Influence of genetic variation in C7 gene regulatory regions on susceptibility to colorectal cancer
-
摘要:
目的 探讨补体7(C7)基因遗传变异与结直肠癌易感性的关系。 方法 利用GEPIA数据库分析基因C7在结直肠癌组织与正常组织中的表达差异;利用TIMER数据库分析C7表达及拷贝数变异与结直肠癌免疫细胞浸润的相关关系。 采用病例对照研究分析C7遗传变异对结直肠癌发病风险的影响。 使用PCR-限制性片段长度多态性分析对C7 rs1061429和rs1376178单核苷酸多态性(SNP)进行基因分型。 使用非条件logistic回归计算比值比(OR)和95%置信区间(CI),分析C7 rs1061429和rs1376178遗传变异与结直肠癌易感性的关系。 结果 与结直肠正常组织相比,C7在结直肠癌组织中的表达显著降低(P<0.05)。 C7表达及拷贝数变异可影响结直肠癌免疫细胞浸润。 与C7 rs1061429 CC基因型携带者相比,CA基因型携带者可显著增加直肠癌发病风险(OR=1.42,95%CI:1.08~1.86)。 与C7 rs1376178 CC基因型携带者相比,CA基因型携带者的结肠癌发病风险增加(OR=1.50,95%CI:1.06~2.10),CA或AA基因型携带者有较高的直肠癌发病风险,OR(95%CI)分别为1.46(1.06~2.03)和1.57(1.09~2.28)。 结肠癌易感性的分层分析显示,与C7 rs1376178 CC基因型携带者相比,C7 rs1376178 CA基因型携带者中女性(OR=2.01,95%CI:1.18~3.43)、非吸烟者(OR=1.70,95%CI:1.14~2.54)和非饮酒者(OR=1.57,95%CI:1.06~2.33)的结肠癌发病风险增加。 直肠癌易感性的分层分析表明,与CC 基因型携带者相比,C7 rs1061429 CA基因型携带者中男性(OR=1.64,95%CI:1.17~2.31)、相对低年龄组(OR=1.58,95%CI:1.07~2.33)的直肠癌发病风险增加;与CC基因型携带者相比,C7 rs1376178 AA基因型携带者中女性的直肠癌发病风险增加(OR=1.93,95%CI:1.05~3.54),C7 rs1376178 CA或AA基因型携带者中相对低年龄组(OR=1.86或2.23)、非吸烟者(OR=1.55或1.80)、非饮酒者(OR=1.51或1.62)的直肠癌发病风险增加(P<0.05)。 结论 C7在结直肠癌发生过程中发挥着重要作用,C7 rs1061429和rs1376178多态性可与环境因素交互作用影响结直肠癌易感性。 Abstract:Objective This study aimed to investigate the influence of genetic variation in complement component 7 (C7) on the susceptibility to colorectal cancer. Methods GEPIA database was used to analyze the differential expression of gene C7 in colorectal cancer tissues and colorectal normal tissues. The influence of C7 expression and copy number variation on immune cell infiltration in colorectal cancer were analyzed by using TIMER database. Case-control study was used to evaluate the relationship between C7 genetic variation and the risk of colorectal cancer. The single nucleotide polymorphism (SNP) of C7 rs1061429 and rs1376178 was genotyped using PCR-restriction fragment length polymorphism analysis. Unconditioned logistic regression analysis was used to calculate odd ratio (OR) and 95% confidence interval (CI) to analyze the relationship between polymorphism of C7 rs1061429 and rs1376178 and the susceptibility to colorectal cancer. Results C7 had significantly decreased expression in colorectal cancer tissues than in colorectal normal tissues (P<0.05). C7 expression and copy number variation were correlated with the immune cell infiltration in colorectal cancer. Compared with C7 rs1061429 CC genotype carriers, CA genotype carriers had a significantly increased risk of rectal cancer (OR=1.42, 95%CI: 1.08–1.86). Compared with C7 rs1376178 CC genotype carriers, CA genotype carriers had increased the risk of colon cancer (OR=1.50, 95%CI: 1.06–2.10), CA or AA genotype carriers had increased the risk of rectal cancer (OR=1.46, 95%CI: 1.06–2.03; OR=1.57, 95%CI: 1.09−2.28). Stratified analysis of colon cancer susceptibility showed that compared with C7 rs1376178 CC genotype carriers, C7 rs1376178 CA genotype increased the risk of colon cancer in women (OR=2.01, 95%CI: 1.18−3.43), non-smokers (OR=1.70, 95%CI: 1.14−2.54) and non-drinkers (OR=1.57, 95%CI: 1.06–2.33). Stratified analysis on rectal cancer susceptibility showed that compared with C7 rs1061429 CC genotype carriers, C7 rs1061429 CA genotype increased the risk of rectal cancer in men (OR=1.64, 95%CI: 1.17−2.31) and younger age groups (OR=1.58, 95%CI: 1.07−2.33). Compared with C7 rs1376178 CC genotype carriers, C7 rs1376178 AA genotype increased the risk of rectal cancer in women (OR=1.93, 95%CI: 1.05−3.54), CA or AA genotype increased the risk of rectal cancer in younger age groups (OR=1.86 or OR=2.23), non-smokers (OR=1.55 or OR=1.80), non-drinkers (OR=1.51 or OR=1.62) (P<0.05). Conclusion C7 plays an important role in the development of colorectal cancer. C7 rs1061429 and rs1376178 polymorphism might interact with environmental factors to influence the susceptibility of colorectal cancer. -
表 1 研究对象基本特征
Table 1. Basic characteristics of the research subjects
变量 结肠癌 直肠癌 病例组 对照组 P值a 病例组 对照组 P值a 性别 0.943 0.838 男性 221 (55.39) 222 (55.64) 287 (62.39) 290 (63.04) 女性 178 (44.61) 177 (44.36) 173 (37.61) 170 (36.96) 年龄组 (岁) 0.322 0.843 ≤60 190 (47.62) 204 (51.13) 232 (50.43) 235 (51.09) >60 209 (52.38) 195 (48.87) 228 (49.57) 225 (48.91) 吸烟 0.740 0.553 是 93 (23.31) 97 (24.31) 121 (26.30) 129 (28.04) 否 306 (76.69) 302 (75.69) 339 (73.70) 331 (71.96) 饮酒 0.865 0.478 是 90 (22.56) 88 (22.06) 150 (32.61) 140 (30.43) 否 309 (77.44) 311 (77.94) 310 (67.39) 320 (69.57) 注:a. 双向χ2检验;括号外数据为病例组和对照组例数,括号内数据为各变量例数分别占病例组和对照组例数的百分比(%) 表 2 基因C7 rs1061429和rs1376178遗传变异与结肠癌易感性关系
Table 2. Relationship between genetic variation of C7 rs1061429 and rs1376178 and susceptibility to colon cancer
SNP位点 基因型 病例组a 对照组a OR 值(95%CI) b P值 rs1061429 CC 201(50.38) 202(50.63) 1.00(参照) CA 171(42.86) 170(42.61) 1.01(0.76~1.35) 0.941 AA 27(6.76) 27(6.876) 1.01(0.57~1.77) 0.986 rs1376178 CC 88(22.06) 113(28.32) 1.00(参照) CA 220(55.14) 189(47.37) 1.50(1.06~2.10) 0.020 AA 91(22.80) 97(24.31) 1.21(0.81~1.80) 0.361 注:SNP. 单核苷酸多态性;a. 括号外数据为各基因型的例数,括号内数据为各基因型的例数分别占病例组和对照组例数的百分比(%);b. 非条件logistic回归分析,并根据性别、年龄、饮酒和吸烟状况进行校正 表 3 基因C7 rs1061429和rs1376178遗传变异与直肠癌易感性关系
Table 3. Relationship between genetic variation of C7 rs1061429 and rs1376178 and susceptibility to rectal cancer
SNP位点 基因型 病例组a 对照组a OR 值(95%CI)b P值 rs1061429 CC 203(44.13) 240(52.17) 1.00(参照) CA 220(47.83) 183(39.78) 1.42(1.08~1.86) 0.011 AA 37(8.04) 37(8.05) 1.18(0.72~1.94) 0.505 rs1376178 CC 90(19.57) 123(26.74) 1.00(参照) CA 240(52.17) 224(48.70) 1.46(1.06~2.03) 0.022 AA 130(28.26) 113(24.56) 1.57(1.09~2.28) 0.017 注:SNP. 单核苷酸多态;a. 括号外数据为各基因型的例数,括号内数据为各基因型的例数分别占病例组和对照组例数的百分比(%);b. 非条件logistic回归分析,并根据性别、年龄、饮酒和吸烟状况进行校正 表 4 基因C7 rs1376178遗传变异与结肠癌发病风险关系分层分析
Table 4. Stratified analysis on relationship between genetic variation of C7 rs1376178 and risk of colon cancer
变量 不同基因型病例组/对照组例数 CA/CCOR值(95 %CI)a P值 AA/CCOR值(95 %CI)a P值 CC CA AA 性别 男性 57/61 122/107 42/54 1.21 (0.77~1.89) 0.407 0.83 (0.48~1.43) 0.498 女性 31/52 98/82 49/43 2.01 (1.18~3.43) 0.010 1.90 (1.03~3.48) 0.040 年龄组(岁) ≤60 42/58 97/97 51/49 1.37 (0.84~2.23) 0.208 1.40 (0.80~2.45) 0.245 >60 46/55 123/92 40/48 1.58 (0.98~2.55) 0.063 0.98 (0.55~1.76) 0.955 吸烟 是 27/28 51/52 15/17 0.94 (0.48~1.83) 0.848 0.91 (0.38~2.21) 0.836 否 61/85 169/137 76/80 1.70 (1.14~2.54) 0.009 1.31 (0.83~2.08) 0.241 饮酒 是 23/26 51/48 16/14 1.06 (0.52~2.14) 0.872 1.26 (0.50~3.16) 0.625 否 65/87 169/141 75/83 1.57 (1.06~2.33) 0.024 1.18 (0.75~1.85) 0.484 注:a. 非条件logistic回归,并根据性别、年龄、饮酒和吸烟状况进行校正 表 5 基因C7 rs1061429遗传变异与直肠癌发病风险关系分层分析
Table 5. Stratified analysis on relationship between genetic variation of C7 rs1061429 and risk of rectal cancer
变量 不同基因型病例组/对照组例数 CA/CCOR值(95 %CI)a P值 AA/CCOR值(95 %CI)a P值 CC CA AA 性别 男性 123/160 143/112 21/18 1.64 (1.17~2.31) 0.005 1.43 (0.72~2.82) 0.303 女性 80/80 77/71 16/19 1.00 (0.63~1.58) 0.986 0.87 (0.41~1.83) 0.705 年龄组(岁) ≤60 104/129 110/89 18/17 1.58 (1.07~2.33) 0.021 1.22 (0.59~2.51) 0.590 >60 99/111 110/94 19/20 1.28 (0.86~1.89) 0.221 1.20 (0.60~2.41) 0.601 吸烟 是 53/68 65/52 3/9 1.62 (0.96~2.76) 0.073 0.35 (0.08~1.42) 0.141 否 150/172 155/131 34/28 1.35 (0.98~1.87) 0.065 1.48 (0.85~2.56) 0.164 饮酒 是 66/74 81/59 3/7 1.37 (0.84~2.25) 0.212 0.40 (0.09~1.74) 0.221 否 137/166 139/124 34/30 1.36 (0.98~1.90) 0.069 1.41 (0.82~2.42) 0.219 注:a. 非条件logistic回归,并根据性别、年龄、饮酒和吸烟状况进行校正 表 6 基因C7 rs1376178遗传变异与直肠癌发病风险关系分层分析
Table 6. Stratified analysis on relationship between genetic variation of C7 rs1376178 and risk of rectal cancer
变量 不同基因型病例组/对照组例数 CA/CCOR值(95 %CI)a P值 AA/CCOR值(95 %CI)a P值 CC CA AA 性别 男性 57/74 155/148 75/68 1.39 (0.92~2.10) 0.123 1.44 (0.89~2.32) 0.140 女性 33/49 85/76 55/45 1.66 (0.95~2.89) 0.075 1.93 (1.05~3.54) 0.035 年龄组(岁) ≤60 39/66 122/116 71/53 1.86 (1.15~3.01) 0.011 2.23 (1.30~3.83) 0.004 >60 51/57 118/108 59/60 1.18 (0.74~1.88) 0.483 1.14 (0.67~1.93) 0.630 吸烟 是 25/32 72/70 24/27 1.32 (0.70~2.49) 0.393 1.14 (0.52~2.49) 0.736 否 65/91 168/154 106/86 1.55 (1.05~2.28) 0.029 1.80 (1.17~2.76) 0.008 饮酒 是 33/39 82/74 35/27 1.27 (0.70~2.29) 0.429 1.58 (0.77~3.24) 0.217 否 57/84 158/150 95/86 1.51 (1.00~2.26) 0.048 1.62 (1.04~2.53) 0.035 注:a. 非条件logistic回归,并根据性别、年龄、饮酒和吸烟状况进行校正 -
[1] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209–249. DOI: 10.3322/caac.21660. [2] Cao W, Chen HD, Yu YW, et al. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020[J]. Chin Med J (Engl), 2021, 134(7): 783–791. DOI: 10.1097/cm9.0000000000001474. [3] Roumenina LT, Daugan MV, Petitprez F, et al. Context-dependent roles of complement in cancer[J]. Nat Rev Cancer, 2019, 19(12): 698–715. DOI: 10.1038/s41568−019−0210−0. [4] Afshar-Kharghan V. The role of the complement system in cancer[J]. J Clin Invest, 2017, 127(3): 780–789. DOI: 10.1172/jci90962. [5] 桑楠, 张会爱, 葛献, 等. 补体C7在结直肠癌组织中的表达及其对结肠癌细胞株增殖的影响[J]. 胃肠病学和肝病学杂志,2018,27(12):1377–1382. DOI:10.3969/j.issn.1006−5709.2018.12.011.Sang N, Zhang HA, Ge X, et al. Expression of complement C7 in colorectal cancer and its effect on the proliferation of colorectal cancer cell lines[J]. Chin J Gastroenterol Hepatol, 2018, 27(12): 1377–1382. DOI: 10.3969/j.issn.1006−5709.2018.12.011. [6] Hajibabaie F, Abedpoor N, Assareh N, et al. The importance of SNPs at miRNA binding sites as biomarkers of gastric and colorectal cancers: a systematic review[J]. J Pers Med, 2022, 12(3): 456. DOI: 10.3390/jpm12030456. [7] Yu XF, Rao J, Lin J, et al. Tag SNPs in complement receptor-1 contribute to the susceptibility to non-small cell lung cancer[J]. Mol Cancer, 2014, 13: 56. DOI: 10.1186/1476−4598−13−56. [8] Song QQ, Zhang Z, Liu YW, et al. The tag SNP rs10746463 in decay-accelerating factor is associated with the susceptibility to gastric cancer[J]. Mol Immunol, 2015, 63(2): 473–478. DOI: 10.1016/j.molimm.2014.10.006. [9] 金敏, 仵红娇, 付宁, 等. DAF rs150046210遗传变异与老年结直肠癌易感性关系研究[J]. 实用老年医学,2021,35(11):1144–1148. DOI:10.3969/j.issn.1003−9198.2021.11.010.Jin M, Wu HJ, Fu N, et al. Genetic variation of DAF rs150046210 affects the risk of colorectal cancer in the elderly[J]. Pract Geriatr, 2021, 35(11): 1144–1148. DOI: 10.3969/j.issn.1003−9198.2021.11.010. [10] 付宁, 仵红娇, 谢俞宁, 等. CD55启动子区多态性与直肠癌发病风险的研究[J]. 实用医学杂志,2019,35(18):2886–2890. DOI:10.3969/j.issn.1006−5725.2019.18.012.Fu N, Wu HJ, Xie YN, et al. Genetic variation in the promoter region of CD55 affects the risk of rectal cancer[J]. J Pract Med, 2019, 35(18): 2886–2890. DOI: 10.3969/j.issn.1006−5725.2019.18.012. [11] Wang SY, Hu WQ, Xie YN, et al. Functional genetic variants in complement component 7 confer susceptibility to gastric cancer[J]. PeerJ, 2022, 10: e12816. DOI: 10.7717/peerj.12816. [12] 李昂. Toll样受体基因遗传变异与结直肠癌易感性关系[D]. 唐山: 华北理工大学, 2020. DOI: 10.27108/d.cnki.ghelu.2020.000389.Li A. Association of genetic variants of toll like receptor key genes with colorectal cancer risk[D]. Tangshan: North China University of Science and Technology, 2020. DOI: 10.27108/d.cnki.ghelu.2020.000389. [13] Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(12): 713–732. DOI: 10.1038/s41575−019−0189−8. [14] Geller A, Yan J. The role of membrane bound complement regulatory proteins in tumor development and cancer immunotherapy[J]. Front Immunol, 2019, 10: 1074. DOI: 10.3389/fimmu.2019.01074. [15] Roumenina LT, Daugan MV, Noé R, et al. Tumor cells hijack macrophage-produced complement C1q to promote tumor growth[J]. Cancer Immunol Res, 2019, 7(7): 1091–1105. DOI: 10.1158/2326−6066.Cir−18−0891. [16] Ying LS, Zhang FR, Pan XD, et al. Complement component 7 (C7), a potential tumor suppressor, is correlated with tumor progression and prognosis[J]. Oncotarget, 2016, 7(52): 86536–86546. DOI: 10.18632/oncotarget.13294. [17] Reis ES, Mastellos DC, Ricklin D, et al. Complement in cancer: untangling an intricate relationship[J]. Nat Rev Immunol, 2018, 18(1): 5–18. DOI: 10.1038/nri.2017.97. [18] Ning G, Huang YL, Zhen LM, et al. Prognostic value of complement component 2 and its correlation with immune infiltrates in hepatocellular carcinoma[J]. Biomed Res Int, 2020, 2020: 3765937. DOI: 10.1155/2020/3765937. [19] Jeon J, Du MM, Schoen RE, et al. Determining risk of colorectal cancer and starting age of screening based on lifestyle, environmental, and genetic factors[J]. Gastroenterology, 2018, 154(8): 2152–2164.e19. DOI: 10.1053/j.gastro.2018.02.021. [20] Kim SE, Paik HY, Yoon H, et al. Sex- and gender-specific disparities in colorectal cancer risk[J]. World J Gastroenterol, 2015, 21(17): 5167–5175. DOI: 10.3748/wjg.v21.i17.5167. [21] Archambault AN, Jeon J, Lin Y, et al. Risk stratification for early-onset colorectal cancer using a combination of genetic and environmental risk scores: an international multi-center study[J]. J Natl Cancer Inst, 2022, 114(4): 528–539. DOI: 10.1093/jnci/djac003. [22] Botteri E, Borroni E, Sloan EK, et al. Smoking and colorectal cancer risk, overall and by molecular subtypes: a meta-analysis[J]. Am J Gastroenterol, 2020, 115(12): 1940–1949. DOI: 10.14309/ajg.0000000000000803. -