引用本文

劉莉, 張嘉, 繆小平. 結(jié)直腸癌的環(huán)境及遺傳影響因素研究進(jìn)展[J]. 中華流行病學(xué)雜志, 2020, 41(10): 1745-1750

Liu Li, Zhang Jia, Miao Xiaoping. Progress of research on the environmental and genetic influencing factors of colorectal cancer[J]. Chinese Journal of Epidemiology, 2020, 41(10): 1745-1750.

結(jié)直腸癌的環(huán)境及遺傳影響因素研究進(jìn)展

華中科技大學(xué)同濟(jì)醫(yī)學(xué)院公共衛(wèi)生學(xué)院流行病與衛(wèi)生統(tǒng)計(jì)學(xué)系, 武漢 430030

收稿日期: 2020-04-01

基金項(xiàng)目: 國(guó)家自然科學(xué)基金（81974491，81925032）；國(guó)家重點(diǎn)研發(fā)計(jì)劃（2016YFC1302702）；湖北省衛(wèi)生健康委員會(huì)2019－2020年度青年人才項(xiàng)目（WJ2019Q027）

摘要: 結(jié)直腸癌是全球性的公共衛(wèi)生問(wèn)題，對(duì)人類健康構(gòu)成嚴(yán)重威脅。發(fā)達(dá)國(guó)家與地區(qū)的結(jié)直腸癌發(fā)病率常位居前列，且部分發(fā)展中國(guó)家發(fā)病率亦急劇上升。結(jié)直腸癌的發(fā)生與飲食、生活方式等環(huán)境因素以及遺傳因素密切相關(guān)，基因-環(huán)境交互作用也對(duì)其發(fā)生有一定的調(diào)控作用。目前已有較多關(guān)于結(jié)直腸癌影響因素的研究，本文對(duì)已有研究進(jìn)行綜述，從環(huán)境因素、遺傳因素及基因-環(huán)境交互作用出發(fā)，探討上述因素與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)的關(guān)聯(lián)，為結(jié)直腸癌的預(yù)防提供一定證據(jù)。流行病學(xué)揭示的結(jié)直腸癌環(huán)境危險(xiǎn)因素為腸癌的群體預(yù)防提供了更多依據(jù)，測(cè)序、組學(xué)等技術(shù)的不斷發(fā)展則為結(jié)直腸癌遺傳易感性的解析提供了新的契機(jī)，兩者的有機(jī)結(jié)合有利于構(gòu)建更為精準(zhǔn)的風(fēng)險(xiǎn)預(yù)測(cè)模型，并制定個(gè)體化干預(yù)方案，以達(dá)到降低結(jié)直腸癌疾病負(fù)擔(dān)的最終目標(biāo)。

關(guān)鍵詞: 結(jié)直腸腫瘤    環(huán)境因素    遺傳因素    基因-環(huán)境交互作用    

Progress of research on the environmental and genetic influencing factors of colorectal cancer

Liu Li , Zhang Jia , Miao Xiaoping     

Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

Fund program: National Natural Science Foundation of China (81974491, 81925032); National Key Research and Development Program of China (2016YFC1302702); Young Talent Program of Health Commission of Hubei Province in 2019-2020 (WJ2019Q027)

Abstract: Colorectal cancer is a global public health issue which possesses serious challenge. The incidence of colorectal cancer in developed countries and regions stands in the forefront worldwide, and has been rising sharply in some of the developing countries. It is unanimously recognized that the occurrence of colorectal cancer is closely related to environmental factors as diet and lifestyle, genetic factors, and gene-environment interactions of the people. Since there have been many studies on the influencing factors of colorectal cancer, the current review aims at providing evidence on colorectal cancer prevention by evaluating the relationships between the influencing factors and colorectal cancer, based on the published literatures. Environmental risk factors revealed by previous epidemiological studies facilitate the population-based prevention programs against colorectal cancer. The developments of sequencing and omics technologies provide more chances to illustrate the genetic susceptibility of colorectal cancer. With both, we are able to construct more accurate risk prediction models and subsequently developing personalized intervention plans to achieve the ultimate goal of reducing the burden of colorectal cancer.

Key words: Colorectal neoplasm    Environmental factors    Genetic factors    Gene-environment interactions    

結(jié)直腸癌（Colorectal Cancer，CRC）是嚴(yán)重威脅人類健康的惡性腫瘤。據(jù)國(guó)際癌癥研究機(jī)構(gòu)（International Agency for Research on Cancer，IARC）評(píng)估，2018年全球有180萬(wàn)結(jié)直腸癌新發(fā)病例和88萬(wàn)死亡病例，居腫瘤發(fā)病順位第3位，死亡順位第2位，是全球性的公共衛(wèi)生問(wèn)題[1]。結(jié)直腸癌的發(fā)生與經(jīng)濟(jì)水平、生活方式等環(huán)境因素息息相關(guān)，澳大利亞、新西蘭、歐洲地區(qū)、北美地區(qū)的發(fā)病率多年來(lái)居全球前列[2]。近年來(lái)，由于經(jīng)濟(jì)和營(yíng)養(yǎng)轉(zhuǎn)型、生活方式西化及人口老齡化，部分發(fā)展中國(guó)家的結(jié)直腸癌發(fā)病率亦急劇增加[3]。除此之外，遺傳因素也在一定程度上決定了結(jié)直腸癌的發(fā)病風(fēng)險(xiǎn)。結(jié)直腸癌遺傳度為12%~35%[4]。結(jié)直腸癌患者的一級(jí)親屬患腸癌的風(fēng)險(xiǎn)比一般人群高2~4倍[5-6]。鑒于結(jié)直腸癌的發(fā)生與環(huán)境及遺傳因素密不可分，本文將從環(huán)境、遺傳及基因-環(huán)境交互作用出發(fā)，闡述結(jié)直腸癌影響因素的流行病學(xué)研究結(jié)果，為結(jié)直腸癌的預(yù)防提供更多證據(jù)。

一、環(huán)境因素與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)的關(guān)聯(lián)

1.飲食因素：紅肉和加工肉類中的一些元素被認(rèn)為有致癌作用，包括防腐劑（如硝酸鹽、亞硝酸鹽）、肉類加工和烹飪過(guò)程中產(chǎn)生的化學(xué)物質(zhì)（如雜環(huán)胺和多環(huán)芳烴）等。IARC將紅肉和加工肉類列為致癌物，認(rèn)為其與癌癥特別是結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)增加相關(guān)。基于約400項(xiàng)隊(duì)列研究的薈萃分析表明，每天攝入100 g紅肉與加工肉類會(huì)使結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)增加12%，且加工肉類可能要比紅肉更容易導(dǎo)致結(jié)直腸癌，這可能是由于制作方法（煙熏、腌制）暴露于致癌物質(zhì)所致[7]。

2018年，世界癌癥研究基金會(huì)（World Cancer Research Fund，WCRF）和美國(guó)癌癥研究所（American Institute for Cancer Research，AICR）的專家報(bào)告指出食用富含膳食纖維的食物可以預(yù)防結(jié)直腸癌[8]。薈萃分析表明，與飲食中含膳食纖維較低者比，攝入較高含量膳食纖維的人群患結(jié)直腸腫瘤的風(fēng)險(xiǎn)可降低12%~28%[9-10]。WCRF/AICR進(jìn)一步量化了這種關(guān)聯(lián)，指出每天每增加90 g全谷物食物攝入可使結(jié)直腸癌的風(fēng)險(xiǎn)降低17%[7]。膳食纖維預(yù)防結(jié)直腸癌的潛在機(jī)制包括增加糞便的體積、加快糞便排出，從而減少潛在有毒致癌物與結(jié)腸上皮的接觸時(shí)間。此外，膳食纖維也可與消化過(guò)程中的有害副產(chǎn)品如次級(jí)膽汁酸等結(jié)合，降低其對(duì)腸上皮細(xì)胞的致癌作用[9]。

鈣被認(rèn)為能夠在結(jié)腸環(huán)境中結(jié)合游離脂肪酸和膽汁酸等化合物，限制其致癌潛力，同時(shí)也被證實(shí)能夠抑制DNA損傷及細(xì)胞增殖，誘導(dǎo)分化和凋亡，從而降低結(jié)直腸癌的風(fēng)險(xiǎn)[11-12]。與攝入較少的乳制品和牛奶相比，較高的乳制品及牛奶的攝入可使結(jié)直腸癌的風(fēng)險(xiǎn)降低約20%[13]。這種關(guān)聯(lián)主要?dú)w因于乳制品中較高的鈣含量[14]。維生素D可以促進(jìn)鈣的吸收。有關(guān)飲食中補(bǔ)充維生素D和循環(huán)25-羥基維生素D水平的研究表明，循環(huán)25-羥基維生素D水平與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)之間存在負(fù)相關(guān)關(guān)系，維生素D可降低結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)[15]。

此外，魚(yú)類的攝入也與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)相關(guān)。每天攝入100 g魚(yú)類可使結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)降低11%（95%CI：1%~20%）[7]。魚(yú)類尤其是海洋魚(yú)類對(duì)結(jié)直腸癌的保護(hù)作用很可能與海洋ω-3脂肪酸有關(guān)。對(duì)美國(guó)成年人進(jìn)行的大型前瞻性研究表明，與海洋ω-3脂肪酸攝入量＜0.15 g/d相比，攝入量至少為0.35 g/d者結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)可降低43%[16-17]。蔬菜和水果的攝入也有較微效的結(jié)直腸癌預(yù)防作用。AICR基于10項(xiàng)研究的薈萃分析表明，每天攝入100 g不含淀粉的蔬菜與水果可使結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)降低2%（95%CI：1%~3%）[18]。動(dòng)物實(shí)驗(yàn)表明膳食脂肪在增加結(jié)腸細(xì)胞增殖和致瘤性方面具有一定作用[19-20]，但流行病學(xué)研究尚未顯示飲食脂肪攝入與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)之間存在明確的關(guān)聯(lián)關(guān)系[21]。

鑒于多種食物與結(jié)直腸癌的風(fēng)險(xiǎn)相關(guān)，近年來(lái)，學(xué)界進(jìn)一步研究了飲食模式對(duì)結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)的影響。研究表明，以蔬菜水果、魚(yú)類、五谷雜糧、豆類和橄欖油為主的地中海飲食（Mediterranean Diet，MED Diet）模式與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)呈負(fù)相關(guān)[22-23]。堅(jiān)持地中海飲食模式可使結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)降低18%（RR＝0.82，95%CI：0.75~0.88）[24]。來(lái)自35 372名英國(guó)女性的隊(duì)列研究對(duì)地中海飲食進(jìn)行評(píng)分（范圍0~10分），結(jié)果表明飲食評(píng)分每升高2分，結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)可降低12%（HR＝0.88，95%CI：0.78~0.99）[25]。最新的薈萃分析表明，阻止高血壓膳食療法（Dietary Approaches to Stop Hypertension，DASH）也具有降低結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)的作用，相對(duì)于依從性不高的個(gè)體，遵循DASH飲食者的結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)降低20%（RR＝0.80，95%CI：0.74~0.85）[26]。哈佛大學(xué)Nurses’ Health Study（NHS）及Health Professionals Follow-up Study（HPFS）的數(shù)據(jù)顯示，替代性健康飲食指數(shù)-2010（The Alternative Healthy Eating Index，AHEI-2010）、替代性MED Diet、DASH飲食評(píng)分較高者結(jié)直腸癌發(fā)生風(fēng)險(xiǎn)減少5%~11%（HR值分別為0.95、0.89、0.89）[27]。而長(zhǎng)期西化飲食模式（飲食中紅肉和加工肉類、精制谷物、蘇打水、脂肪含量高，水果、蔬菜和全谷物制品含量低）則可使得腸癌風(fēng)險(xiǎn)增加50%~60%[28-29]。另一項(xiàng)研究利用NHS、HPFS兩個(gè)隊(duì)列研究的數(shù)據(jù)構(gòu)建了經(jīng)驗(yàn)性飲食炎癥模式（empirical dietary inflammatory pattern，EDIP）評(píng)分來(lái)估計(jì)飲食的致炎潛能，結(jié)果表明高水平促炎飲食攝入與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)升高相關(guān)（最高相對(duì)于最低五分位EDIP評(píng)分，結(jié)直腸癌的HR＝1.30，95%CI：1.12~1.55）[30]。

2.生活方式因素：重度飲酒已被確立為結(jié)直腸癌的危險(xiǎn)因素[31]。最新一項(xiàng)飲酒與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)的薈萃分析表明，與不/偶爾飲酒（≤1 g/d）相比，重度（每天2~3杯）或重度以上飲酒（每天＞3杯）與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)顯著增加有關(guān)[OR值（95%CI）分別為1.11（0.99~1.24）、1.25（1.11~1.40）][32]。WCFR/AICR的最新專家報(bào)告指出，重度飲酒與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)升高相關(guān)且呈現(xiàn)劑量依賴關(guān)系：每天飲用40、50、60 g酒精，其結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)分別增加25%、41%、60%[8]。

吸煙與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)增加相關(guān)，且作用期較長(zhǎng)。來(lái)自24項(xiàng)前瞻性隊(duì)列研究的薈萃分析表明，吸煙者患結(jié)腸癌、直腸癌的風(fēng)險(xiǎn)將分別增加9%、24%，且具有明顯的劑量效應(yīng)關(guān)系[33]。相較于不吸煙者，當(dāng)前吸煙者的結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)顯著增加38%，過(guò)去吸煙者結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)增加18%[34]，且曾經(jīng)吸煙的人在戒煙后的25年內(nèi)仍有較高的結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)[35]。在被動(dòng)吸煙者中，也觀察到了類似的關(guān)聯(lián)，被動(dòng)吸煙者患結(jié)直腸癌的風(fēng)險(xiǎn)增加14%，且男性被動(dòng)吸煙者患結(jié)直腸癌的風(fēng)險(xiǎn)高于女性[36]。

超重/肥胖同樣被認(rèn)為是結(jié)直腸癌的危險(xiǎn)因素[37]。最近的薈萃分析表明，體重每增加5 kg，結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)將增加2%，BMI每增加5.0 kg/m2，結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)將增加6%，成年期較高的全身和腹部脂肪是結(jié)直腸癌的危險(xiǎn)因素，這些關(guān)聯(lián)在男性中比女性更強(qiáng)[38]。相對(duì)于全身肥胖，腹部肥胖可能在結(jié)直腸癌的發(fā)生發(fā)展中起到更為重要作用。最近的薈萃分析研究了腹型肥胖[以腰圍（waist circumference，WC）和腰臀比（waist-to-hip ratio，WHR）來(lái)衡量]與結(jié)直腸癌之間的關(guān)聯(lián)，結(jié)果表明相對(duì)于較低的WC和WHR，較高WC和WHR者結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)分別增加42%和39%[39]。一項(xiàng)納入了58 667名絕經(jīng)后婦女的隊(duì)列研究表明，減肥可使結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)降低21%[40]。

與過(guò)多的能量攝入、超重和肥胖相反，體育鍛煉與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)成反比[22, 41]。來(lái)自美國(guó)和歐洲地區(qū)大隊(duì)列的數(shù)據(jù)表明，與低水平的休閑體育活動(dòng)（P10）相比，高水平的體育活動(dòng)者（P90）結(jié)腸癌發(fā)病風(fēng)險(xiǎn)降低16%，直腸癌發(fā)病風(fēng)險(xiǎn)降低13%[42]。與體力活動(dòng)可降低結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)相反，久坐行為可增加多種癌癥的發(fā)病風(fēng)險(xiǎn)，包括結(jié)直腸癌和晚期腺瘤[43]。久坐時(shí)間每天每增加2 h，結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)將增加8%（95%CI：4%~11%）[44]。

3.非甾體類抗炎藥物：包括阿司匹林在內(nèi)的非甾體類抗炎藥物（non-steroidal anti-inflammatory drugs，NSAIDs）是公認(rèn)的結(jié)直腸癌保護(hù)因素，可作為結(jié)直腸癌化學(xué)預(yù)防手段，研究認(rèn)為NSAIDs主要通過(guò)抑制COX-2來(lái)預(yù)防結(jié)直腸癌[45]。薈萃分析表明，服用阿司匹林與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)之間呈負(fù)相關(guān)（RR＝0.73，95%CI：0.67~0.79），且長(zhǎng)期服用保護(hù)性更加明顯[46-47]。除阿司匹林外，服用其他NSAIDs藥物可使＞40歲人群的結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)降低26%（OR＝0.74，95%CI：0.67~0.81）[48]。

4.微生物：隨著腸道微生物研究的進(jìn)展，越來(lái)越多證據(jù)表明腸道微生物失調(diào)與結(jié)直腸癌發(fā)生密切相關(guān)。最初，通過(guò)對(duì)糞便進(jìn)行培養(yǎng)，研究者發(fā)現(xiàn)結(jié)直腸癌高危人群和低危人群腸道微生物組成不同[49]。對(duì)來(lái)自澳大利亞、法國(guó)、中國(guó)、美國(guó)、德國(guó)、意大利和日本的386例病例和382例對(duì)照的宏基因組數(shù)據(jù)進(jìn)行Meta分析，發(fā)現(xiàn)了在結(jié)直腸癌病例與對(duì)照組中差異表達(dá)最顯著的29個(gè)核心物種，包括梭桿菌、卟啉單胞菌、微單胞菌、消化道鏈球菌等，均在結(jié)直腸癌患者中顯著富集[50]。在所有腸道微生物中，具核梭桿菌與結(jié)直腸癌發(fā)生發(fā)展的關(guān)聯(lián)比較明確，多項(xiàng)研究中都發(fā)現(xiàn)結(jié)直腸癌患者糞便及腸癌組織中具核梭桿菌顯著聚集[51]，功能學(xué)研究表明具核梭桿菌可通過(guò)促進(jìn)腸道炎性微環(huán)境而有助于結(jié)直腸癌的發(fā)生[52-53]。此外，還有研究表明，幽門(mén)螺桿菌、溶血鏈球菌感染亦可能是腸癌的危險(xiǎn)因素，但上述關(guān)聯(lián)還有待進(jìn)一步證實(shí)[54-55]。

5.其他環(huán)境因素：環(huán)境中的苯、有機(jī)氯等污染物也會(huì)影響結(jié)直腸癌的發(fā)生。2018年，對(duì)4個(gè)北歐國(guó)家進(jìn)行的大型病例對(duì)照研究發(fā)現(xiàn)，工作場(chǎng)所苯暴露可使結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)升高12%，且存在一定的劑量反應(yīng)關(guān)系[56]。此外，結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)的升高可能與血清中多氯聯(lián)苯的濃度升高有關(guān)[57]。

二、遺傳因素與結(jié)直腸癌的發(fā)病風(fēng)險(xiǎn)的關(guān)聯(lián)

早期的結(jié)直腸癌遺傳易感性研究基于已知的病理生理基礎(chǔ)，選擇可能與結(jié)直腸癌相關(guān)的基因作為候選基因，通過(guò)比較病例及對(duì)照中候選基因中的遺傳變異如單核苷酸多態(tài)性（single nucleotide polymorphism，SNP），分析結(jié)直腸癌的遺傳易感性基礎(chǔ)[58]。在這一時(shí)期，結(jié)直腸癌易感性的研究重點(diǎn)多集中于DNA錯(cuò)配修復(fù)、WNT/β-catenin、MYC、P53等原癌、抑癌信號(hào)通路上的遺傳變異[59-62]。然而候選基因策略僅從既定的單個(gè)或多個(gè)SNP出發(fā)，難以全面揭示結(jié)直腸癌的遺傳背景，遺漏了大量的致病性遺傳信息。

隨著芯片技術(shù)的發(fā)展，研究者得以同時(shí)檢測(cè)基因組中數(shù)以百萬(wàn)計(jì)的遺傳標(biāo)記（主要為SNP），并進(jìn)行全基因組關(guān)聯(lián)研究分析（Genome-wide association study，GWAS）[63]。目前，GWAS已確定了50余個(gè)與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)有關(guān)的候選基因座及100個(gè)左右的遺傳變異[64-66]。繼早期基于歐美人群的GWAS研究發(fā)現(xiàn)了rs6983267、rs10505477、rs7014346、rs719725、rs4939827、rs4779584、rs16892766、rs10795668、rs3802842、rs1957636、rs4813802等經(jīng)典結(jié)直腸癌位點(diǎn)后，基于歐美人群的GWAS的薈萃分析，進(jìn)一步確證了rs36053993、rs34612342、rs12953717、rs4464148、rs10505477、rs961253、rs16892766、rs10795668、rs3802842、rs355527、rs1862748、rs7259371、rs2736100、rs1800469，14個(gè)獨(dú)立變體與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)高度相關(guān)[67]。最近基于亞洲結(jié)直腸癌協(xié)作組的大規(guī)模GWAS研究也在前期發(fā)掘的rs647161、rs2423279、rs10774214、rs4711689、rs4919687、rs11064437、rs2450115、rs6469656、rs7229639、rs58920878、rs12953717、rs4464148、rs4939827位點(diǎn)的基礎(chǔ)之上[68-70]，進(jìn)一步揭示出rs7542665、rs201395236、rs7606562、rs113569514、rs12659017、rs3830041、rs6584283、rs77969132、rs2730985、rs1886450、rs4341754、rs1078643、rs67052019、rs60911071、rs62558833、rs11108175、rs9634162等新的易感性位點(diǎn)，且進(jìn)一步證實(shí)了之前與歐美人群結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)相關(guān)的大多數(shù)位點(diǎn)也與東亞人群的腸癌風(fēng)險(xiǎn)有關(guān)[71-72]。為了最大化利用GWAS挖掘出來(lái)的遺傳位點(diǎn)，研究者利用多個(gè)與結(jié)直腸癌相關(guān)的SNP構(gòu)建了多基因風(fēng)險(xiǎn)評(píng)分（polygenic risk score，PRS），并以此來(lái)評(píng)估不同遺傳背景人群的結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)。Frampton等[73]利用37個(gè)高加索人群結(jié)直腸癌易感性位點(diǎn)建立了PRS，且發(fā)現(xiàn)最高1% PRS攜帶者的結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)為一般人群的2.9倍。倘若人群中所有結(jié)直腸癌易感性位點(diǎn)已知的話，最高1% PRS攜帶者的腸癌發(fā)病風(fēng)險(xiǎn)為一般人群的7.7倍。Hsu等[74]的研究也證實(shí)了基于27個(gè)SNP的PRS可用于高加索人群的結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)分層，且在基于腫瘤家族史的風(fēng)險(xiǎn)預(yù)測(cè)模型中加入PRS后，該模型在男性中的預(yù)測(cè)精確性提高8%，女性中的預(yù)測(cè)精確性提高4%。Weigl等[75]利用53個(gè)SNP構(gòu)建的PRS被證實(shí)與德國(guó)人結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)顯著相關(guān)，且最高10% PRS攜帶者的結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)為最低10% PRS攜帶者的3倍。

GWAS研究發(fā)現(xiàn)的結(jié)直腸癌相關(guān)的SNP位點(diǎn)大多位于基因的非編碼區(qū)，如何從中找到真正與疾病相關(guān)的SNP，并從生物學(xué)上詮釋其功能及其與疾病的關(guān)系是后GWAS時(shí)代的重大挑戰(zhàn)之一。據(jù)評(píng)估，結(jié)直腸癌的遺傳度是12%~35%[4]，但是GWAS中達(dá)到統(tǒng)計(jì)學(xué)顯著的SNP能解釋的遺傳度相當(dāng)有限，相當(dāng)一部分的遺傳位點(diǎn)亟待發(fā)現(xiàn)，尤其是一些高外顯度的低頻編碼變異。后基因組時(shí)代，利用多組學(xué)手段尤其是全轉(zhuǎn)錄組關(guān)聯(lián)研究（transcriptome-wide association studies，TWAS）成為尋找“消失的遺傳變異”的新的研究策略。TWAS可以圍繞GWAS基因座的精細(xì)定位（fine-mapping）促進(jìn)功能候選基因和其他獨(dú)立風(fēng)險(xiǎn)變體的檢測(cè)，以發(fā)現(xiàn)最終的致病SNP[76-77]。研究表明，基于先前GWAS研究發(fā)現(xiàn)的21個(gè)結(jié)直腸癌易感區(qū)域（包括29個(gè)SNP）進(jìn)行精細(xì)定位，發(fā)現(xiàn)1q41（rs12759486）、19q13.1（rs7252505）與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)高度相關(guān)且具有統(tǒng)計(jì)學(xué)意義（P＜0.000 6），在非洲裔美國(guó)人中，這兩個(gè)新風(fēng)險(xiǎn)SNP對(duì)結(jié)直腸癌遺傳力的貢獻(xiàn)度約為1.5%[78]。大型病例-對(duì)照研究在GWAS識(shí)別的10q22.3區(qū)域進(jìn)行了精細(xì)定位分析，識(shí)別出rs12263636、rs3740253和rs7071351 3個(gè)遺傳變異，可影響RPS24基因的表達(dá)并與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)顯著相關(guān)[79]。基于The Hispanic Colorectal Cancer Study與The Multiethnic cohort study數(shù)據(jù)的精細(xì)定位分析發(fā)現(xiàn)了rs7528276、rs1367374、rs142319636、rs143046984、rs185423955、rs60892987等結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)位點(diǎn)[80]。

此外，高通量測(cè)序技術(shù)也為后GWAS時(shí)代注入了新的活力。最近的全基因組測(cè)序（Whole genome sequencing，WGS）與全外顯子測(cè)序（Whole exome sequencing，WES）已經(jīng)確定多個(gè)結(jié)直腸癌易感基因與變異位點(diǎn)，如rs112298707（DDX20）、rs68264412（ZFYVE26）、rs46509382（PIK3R3）、rs35911730（SLC26A8）、rs145156750（ZEB2）、rs95952304（TP53INP1）、rs219249005（SLC11A1）、rs151827481（LRBA）、rs37439069（CEBPZ）、rs67630823（ETAA1）、rs52474994（SEMA3G）、rs50325883（IFRD2）、rs187541196（FAT1）等[81]。最新的一項(xiàng)對(duì)結(jié)直腸癌的WGS與GWAS研究所進(jìn)行的薈萃分析，確定了30個(gè)新的結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)位點(diǎn)，包括常見(jiàn)變異rs12144319（1p32.3）、rs983402（2q33.1）、rs9271695（6p21.32）、rs7333607（13q13.3）、rs56324967（15q22.33）、rs1391441（15q22.33），低頻變異rs72942485（3q13.2），及首次發(fā)現(xiàn)的5q21.1染色體處的罕見(jiàn)變異rs145364999[65]。近期的功能基因組學(xué)研究基于高通量RNA干擾技術(shù)篩選出位于12q13.12區(qū)域的基因ATF1是結(jié)直腸癌的關(guān)鍵驅(qū)動(dòng)因素，并通過(guò)精細(xì)定位分析發(fā)現(xiàn)了rs61926301和rs7959129兩個(gè)可增加結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)的變異位點(diǎn)[82]。

三、基因-環(huán)境交互作用與結(jié)直腸癌的發(fā)病風(fēng)險(xiǎn)

結(jié)直腸癌的風(fēng)險(xiǎn)既取決于環(huán)境因素和遺傳因素，還受到基因-環(huán)境交互作用的調(diào)控[83]。有關(guān)結(jié)直腸癌的基因-環(huán)境交互作用研究主要集中在前期已經(jīng)確證的結(jié)直腸癌相關(guān)的環(huán)境危險(xiǎn)因素，如飲酒、紅肉及加工肉、阿司匹林等與遺傳因素的交互作用上?；?0篇有關(guān)結(jié)直腸癌候選基因研究的薈萃分析確定了5種經(jīng)多重比較調(diào)整后仍有意義的（P＜0.05）基因-環(huán)境交互作用，即：N-乙酰轉(zhuǎn)移酶2（NAT2）和加工肉攝入量、NAT2和紅肉攝入量、rs16892766（8q23.3）和蔬菜消耗量、SHMT1 C1420T多態(tài)性和葉酸攝入量、rs6983267（8q24）和阿司匹林使用。研究中，對(duì)環(huán)境暴露與遺傳變異之間相互作用的觀察證據(jù)強(qiáng)度進(jìn)行了觀察評(píng)分，并基于主要環(huán)境效應(yīng)和主要遺傳效應(yīng)的證據(jù)強(qiáng)度（1＝強(qiáng)，2＝中度，3＝弱）建立了相互作用的先驗(yàn)得分。根據(jù)觀察與先驗(yàn)評(píng)分，發(fā)現(xiàn)了rs6983267（8q24）與阿司匹林使用之間的相互作用具有中等的總體可信評(píng)分和主要的遺傳效應(yīng)（P＝7.45×10-13）[84]。有研究表明，經(jīng)常使用阿司匹林或非甾體抗炎藥與降低結(jié)腸癌的風(fēng)險(xiǎn)有關(guān)（OR＝0.69，95%CI：0.64~0.74），而這種關(guān)聯(lián)與12p12.3上的SNP rs2965667高度相關(guān)[85]。除了單個(gè)遺傳和環(huán)境因素的交互作用與結(jié)直腸癌的關(guān)聯(lián)，近期的研究還進(jìn)一步探討了遺傳評(píng)分與生活方式評(píng)分的交互作用對(duì)結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)的影響。Jeon等[86]的研究表明，基于19個(gè)生活及環(huán)境因素的環(huán)境風(fēng)險(xiǎn)評(píng)分與63個(gè)SNP的遺傳風(fēng)險(xiǎn)評(píng)分建立模型，將PRS與生活方式評(píng)分結(jié)合起來(lái)可顯著提高結(jié)直腸癌的風(fēng)險(xiǎn)分層作用。模型對(duì)男性及女性結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)預(yù)測(cè)的AUC（ROC曲線下面積）分別為0.63和0.62。對(duì)于無(wú)結(jié)直腸癌家族史者，目前平均推薦篩查年齡為50歲。以此風(fēng)險(xiǎn)作為篩查閾值，利用環(huán)境風(fēng)險(xiǎn)評(píng)分與遺傳風(fēng)險(xiǎn)評(píng)分進(jìn)一步細(xì)分后發(fā)現(xiàn)，最低10%風(fēng)險(xiǎn)的個(gè)體，男性適宜的篩查年齡為56歲，女性為64歲；而最高10%風(fēng)險(xiǎn)的個(gè)體，男性適宜的篩查年齡為44歲，女性為50歲。對(duì)于最高1% PRS攜帶者，最高1%健康生活方式評(píng)分相對(duì)于最低1%生活方式評(píng)分可使50歲人群10年結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)降低約90%。

目前，基因-環(huán)境交互作用對(duì)結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)的影響仍然處于研究中，需要進(jìn)行大樣本和更進(jìn)一步的研究，以確定可能對(duì)公共衛(wèi)生產(chǎn)生重要影響的環(huán)境-基因交互作用。

四、小結(jié)

結(jié)直腸癌是一種復(fù)雜性疾病，除受環(huán)境因素影響外，也受到遺傳因素的影響，同時(shí)基因-環(huán)境交互作用也在結(jié)直腸癌的發(fā)生發(fā)展中起著重要作用。多種飲食相關(guān)因素以及生活方式因素都與結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)有較強(qiáng)的關(guān)聯(lián)。在有關(guān)結(jié)直腸癌的遺傳因素研究中，由于測(cè)序技術(shù)的不斷發(fā)展，先后經(jīng)歷了候選基因策略、GWAS以及后GWAS時(shí)代，這將使人們?cè)诓粩嘌芯堪l(fā)現(xiàn)新的結(jié)直腸癌發(fā)病風(fēng)險(xiǎn)相關(guān)的SNP基礎(chǔ)上，進(jìn)一步篩選并確定真正與結(jié)直腸癌相關(guān)的基因與遺傳變異，也有助于人們更進(jìn)一步了解結(jié)直腸癌分子流行病學(xué)方面的病因，并綜合遺傳與環(huán)境因素構(gòu)建更為完善的預(yù)測(cè)模型與干預(yù)方案，最終實(shí)現(xiàn)降低結(jié)直腸癌疾病負(fù)擔(dān)的目標(biāo)。

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