Construction of immune related gene risk markers for prognosis of colon cancer and its prediction of prognosis in colon cancer patients_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

REN Jun ¹ , FENG Juan ² , SONG Wei ¹ , WU Jing ¹ , JIN Tianli ¹ ,  FU Tao ¹

1. Department of Gastrointestinal Surgery Ⅱ, Renmin Hospital of Wuhan University, Wuhan 430060, P. R. China;
2. Department of Breast Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, P. R. China;

Corresponding author：

FU Tao, Email: tfu001@whu.edu.cn

Keywords：

colon cancer; immune related gene; prognosis

DOI：

10.7507/1007-9424.202103004

Video：

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Objective To develop an immune-related genes (IRGs) based prognostic signature and evaluate the value in predicting prognosis in patients with colon cancer.Methods Gene chip data sets of 452 colon cancer patients were collected from the TCGA database, and 2 498 IRGs data sets were obtained from the ImmPort database. After taking the intersection, univariate and multivariate Cox proportional hazards regression analysis were used to screen and construct the IRGs gene model. To evaluate the prognostic value of genetic models, Cox proportional hazards regression was used to analyze the correlation between IRGs model/clinicopathological features with prognosis of colon cancer. The relationship between risk score and immune cell infiltration was analyzed too.Results A total of 206 differentially expressed IRGs were identified in colon cancer tissues, and 11 kinds of IRGs were identified by univariate and multivariate Cox proportional hazards regression analysis: solute carrier family 10 member 2 (SLC10A2), C-X-C motif chemokine ligand 5 (CXCL5), C-C motif chemokine ligand 28 (CCL28), immunoglobulin kappa variable 1D-42 (IGKV1D-42), chromogranin A (CHGA), endothelial cell specific molecule 1 (ESM1), gastrin releasing peptide (GRP), stanniocalcin 2 (STC2), urocortin (UCN), oxytocin receptor (OXTR) and immunoglobulin heavy constant gamma 1 (IGHG1). Colon cancer patients were divided into high risk group and low risk group according to the median value of risk value of IRGs risk markers. Patients in the high risk group had shorter overall survival (OS) than that in the low risk group (P<0.001). The area of the time-dependent ROC curve (AUC) was 0.754, suggesting that IRGs model had a good ability to predict the prognosis of colon cancer patients. The higher the risk value of IRGs, the later T stage of colon cancer (T3–T4), the more lymph node metastasis (N1–N2) and the later clinical stage of colon cancer (Ⅲ–Ⅳ), P<0.05. Except for neutrophils, the infiltration density of B cells, CD4⁺ T cells, CD8⁺ T cells, dendritic cells and macrophages were significantly increased with the increased of the risk value (P<0.05).Conclusion The risk values of the 11 kinds of IRGs gene models screened in this study can be used to predict the prognosis of colon cancer patients, and can be used as biomarkers to evaluate the prognosis of colon cancer patients.

Citation： REN Jun, FENG Juan, SONG Wei, WU Jing, JIN Tianli, FU Tao. Construction of immune related gene risk markers for prognosis of colon cancer and its prediction of prognosis in colon cancer patients. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(11): 1469-1476. doi: 10.7507/1007-9424.202103004 Copy

1.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2.	Guo L, Wang C, Qiu X, et al. Colorectal cancer immune infiltrates: significance in patient prognosis and immunotherapeutic efficacy. Front Immunol, 2020, 11: 1052.
3.	Fan XJ, Wan XB, Fu XH, et al. Phosphorylated p38, a negative prognostic biomarker, complements TNM staging prognostication in colorectal cancer. Tumour Biol, 2014, 35(10): 10487-10495.
4.	Fridman WH, Zitvogel L, Sautès-Fridman C, et al. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol, 2017, 14(12): 717-734.
5.	Bhattacharya S, Andorf S, Gomes L, et al. ImmPort: disseminating data to the public for the future of immunology. Immunol Res, 2014, 58(2-3): 234-239.
6.	Kamarudin AN, Cox T, Kolamunnage-Dona R. Time-dependent ROC curve analysis in medical research: current methods and applications. BMC Med Res Methodol, 2017, 17(1): 53.
7.	Wolbers M, Koller MT, Witteman JC, et al. Prognostic models with competing risks: methods and applicationto coronary risk prediction. Epidemiology, 2009, 20(4): 555-561.
8.	Li T, Fan J, Wang B, et al. TIMER: A web server for compre-hensive analysis of tumor-infiltrating immune cells. Cancer Res, 2017, 77(21): e108-e110.
9.	Lin A, Zhang J, Luo P. Crosstalk between the MSI status and tumor microenvironment in colorectal cancer. Front Immunol, 2020, 11: 2039.
10.	Wang Z, Song Q, Yang Z, et al. Construction of immune-related risk signature for renal papillary cell carcinoma. Cancer Med, 2019, 8(1): 289-304.
11.	Song Q, Shang J, Yang Z, et al. Identification of an immune signature predicting prognosis risk of patients in lung adenocarcinoma. J Transl Med, 2019, 17(1): 70.
12.	Hu D, Zhou M, Zhu X. Deciphering immune-associated genes to predict survival in clear cell renal cell cancer. Biomed Res Int, 2019, 2019: 2506843.
13.	Qiu H, Hu X, He C, et al. Identification and validation of an individualized prognostic signature of bladder cancer based on seven immune related genes. Front Genet, 2020, 11: 12.
14.	Jin H, Rugira T, Ko YS, et al. ESM-1 overexpression is involved in increased tumorigenesis of radiotherapy-resistant breast cancer cells. Cancers (Basel), 2020, 12(6): 1363.
15.	Kano K, Sakamaki K, Oue N, et al. Impact of the ESM-1 gene expression on outcomes in stage Ⅱ/Ⅲ gastric cancer patients who received adjuvant S-1 chemotherapy. In Vivo, 2020, 34(1): 461-467.
16.	Kim JH, Park MY, Kim CN, et al. Expression of endothelial cell-specific molecule-1 regulated by hypoxia inducible factor-1α in human colon carcinoma: impact of ESM-1 on prognosis and its correlation with clinicopathological features. Oncol Rep, 2012, 28(5): 1701-1708.
17.	Kang YH, Ji NY, Han SR, et al. ESM-1 regulates cell growth and metastatic process through activation of NF-κB in colorectal cancer. Cell Signal, 2012, 24(10): 1940-1949.
18.	Yildirim K, Colak E, Aktimur R, et al. Clinical value of CXCL5 for determining of colorectal cancer. Asian Pac J Cancer Prev, 2018, 19(9): 2481-2484.
19.	Zhang W, Wang H, Sun M, et al. CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target. Cancer Commun (Lond), 2020, 40(2-3): 69-80.
20.	Hu B, Fan H, Lv X, et al. Prognostic significance of CXCL5 expression in cancer patients: a meta-analysis. Cancer Cell Int, 2018, 18: 68.
21.	Zhang Y, Zheng S, Liao N, et al. CircCTNNA1 acts as a ceRNA for miR-363-3p to facilitate the progression of colorectal cancer by promoting CXCL5 expression. J Biol Res (Thessalon), 2021, 28(1): 7.
22.	Chen C, Xu ZQ, Zong YP, et al. CXCL5 induces tumor angiogenesis via enhancing the expression of FOXD1 mediated by the AKT/NF-κB pathway in colorectal cancer. Cell Death Dis, 2019, 10(3): 178.
23.	Zhao J, Ou B, Han D, et al. Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways. Mol Cancer, 2017, 16(1): 70.
24.	Novillo A, Gaibar M, Romero-Lorca A, et al. Efficacy of bevacizumab-containing chemotherapy in metastatic colorectal cancer and CXCL5 expression: Six case reports. World J Gastroenterol, 2020, 26(16): 1979-1986.
25.	Ieta K, Tanaka F, Yokobori T, et al. Clinicopathological significance of stanniocalcin 2 gene expression in colorectal cancer. Int J Cancer, 2009, 125(4): 926-931.
26.	Yang XL, Liu KY, Lin FJ, et al. CCL28 promotes breast cancer growth and metastasis through MAPK-mediated cellular anti-apoptosis and pro-metastasis. Oncol Rep, 2017, 38(3): 1393-1401.
27.	Dimberg J, Hugander A, Wågsäter D. Protein expression of the chemokine, CCL28, in human colorectal cancer. Int J Oncol, 2006, 28(2): 315-319.
28.	Miao Y, Wang J, Ma X, et al. Identification prognosis-associated immune genes in colon adenocarcinoma. Biosci Rep, 2020, 40(11): BSR20201734.
29.	Raufman JP, Dawson PA, Rao A, et al. Slc10a2-null mice uncover colon cancer-promoting actions of endogenous fecal bile acids. Carcinogenesis, 2015, 36(10): 1193-1200.
30.	Li Y, Wang P, Ye D, et al. IGHG1 induces EMT in gastric cancer cells by regulating TGF-β/SMAD3 signaling pathway. J Cancer, 2021, 12(12): 3458-3467.
31.	Michele S, Mariachiara B, Emanuela P, et al. UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response. Oncotarget, 2016, 7(28): 44113-44128.
32.	Kikuchi T, Mimura K, Ashizawa M, et al. Characterization of tumor-infiltrating immune cells in relation to microbiota in colorectal cancers. Cancer Immunol Immunother, 2020, 69(1): 23-32.
33.	Fan CW, Kopsida M, Liu YB, et al. Prognostic heterogeneity of MRE11 based on the location of primary colorectal cancer is caused by activation of different immune signals. Front Oncol, 2020, 9: 1465.
34.	Hsu YL, Chen YJ, Chang WA, et al. Interaction between tumor-associated dendritic cells and colon cancer cells contributes to tumor progression via CXCL1. Int J Mol Sci, 2018, 19(8): 2427.
35.	De la Fuente López M, Landskron G, Parada D, et al. The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer. Tumour Biol, 2018, 40(11): 1010428318810059.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Guo L, Wang C, Qiu X, et al. Colorectal cancer immune infiltrates: significance in patient prognosis and immunotherapeutic efficacy. Front Immunol, 2020, 11: 1052.
3. Fan XJ, Wan XB, Fu XH, et al. Phosphorylated p38, a negative prognostic biomarker, complements TNM staging prognostication in colorectal cancer. Tumour Biol, 2014, 35(10): 10487-10495.
4. Fridman WH, Zitvogel L, Sautès-Fridman C, et al. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol, 2017, 14(12): 717-734.
5. Bhattacharya S, Andorf S, Gomes L, et al. ImmPort: disseminating data to the public for the future of immunology. Immunol Res, 2014, 58(2-3): 234-239.
6. Kamarudin AN, Cox T, Kolamunnage-Dona R. Time-dependent ROC curve analysis in medical research: current methods and applications. BMC Med Res Methodol, 2017, 17(1): 53.
7. Wolbers M, Koller MT, Witteman JC, et al. Prognostic models with competing risks: methods and applicationto coronary risk prediction. Epidemiology, 2009, 20(4): 555-561.
8. Li T, Fan J, Wang B, et al. TIMER: A web server for compre-hensive analysis of tumor-infiltrating immune cells. Cancer Res, 2017, 77(21): e108-e110.
9. Lin A, Zhang J, Luo P. Crosstalk between the MSI status and tumor microenvironment in colorectal cancer. Front Immunol, 2020, 11: 2039.
10. Wang Z, Song Q, Yang Z, et al. Construction of immune-related risk signature for renal papillary cell carcinoma. Cancer Med, 2019, 8(1): 289-304.
11. Song Q, Shang J, Yang Z, et al. Identification of an immune signature predicting prognosis risk of patients in lung adenocarcinoma. J Transl Med, 2019, 17(1): 70.
12. Hu D, Zhou M, Zhu X. Deciphering immune-associated genes to predict survival in clear cell renal cell cancer. Biomed Res Int, 2019, 2019: 2506843.
13. Qiu H, Hu X, He C, et al. Identification and validation of an individualized prognostic signature of bladder cancer based on seven immune related genes. Front Genet, 2020, 11: 12.
14. Jin H, Rugira T, Ko YS, et al. ESM-1 overexpression is involved in increased tumorigenesis of radiotherapy-resistant breast cancer cells. Cancers (Basel), 2020, 12(6): 1363.
15. Kano K, Sakamaki K, Oue N, et al. Impact of the ESM-1 gene expression on outcomes in stage Ⅱ/Ⅲ gastric cancer patients who received adjuvant S-1 chemotherapy. In Vivo, 2020, 34(1): 461-467.
16. Kim JH, Park MY, Kim CN, et al. Expression of endothelial cell-specific molecule-1 regulated by hypoxia inducible factor-1α in human colon carcinoma: impact of ESM-1 on prognosis and its correlation with clinicopathological features. Oncol Rep, 2012, 28(5): 1701-1708.
17. Kang YH, Ji NY, Han SR, et al. ESM-1 regulates cell growth and metastatic process through activation of NF-κB in colorectal cancer. Cell Signal, 2012, 24(10): 1940-1949.
18. Yildirim K, Colak E, Aktimur R, et al. Clinical value of CXCL5 for determining of colorectal cancer. Asian Pac J Cancer Prev, 2018, 19(9): 2481-2484.
19. Zhang W, Wang H, Sun M, et al. CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target. Cancer Commun (Lond), 2020, 40(2-3): 69-80.
20. Hu B, Fan H, Lv X, et al. Prognostic significance of CXCL5 expression in cancer patients: a meta-analysis. Cancer Cell Int, 2018, 18: 68.
21. Zhang Y, Zheng S, Liao N, et al. CircCTNNA1 acts as a ceRNA for miR-363-3p to facilitate the progression of colorectal cancer by promoting CXCL5 expression. J Biol Res (Thessalon), 2021, 28(1): 7.
22. Chen C, Xu ZQ, Zong YP, et al. CXCL5 induces tumor angiogenesis via enhancing the expression of FOXD1 mediated by the AKT/NF-κB pathway in colorectal cancer. Cell Death Dis, 2019, 10(3): 178.
23. Zhao J, Ou B, Han D, et al. Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways. Mol Cancer, 2017, 16(1): 70.
24. Novillo A, Gaibar M, Romero-Lorca A, et al. Efficacy of bevacizumab-containing chemotherapy in metastatic colorectal cancer and CXCL5 expression: Six case reports. World J Gastroenterol, 2020, 26(16): 1979-1986.
25. Ieta K, Tanaka F, Yokobori T, et al. Clinicopathological significance of stanniocalcin 2 gene expression in colorectal cancer. Int J Cancer, 2009, 125(4): 926-931.
26. Yang XL, Liu KY, Lin FJ, et al. CCL28 promotes breast cancer growth and metastasis through MAPK-mediated cellular anti-apoptosis and pro-metastasis. Oncol Rep, 2017, 38(3): 1393-1401.
27. Dimberg J, Hugander A, Wågsäter D. Protein expression of the chemokine, CCL28, in human colorectal cancer. Int J Oncol, 2006, 28(2): 315-319.
28. Miao Y, Wang J, Ma X, et al. Identification prognosis-associated immune genes in colon adenocarcinoma. Biosci Rep, 2020, 40(11): BSR20201734.
29. Raufman JP, Dawson PA, Rao A, et al. Slc10a2-null mice uncover colon cancer-promoting actions of endogenous fecal bile acids. Carcinogenesis, 2015, 36(10): 1193-1200.
30. Li Y, Wang P, Ye D, et al. IGHG1 induces EMT in gastric cancer cells by regulating TGF-β/SMAD3 signaling pathway. J Cancer, 2021, 12(12): 3458-3467.
31. Michele S, Mariachiara B, Emanuela P, et al. UCN-01 enhances cytotoxicity of irinotecan in colorectal cancer stem-like cells by impairing DNA damage response. Oncotarget, 2016, 7(28): 44113-44128.
32. Kikuchi T, Mimura K, Ashizawa M, et al. Characterization of tumor-infiltrating immune cells in relation to microbiota in colorectal cancers. Cancer Immunol Immunother, 2020, 69(1): 23-32.
33. Fan CW, Kopsida M, Liu YB, et al. Prognostic heterogeneity of MRE11 based on the location of primary colorectal cancer is caused by activation of different immune signals. Front Oncol, 2020, 9: 1465.
34. Hsu YL, Chen YJ, Chang WA, et al. Interaction between tumor-associated dendritic cells and colon cancer cells contributes to tumor progression via CXCL1. Int J Mol Sci, 2018, 19(8): 2427.
35. De la Fuente López M, Landskron G, Parada D, et al. The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer. Tumour Biol, 2018, 40(11): 1010428318810059.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Construction of immune related gene risk markers for prognosis of colon cancer and its prediction of prognosis in colon cancer patients

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