A chemokine/chemokine receptor signature potentially predicts clinical outcome in colorectal cancer patients

Article type: Research Article

Authors: Mitchell, Andrew^{a; 1} | Hasanali, Sarrah L.^{b; 1} | Morera, Daley S.^b | Baskar, Rohitha^b | Wang, Xin^b | Khan, Rahil^c | Talukder, Asif^a | Li, Charles S.^b | Manoharan, Meenakkshy^d | Jordan, Andre R.^{b; e} | Wang, Jiaojiao^b | Bollag, Roni J.^{c; f} | Singh, Nagendra^b | Albo, Daniel^a | Ghosh, Santu^{g; *} | Lokeshwar, Vinata B.^{b; *}

Affiliations: [a] Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, USA | [b] Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA | [c] Bio-Repository Alliance of Georgia for Oncology at Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, USA | [d] Washington University at St Louis, St Louis, MO, USA | [e] Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, University of Miami-Miller School of Medicine, Miami, FL, USA | [f] Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, USA | [g] Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, GA, USA

Correspondence: [*] Corresponding authors: Santu Ghosh, Department of Population Health Sciences, Medical College of Georgia, Augusta University, 1120 15th Street, AE-1032, Augusta, GA 30912-2100, USA. Tel.: +1 706 721 4454; E-mail: sghosh@augusta.edu; Vinata B. Lokeshwar, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, 1410 Laney Walker Blvd., Room CN 1177A, Augusta, GA 30912-2100, USA. Tel.: +1 706 721 7652; Fax: +1 706 721 6608; E-mail: vlokeshwar@augusta.edu.

Note: [1] Equal contribution; joint first authors.

Abstract: BACKGROUND: Differential expression of chemokines/chemokine receptors in colorectal cancer (CRC) may enable molecular characterization of patients’ tumors for predicting clinical outcome. OBJECTIVE: To evaluate the prognostic ability of these molecules in a CRC cohort and the CRC TCGA-dataset. METHODS: Chemokine (CXCL-12α, CXCL-12β, IL-17A, CXCL-8, GM-CSF) and chemokine receptor (CXCR-4, CXCR-7) transcripts were analyzed by RT-qPCR in 76 CRC specimens (normal: 27, tumor: 49; clinical cohort). RNA-Seq data was analyzed from the TCGA-dataset (n= 375). Transcript levels were correlated with outcome; analyses: univariate, multivariable, Kaplan-Meier. RESULTS: In the clinical cohort, chemokine/chemokine receptor levels were elevated 3-10-fold in CRC specimens (P⩽ 0.004) and were higher in patients who developed metastasis (P= 0.03 – < 0.0001). CXCR-4, CXCR-7, CXCL-12α, CXCL-8, IL-17 and GM-CSF levels predicted metastasis (P⩽ 0.0421) and/or overall survival (OS; P⩽ 0.0373). The CXCR-4+CXCR-7+CXCL-12 marker (CXCR-4/7+CXCL-12 (α/b) signature) stratified patients into risk for metastasis (P= 0.0014; OR, 2.72) and OS (P= 0.0442; OR, 2.7); sensitivity: 86.67%, specificity: 97.06%. In the TCGA-dataset, the CXCR-4/7+CXCL-12 signature predicted metastasis (P= 0.011; OR, 2.72) and OS (P= 0.0006; OR: 4.04). In both datasets, the signature was an independent predictor of clinical outcome. CONCLUSIONS: Results of 451 specimens from both cohorts reveal that the CXCR-4/7+CXCL-12 signature potentially predicts outcome in CRC patients and may allow earlier intervention.

Keywords: CXCL-12, CXCR-7, CXCR-4, CXCL-8, colorectal cancer

DOI: 10.3233/CBM-190210

Journal: Cancer Biomarkers, vol. 26, no. 3, pp. 291-301, 2019