CLINICAL AND TRANSLATIONAL RESEARCH Role of Oncogenic Pathways and KRAS/BRAF Mutations in the Behavior of Colon Adenocarcinoma in Renal Transplant Patients Ignacio Revuelta, 1,2,7 Daniel Moya-Rull, 2 Adriana García-Herrera, 3 Jordi Rovira, 2 Francisco Ayala de la Pen ˜a, 4 Antonio Misiego, 5 Flavia Guzma ´n, 3 Federico Oppenheimer, 1 Joan Albanell, 6 and Josep M. Campistol 1,2 Background. The behavior and mechanisms of colorectal carcinoma in solid organ transplantation have not been well characterized. Our aim was to determine the clinical and molecular phenotypes of colorectal carcinoma in kidney transplant recipients and compare with those in the nonimmunosuppressed population. For the first time, we analyzed the impact of KRAS and BRAF mutations in kidney transplantation. Methods. Kidney transplant recipients with colorectal carcinoma were diagnosed and followed up from 1992 to 2007. Twelve patients fulfilled inclusion criteria and were matched with the general population with colorectal cancer. To assess the possible mechanisms involved in the clinical behavior of colorectal carcinoma, we compared the tumoral expression by immunohistochemical analysis of molecule markers of mammalian target of rapamycin (mTOR) pathway, angiogenesis and proliferation, and the role of activating mutations in KRAS and BRAF genes. Results. Colorectal carcinoma was more prevalent and exhibited a trend for worse prognosis in transplant patients. Although the mTOR pathway was activated in both populations, activation was lower in transplant patients because of relatively higher phosphatase and tensin homolog expression in the former. Angiogenesis was activated in colorectal carcinoma in both groups. KRAS mutations were found in transplant recipients treated with calcineurin inhibitors and with high expression of phosphatase and tensin homolog. Conclusion. The activation of oncogenic pathways could be responsible for the clinical behavior of posttransplant colorectal carcinoma. The mutation status of the KRAS gene is likely involved in mTOR pathway and to be a prognosis marker for colorectal cancer in kidney transplantation. Keywords: Colorectal cancer, Immunosuppressive therapy, Solid organ transplantation, mTOR pathway, KRAS and BRAF mutations. (Transplantation 2012;93: 509–517) K idney transplantation is the treatment of choice for most patients with end-stage kidney disease. Immunosuppres- sive therapy has decreased the risk of acute rejection and has improved graft and patient survival (1, 2). However, long- term patient survival increases the risk of malignancies (3, 4). Posttransplant malignancies are one of the main causes of morbidity, mortality, and graft loss (5, 6). Colorectal cancer (CRC) is one of the leading causes of cancer worldwide (7, 8); however, in solid organ transplantation (SOT) its prevalence compared with that in the general population remains con- troversial (9, 10). Several studies agree on the greater aggres- This work was supported by a grant from the Instituto de Salud Carlos III (ISCIII), Ministerio de Sanidad y Consumo (Spain); the Catalan Society of Transplantation (I.R.); and an intensification grant of ISCIII and DIUE Generalitat de Catalunya (J.A.). The authors declare no conflicts of interest. 1 Renal Transplant Unit, Department of Nephrology and Renal Transplant, Hospital Clinic, Barcelona, Spain. 2 Laboratori Experimental de Nefrologia i Transplantament (LENIT), Hos- pital Clinic, Barcelona, Spain. 3 Department of Pathology, Hospital Clínic, Barcelona, Spain. 4 Department of Hematology and Medical Oncology, Hospital Universitario JM Morales Meseguer, Murcia, Spain. 5 Department of Preventive Medicine, Hospital Alcan ˜iz, Teruel, Spain. 6 Department of Oncology, Hospital del Mar, Barcelona, Spain. 7 Address correspondence to: Ignacio Revuelta, M.D., Ph.D., Renal Trans- plant Unit, Department of Nephrology and Renal Transplant Hospital Clinic, 170 Villarroel Street (Stair 12 Floor 5), 08036 Barcelona, Spain. E-mail: irevuelt@clinic.ub.es I.R. conceived the idea of the project and participated in the study design and performance, data analysis, and drafting of the manuscript; D.M.-R. par- ticipated in the performance of the research; A.G.-H. participated in the histological analysis and drafting of the manuscript; J.R. participated in the performance of the research and drafting of the manuscript; F.A.d.l.P. participated in the data analysis and drafting of the manuscript; A.M. participated in the statistical design and analysis and drafting of the man- uscript; F.G. participated in the histological analysis; F.O. participated in patient selection and reviewed the manuscript; J.A. reviewed the manu- script; and J.M.C. conceived the idea of the project with the first author and participated in the study design, data analysis, and drafting of the manuscript. Received 22 September 2011. Revision requested 1 November 2011. Accepted 17 November 2011. Copyright © 2012 by Lippincott Williams & Wilkins ISSN 0041-1337/12/9305-509 DOI: 10.1097/TP.0b013e318242be46 Transplantation • Volume 93, Number 5, March 15, 2012 www.transplantjournal.com | 509