡、遷移侵襲等過程。

(1)影響啟動子活性。啟動子區上的SNP一般通過影響與轉錄因子的結合，發揮調控作用。如：rs13278062和rs2243828分別位于和啟動子區，體內體外實驗表明，這兩個SNP的[T]等位基因在結直腸癌發展中有著不同的作用，前者抑制克隆形成，后者促進細胞增殖，但它們的分子機制相似，都是通過增加與轉錄因子(Sp1/NF1、AP-2α)的結合親和力，使DR4和MPO表達增加[40,47]。

(2)影響增強子活性。內含子區的SNP常位于增強子元件，也會改變與轉錄因子的結合，主要發揮遠距離調控作用。發生在內含子區的rs7198799能夠靶向轉錄因子NFATC2，遠距離增強(距離致病位點超過200 kb)的表達，通過NFATC2- ZFP90-BMP4通路促進癌癥發生[43]；類似地，rs174575可以在轉錄因子E2F1的參與下，作為和位點特異的遠距離增強子[50]，有趣的是后者又能夠促進FADS2的表達，形成環路，影響結直腸癌發生[50]。

單個SNP的效應可能較小，但是多個致病SNP對TFBS產生的累積效應可能對靶基因表達的影響很大。例如，rs61926301和rs7959129是分別發生在啟動子區和內含子區上的SNP，這兩個SNP的[T]風險等位基因能夠分別增加與轉錄因子SP1和GATA3的結合能力，通過啟動子與增強子相互作用的方式促進潛在癌基因的轉錄，影響細胞增殖、抑制細胞凋亡；基因表達的調控與染色質的高級結構密切相關，分析發現這兩個SNP所在的區域富集活躍的組蛋白修飾峰和開放的染色質可及性[41]。

表2 后GWAS實驗性研究闡明的非編碼SNP作用機制

ChIP (chromatin immunoprecipitation)：染色質免疫沉淀；3C (chromosome conformation capture)：染色體構象捕獲；4C (circular chromosome conformation capture)：環形染色體構象捕獲；UTR (untranslated region)：非翻譯區。

(3)其他。miRNA能夠靶向基因3?非翻譯區(untranslated region, UTR)，沉默基因表達。如，發生在3?UTR區的rs6504593突變位點減弱了與該區域的結合，使表達上調，引起結直腸癌發生[56]。發揮類似機制的還有位于、、等基因3?UTR區的SNP[38,53,54]，此外，長鏈非編碼RNA上的一些SNP也能通過改變與miRNA的結合發揮作用，如rs1317082、rs664589、rs12982687[58~60]等。若SNP發生在miRNA上，同樣會影響其與靶基因的結合親和力[61]。

圖2 致病SNP潛在功能機制總結

A：啟動子區SNP的潛在功能機制。通過影響與轉錄因子的結合，調控靶基因的表達，影響結直腸癌發生；B：內含子區SNP的潛在功能機制。常在轉錄因子的參與下，通過遠距離啟動子增強子相互作用，影響靶基因表達；C：3?UTR區SNP的潛在功能機制。往往通過改變與miRNA的結合，影響靶基因轉錄后水平；D：外顯子區SNP的潛在功能機制。可能通過改變氨基酸序列，影響蛋白與蛋白之間的相互作用。

3 結直腸癌GWAS的應用

GWAS和后GWAS研究不僅可以幫助人們更好地在遺傳水平上理解結直腸癌的發病機制，也有助于篩查預防、風險分層和臨床治療等。

3.1 風險預測

通過組合已發現的結直腸癌風險位點計算遺傳風險評分(genetic risk score, GRS)是GWAS-SNP重要的公共衛生價值之一[62]，該方法對每個SNP的微弱效應進行疊加，大大提高了對疾病風險的預測能力，有潛力成為藥物治療、行為矯正的基礎。基于37個已知CRC風險變異的GRS表明，與人群中位數相比，得分排在前1%的個體患CRC的風險增加了2.9倍[63]；在中國南方漢族人群中，GRS結合傳統風險因素構建的風險模型預測能力優于傳統風險因素模型[64]。隨著風險位點的數量不斷增加，基于此建立的GRS風險模型的預測效能也將不斷提高，有望實現腫瘤精準預防。

3.2 預后分析

rs5030740、rs9939049、rs11196172等結直腸癌風險SNP與患者的生存期顯著相關，有可能發展成為可靠的預后標志物[55,65~67]。其中，rs5030740能夠調控的表達，而低表達增加了結直腸癌細胞對奧沙利鉑的敏感性，抑制了奧沙利鉑治療后的細胞增殖[55]；另外，在接受貝伐單抗一線化療的結直腸癌患者中開展的試驗表明，攜帶rs699947-AA()和rs1799969-GA ()基因型的患者總生存期比其他患者更長[68]。上述研究表明風險SNP可用于分析預后、指導用藥，實現個體化治療。

4 結語與展望

盡管GWAS研究已經發現了大量結直腸癌風險相關位點，但大部分SNP的功能效應較小，更多高效力的位點有待發掘。相信隨著測序技術的進步、人群研究規模的擴大、分析水平的提高，新的結直腸癌易感位點(包括一些低頻、稀有變異)將會不斷被發現[15,69~71]。目前，對結直腸癌潛在功能變異的篩選稍顯不足，對其進行機制探索的實驗更是屈指可數。各種組學、基因組結構等數據的涌現，以及孟德爾隨機化的應用，為篩選潛在致病變異提供了可靠信息[72,73]；實驗技術的發展為闡明致病變異的生物學功能提供更可靠的證據，如：CRISPR/Cas9使單堿基編輯成為可能，染色體構象捕獲及其衍生技術可探究SNP的遠距離調控機制等等，相信未來將會有更多致病變異的分子機制被闡明。此外，已有研究表明幾個不同區域的SNP同時突變時，結直腸癌的患病風險大大增加[38,49]；SNP還與多種因素(如阿司匹林的服用、吸煙等)存在交互作用，影響結直腸癌風險[74,75]。可見癌癥作為復雜疾病，遺傳與遺傳、遺傳與環境之間的相互作用不可忽視[76]。因此在研究風險SNP的功能時，需要更多的關注SNP與SNP以及SNP與環境之間的作用。相信隨著后GWAS研究的開展和深入，將會幫助我們更好地認識變異與結直腸癌發生發展之間的關系，推動個體化預防和精準治療的發展。

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

Yige Li1,2,3, Dandan Zhang1,2,3

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.

colorectal cancer; post-GWAS; SNP; casual variant

2020-12-01;

2021-01-11

國家自然科學基金項目(編號：81773027，81101640)，浙江省自然科學基金項目(編號：LY21H160027)，中央高校基本科研業務費專項資金資助[Supported by the National Natural Science Foundation of China (Nos. 81773027, 81101640), Natural Science Foundation of Zhejiang Province of China (No. LY21H160027) , and Fundamental Research Funds for the Central Universities]

李以格，在讀碩士研究生，專業方向：病理學與病理生理學。E-mail: yigelee@zju.edu.cn

張丹丹，博士，副教授，研究方向：復雜疾病遺傳學及分子機制。E-mail: dandanz@zju.edu.cn

10.16288/j.yczz.20-320

2021/1/22 11:06:54

URI: https://kns.cnki.net/kcms/detail/11.1913.R.20210122.1052.005.html

(責任編委: 周鋼橋)