切换至 "中华医学电子期刊资源库"
高级检索
中华结直肠疾病电子杂志

中华结直肠疾病电子杂志 ›› 2019, Vol. 08 ›› Issue (04) : 363 -369. doi: 10.3877/cma.j.issn.2095-3224.2019.04.008

所属专题： 文献；

论著

基于COSMIC数据库的结直肠转移性癌的体细胞突变基因变化的研究
康争春1, 鄂继福1,†(), 朱良亮1, 闫飞虎1, 于恩达1,†()   
  1. 1. 200433　上海，海军军医大学附属长海医院肛肠外科
  • 收稿日期:2018-10-23 出版日期:2019-08-25
  • 通信作者: 鄂继福, 于恩达
  • 基金资助:
    上海市科学技术委员会基础研究重大重点项目(No.13JC1407201); 国家重点基础研究发展计划(973计划；No.2015CB554001); 第二军医大学精准医学转化应用研究专项项目(No.2017JZ19); 国家自然科学基金青年科学基金项目(No.81802434)

Study on the changes of somatic mutation in colorectal metastatic cancer based on COSMIC database

Zhengchun Kang1, Jifu E1,†(), Liangliang Zhu1, Feihu Yan1, Enda Yu1,†()   

  1. 1. Department of Colorectal Surgery, Changhai Hospital, PLA Navy Medical Uneversity, Shanghai 200433, China
  • Received:2018-10-23 Published:2019-08-25
  • Corresponding author: Jifu E, Enda Yu
  • About author:
    Corresponding author: E Jifu, Email:
    Yu Enda, Email:
全文 ( ) 下载PDF ( ) 导出引用
引用本文：

康争春, 鄂继福, 朱良亮, 闫飞虎, 于恩达. 基于COSMIC数据库的结直肠转移性癌的体细胞突变基因变化的研究[J/OL]. 中华结直肠疾病电子杂志, 2019, 08(04): 363-369.

Zhengchun Kang, Jifu E, Liangliang Zhu, Feihu Yan, Enda Yu. Study on the changes of somatic mutation in colorectal metastatic cancer based on COSMIC database[J/OL]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2019, 08(04): 363-369.

目的

利用癌症体细胞突变目录（COSMIC）数据库，筛选结直肠原发性癌和结直肠转移性癌两类癌组织之间的具有显著差异的体细胞基因突变，并分析其可能的功能及通路。

方法

从COSMIC数据库下载结直肠癌全外显子测序数据，在R 3.5.0环境下，利用卡方检验或Fisher确切概率法对结直肠原发性癌和结直肠转移性癌两类癌组织之间的差异体细胞突变基因进行挖掘，记录具有显著差异的体细胞突变基因并进行功能及通路富集分析，探索其可能生物学功能及通路。

结果

共发现120个具有显著差异的体细胞突变基因，包括RHEB、RP11-368J21.2、AGAP10等，对其进行GO和KEGG富集分析显示，这些显著性差异体细胞突变基因可能与如脱氢酶活性、还原酶活性、细胞周期停滞、代谢途径、PI3K-Akt信号通路、细胞周期、细胞粘附分子、癌症中的转录失调、铂类耐药性等功能及通路相关。

结论

挖掘结直肠原发性癌和结直肠转移性癌之间的显著差异体细胞突变基因可为研究结直肠癌的转移调控机制提供借鉴，显著差异体细胞突变基因可能作为结直肠癌转移诊断标志物或转移治疗靶点应用于临床。

关键词: 结直肠肿瘤, 体细胞突变基因, 转移性结直肠癌
Objective

To screen the significant differences in somatic gene mutations between primary colorectal cancer and colorectal metastatic cancer using the Catalogue of Somatic Mutations In Cancer Catalog (COSMIC) Database and analyze its possible functions and pathways.

Methods

The colorectal cancer whole-exome sequencing data was downloaded from the COSMIC database. In the R 3.5.0 environment, the chi-square test or Fisher′ exact test was used to analysis the primary colorectal cancer and colorectal metastatic cancer. The differences in somatic mutation genes were mined, and somatically mutated genes with significant differences were recorded and functional and pathway enrichment analysis was performed to explore their possible biological functions and pathways.

Results

A total of 120 somatic mutations, including RHEB, RP11-368J21.2, AGAP10, etc, were found. The GO and KEGG enrichment analysis showed that these significant differences in somatic mutations may be related to dehydrogenase activity, reductase activity, cell cycle arrest, metabolic pathway, PI3K-Akt signaling pathway, cell cycle, cell adhesion molecules, transcriptional disorders in cancer, platinum resistance, and other functions and pathways.

Conclusion

The significant difference in somatic mutation between primary colorectal cancer and colorectal metastatic cancer can provide a reference for studying the metastasis mechanism of colorectal cancer. Significant differences in somatic mutations may be used as clinical diagnostic markers for metastatic colorectal cancer or as targets for metastasis therapy.

Key words: Colorectal neoplasms, Somatic mutation, Metastatic colorectal cancer
表1 突变率top30的基因位点
CosmicId 突变 基因 样本数目 突变率
COSM476 c.1799T>A BRAF 234 0.100300043
COSM521 c.35G>A KRAS 181 0.077582512
COSM532 c.38G>A KRAS 131 0.056150879
COSM520 c.35G>T KRAS 129 0.055293613
COSM10648 c.524G>A TP53 115 0.049292756
COSM252949 c.1303delA ACVR2A 92 0.039434205
COSM763 c.1633G>A PIK3CA 91 0.039005572
COSM270052 c.1976delG RNF43 88 0.037719674
COSM13127 c.4348C>T APC 86 0.036862409
COSM18852 c.2626C>T APC 77 0.033004715
COSM1180896 c.1742delA BMPR2 70 0.030004286
COSM2851820 c.5549delC DOCK3 69 0.029575654
COSM179404 c.44delA RPL22 68 0.029147021
COSM927946 c.526T>C TRIM48 62 0.026575225
COSM1384188 c.1578delC XYLT2 59 0.025289327
COSM10659 c.817C>T TP53 59 0.025289327
COSM10660 c.818G>A TP53 58 0.024860694
COSM775 c.3140A>G PIK3CA 54 0.023146164
COSM760 c.1624G>A PIK3CA 54 0.023146164
COSM10704 c.844C>T TP53 53 0.022717531
COSM329668 c.542＋8_549del30 IRF5 50 0.021431633
COSM516 c.34G>T KRAS 50 0.021431633
COSM19695 c.4660_4661insA APC 50 0.021431633
COSM1458728 c.1528delA ESRP1 49 0.021003
COSM269905 c.982delG PLEKHA6 49 0.021003
COSM10656 c.742C>T TP53 47 0.020145735
COSM13134 c.637C>T APC 46 0.019717102
COSM1440465 c.163delA AKAP7 43 0.018431204
COSM10662 c.743G>A TP53 43 0.018431204
COSM19404 c.436G>A KRAS 42 0.018002572
表2 结直肠原发性癌和结直肠转移性癌top30差异突变基因结果
基因 结直肠原发性癌突变率 结直肠转移性癌突变率 χ2值 P值
RHEB 0.00286123 0.086206897 32.01980399 1.53×10-08
RP11-368J21.2 0.001430615 0.068965517 27.64667 1.46×10-07
AGAP10 0 0.051724138 24.37795003 7.92×10-07
PRKRIR 0.00286123 0.068965517 21.94934078 2.80×10-06
NMRAL1 0.004291845 0.068965517 17.90125811 2.33×10-05
QPCT 0.001430615 0.051724138 17.09281147 3.56×10-05
TOMM40 0.001430615 0.051724138 17.09281147 3.56×10-05
PYCR2 0.001430615 0.051724138 17.09281147 3.56×10-05
SLC18A1 0.010014306 0.086206897 15.34447432 8.96×10-05
KDR 0.038626609 0.155172414 13.59040229 0.000227345
HSD17B4 0.011444921 0.086206897 13.58267182 0.000228283
ENSG00000188912 0 0.034482759 12.85251807 0.000337025
HIST2H3D 0 0.034482759 12.85251807 0.000337025
RGPD1 0 0.034482759 12.85251807 0.000337025
MORF4L1 0 0.034482759 12.85251807 0.000337025
CSTL1 0 0.034482759 12.85251807 0.000337025
MANSC1 0 0.034482759 12.85251807 0.000337025
CDK7 0 0.034482759 12.85251807 0.000337025
AHSA1 0 0.034482759 12.85251807 0.000337025
TRAPPC6B 0 0.034482759 12.85251807 0.000337025
DGCR6L 0 0.034482759 12.85251807 0.000337025
C17orf77 0.00286123 0.051724138 12.75260599 0.000355513
NPIP 0.00286123 0.051724138 12.75260599 0.000355513
ANAPC1 0.025751073 0.120689655 12.28920299 0.000455586
RASA4 0.008583691 0.068965517 10.70535245 0.00106826
LLPH 0.008583691 0.068965517 10.70535245 0.00106826
OR5B3 0.008583691 0.068965517 10.70535245 0.00106826
PRB2 0.008583691 0.068965517 10.70535245 0.00106826
IPMK 0.008583691 0.068965517 10.70535245 0.00106826
ESCO2 0.008583691 0.068965517 10.70535245 0.00106826
图1 差异基因突变位点的manhattan图（横坐标代表染色体位置，纵坐标代表-log10 p，红线代表P值等于0.05）
表3 结直肠原发性癌和结直肠转移性癌top30差异突变基因位点结果
基因位点 结直肠原发性癌突变率 结直肠转移性癌突变率 χ2值 P值
RHEB|COSM5757012|c.169C>T 0 0.086206897 48.23220622 3.79×10-12
AOC3|COSM5755045|c.1634T>C 0 0.068965517 36.23003121 1.75×10-09
NMRAL1|COSM148011|c.755C>T 0 0.068965517 36.23003121 1.75×10-09
IPMK|COSM5753509|c.1096T>G 0 0.068965517 36.23003121 1.75×10-09
ESCO2|COSM150477|c.239C>T 0 0.068965517 36.23003121 1.75×10-09
TRPV2|COSM148200|c.50G>C 0 0.068965517 36.23003121 1.75×10-09
U2SURP|COSM5756177|c.769G>C 0 0.068965517 36.23003121 1.75×10-09
GCOM1|COSM147926|c.830C>T 0 0.051724138 24.37795003 7.92×10-07
AGAP10|COSM415019|c.683A>G 0 0.051724138 24.37795003 7.92×10-07
SACM1L|COSM149368|c.1301A>T 0 0.051724138 24.37795003 7.92×10-07
HMMR|COSM150009|c.1103T>C 0 0.051724138 24.37795003 7.92×10-07
PTCH2|COSM1162381|c.2963C>T 0 0.051724138 24.37795003 7.92×10-07
FSIP1|COSM147876|c.1583G>C 0 0.051724138 24.37795003 7.92×10-07
IL7R|COSM132904|c.731C>T 0 0.051724138 24.37795003 7.92×10-07
ARHGEF37|COSM149984|c.1388C>T 0 0.051724138 24.37795003 7.92×10-07
MUC7|COSM249589|c.746T>C 0 0.051724138 24.37795003 7.92×10-07
SPATA6|COSM146506|c.1433G>A 0 0.051724138 24.37795003 7.92×10-07
HSD17B4|COSM1130959|c.1675A>G 0 0.051724138 24.37795003 7.92×10-07
CD300LD|COSM148338|c.265G>A 0 0.051724138 24.37795003 7.92×10-07
SYCE1|COSM147098|c.288G>T 0 0.051724138 24.37795003 7.92×10-07
P2RX7|COSM147626|c.809G>A 0 0.051724138 24.37795003 7.92×10-07
PKD1|COSM5754804|c.6779T>C 0 0.051724138 24.37795003 7.92×10-07
C17orf77|COSM148339|c.593C>T 0 0.051724138 24.37795003 7.92×10-07
MRGPRX2|COSM147163|c.185A>G 0 0.051724138 24.37795003 7.92×10-07
OR5B3|COSM147247|c.541G>A 0 0.051724138 24.37795003 7.92×10-07
INADL|COSM1126971|c.1198A>G 0 0.051724138 24.37795003 7.92×10-07
OR10G4|COSM147352|c.883A>C 0 0.051724138 24.37795003 7.92×10-07
MYH4|COSM148193|c.2648C>T 0 0.051724138 24.37795003 7.92×10-07
ALOX15B|COSM148187|c.2026A>G 0 0.051724138 24.37795003 7.92×10-07
OR5B3|COSM147248|c.509A>G 0 0.051724138 24.37795003 7.92×10-07
图2 GO功能富集结果
图3 KEGG通路富集结果
[1]
Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015 [J]. CA Cancer J Clin, 2016, 66(2): 115-132.
[2]
De Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients [J]. Ann Surg, 2009, 250(3): 440-448.
[3]
Lin SH, Raju GS, Huff C, et al. The somatic mutation landscape of premalignant colorectal adenoma [J]. Gut, 2018, 67(7): 1299-1305.
[4]
Ling C, Wang L, Wang Z, et al. A pathway-centric survey of somatic mutations in chinese patients with colorectal carcinomas [J]. PloS One, 2015, 10(1): e0116753.
[5]
Karagkounis G, Torbenson MS, Daniel HD, et al. Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases [J]. Cancer, 2013, 119(23): 4137-4144.
[6]
Russo AL, Borger DR, Szymonifka J, et al. Mutational analysis and clinical correlation of metastatic colorectal cancer [J]. Cancer, 2014, 120(10): 1482-1490.
[7]
Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer [J]. Cancer, 2011, 117(20): 4623-4632.
[8]
Tie J, Lipton L, Desai J, et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer [J]. Clinical Cancer Research An Official Journal of the American Association for Cancer Research, 2011, 17(5): 1122-1130.
[9]
Payandeh M, Sadeghi M, Sadeghi E. The report of KRAS mutation and NRAS wild type in a patient with thyroid metastasis from colon cancer: a rare case report [J]. Iran J Pathol, 2016, 11(1): 71-75.
[10]
Yaeger R, Cowell E, Chou JF, et al. RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer[J]. Cancer, 2015, 121(8): 1195-1203.
[11]
Forbes SA, Bindal N, Bamford S, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer [J]. Nucleic Acids Research, 2011, 39(Database issue): 945-950.
[12]
Liu X, Wang J, Chen L. Whole-exome sequencing reveals recurrent somatic mutation networks in cancer [J]. Cancer Letters, 2013, 340(2): 270-276.
[13]
Zhang D, Li Z, Xu X, et al. Deletions at SLC18A1 increased the risk of CRC and lower SLC18A1 expression associated with poor CRC outcome [J]. Carcinogenesis, 2017, 38(11): 1057-1062.
[14]
Arturo LB, Jensen CE, Stuti S, et al. KDR Mutation as a novel predictive biomarker of exceptional response to regorafenib in metastatic colorectal cancer [J]. Cureus, 2016, 8(2): e478.
[15]
Toiyama Y, Okugawa Y, Goel A. DNA methylation and microRNA biomarkers for noninvasive detection of gastric and colorectal cancer [J]. Biochemical & Biophysical Research Communications, 2014, 455(1-2): 43-57.
[1] 罗青杉, 梅海涛, 郝家领, 蔡锦锋, 周润楷, 温玉刚. 连接蛋白43通过调控细胞周期抑制结直肠癌的增殖机制研究[J/OL]. 中华普通外科学文献(电子版), 2024, 18(05): 344-349.
[2] 徐逸男. 不同术式治疗梗阻性左半结直肠癌的疗效观察[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 72-75.
[3] 谢丽春, 欧庆芬, 张秋萍, 叶升. 简化和标准肝脏MRI方案在结直肠癌肝转移患者随访中的临床应用[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(04): 434-437.
[4] 施烨鑫, 马翔, 鲁明, 夏青城, 王鹏超, 宋青雨, 赵庆洪. 腹腔镜下结直肠肿瘤定位研究进展[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(04): 463-466.
[5] 严虹霞, 王晓娟, 张毅勋. 2 型糖尿病对结直肠癌患者肿瘤标记物、临床病理及预后的影响[J/OL]. 中华结直肠疾病电子杂志, 2024, 13(06): 483-487.
[6] 赵磊, 刘文志, 林峰, 于剑, 孙铭骏, 崔佑刚, 张旭, 衣宇鹏, 于宝胜, 冯宁. 深部热疗在改善结直肠癌术后辅助化疗副反应及生活质量中的作用研究[J/OL]. 中华结直肠疾病电子杂志, 2024, 13(06): 488-493.
[7] 黄海洋, 邝永龙, 陈嘉胜. 基层医院结直肠肿瘤经自然腔道取标本手术30 例分析[J/OL]. 中华结直肠疾病电子杂志, 2024, 13(06): 510-518.
[8] 韩加刚, 王振军. 梗阻性左半结肠癌的治疗策略[J/OL]. 中华结直肠疾病电子杂志, 2024, 13(06): 450-458.
[9] 梁轩豪, 李小荣, 李亮, 林昌伟. 肠梗阻支架置入术联合新辅助化疗治疗结直肠癌急性肠梗阻的疗效及其预后的Meta 分析[J/OL]. 中华结直肠疾病电子杂志, 2024, 13(06): 472-482.
[10] 任佳琪, 刁德昌, 何自衍, 张雪阳, 唐新, 李文娟, 李洪明, 卢新泉, 易小江. 网膜融合线导向的脾曲游离技术在左半结肠癌根治术中的应用[J/OL]. 中华结直肠疾病电子杂志, 2024, 13(05): 362-367.
[11] 张迪, 王春霞, 张学东, 李发馨, 庞淅文, 陈一锋, 张维胜, 王涛. 梗阻性左半结直肠癌自膨式金属支架置入后行腹腔镜手术与开腹手术的短期临床疗效比较[J/OL]. 中华结直肠疾病电子杂志, 2024, 13(05): 375-380.
[12] 张蔚林, 王哲学, 白峻阁, 黄忠诚, 肖志刚. 利用TCGA数据库构建基于miRNA的结直肠癌列线图预后模型[J/OL]. 中华结直肠疾病电子杂志, 2024, 13(05): 381-388.
[13] 张伟伟, 陈启, 翁和语, 黄亮. 随机森林模型预测T1 期结直肠癌淋巴结转移的初步研究[J/OL]. 中华结直肠疾病电子杂志, 2024, 13(05): 389-393.
[14] 季鹏程, 鄂一民, 陆晨, 喻春钊. 循环外泌体相关生物标志物在结直肠癌诊断中的研究进展[J/OL]. 中华结直肠疾病电子杂志, 2024, 13(04): 265-273.
[15] 李佳莹, 王旭丹, 梁雪, 张雷, 李佳英. 1990~2021年中国结直肠癌死亡趋势分析[J/OL]. 中华结直肠疾病电子杂志, 2024, 13(04): 274-279.
阅读次数
全文


摘要

版权所有 中华医学会 中华医学电子音像出版社有限责任公司  京ICP备14006079号-1  网络出版服务许可证：(署)网出证(京)字第075号