Abstract 115: In silico evaluation of DNA-damage-inducible transcript 4 gene (DDIT4) in the outcome of several malignant tumors
Authors: Pinto Joseph A. , Rolfo Christian , Bravo Leny , Fajardo Williams , Morante Zaida D. , Neciosup Silvia , Mas Luis , Aguilar Alfredo , Castañeda Carlos , Pinillos Luis , Vallejos Carlos , Gomez Henry 
Published: July 2016

Objectives: Although DDIT4 gene encodes a protein whose main action is to inhibit mTOR. There are not previous reports relating this gene with the clinical outcome in cancer patients. Our aim was to explore the influence of this gene in the clinical characteristics and the outcome of malignant tumors.

Methods: We evaluated in an in silico study of publicly available datasets, influence of DDIT4 expression in the clinical outcome in terms of either disease-free survival (DFS), progression free survival (PFS) or overall survival (OS), according to the availability of this variable in the dataset. KM Plotter (http://kmplot.com/) and SurvExpress (http://bioinformatica.mty.itesm.mx/) were used to evaluate the influence of DDIT4 gene in the outcome (either DFS, PFS or OS). cbioportal.org was used to explore structural gene changes. The median of expression discriminate two groups at different risk. Twelve types of cancer were evaluated including. Acute Myeloid Leukemia, Brain Cancer, Breast Cancer, Bone Cancer, Cervical Cancer, Head and Neck Cancer, Hematological Cancer, Liver Cancer, Lung Cancer, Pancreatic Cancer, Ovarian Cancer and Prostate Cancer

Results: DDIT4 had low structural alterations rates (0-5.1%); however, in breast tumors xenografts, gene amplification occurs in 17.4%, indicating a key role in tumor progression. High levels of DDIT4 was significantly associated with a worse outcome in breast cancer (n = 4142), P = 3×10-14 (HR = 1.64, CI95%: 1.44-1.87). In this malignancy, high DDIT4 expression was associated with the triple negative phenotype and higher pathological complete response rates. In addition High DDIT4 level was associated to a worse outcome in acute myeloid leukemia (n = 168), P = 3.47×10-5 (HR = 2.31, CI95%:1.55-3.43), glioblastoma multiforme (n = 538), P = 0.005809 (HR = 1.31, CI95%:1.08-1.59); ovarian cancer (n = 1648), P = 0.0096 (HR = 1.2, IC95%:1.04- 1.37); head and neck squamous cell carcinoma (n = 283), P = 0.03347 (HR = 1.49, IC95%:1.03-2.15) and lung adenocarcinoma (n = 866), P = 0.0038 (HR = 1.4, CI95%: 1.02-1.91). In contrast, a high level of DDIT4 was associated with a better prognosis in gastric cancer (n = 641), P = 1.7×10-6 (HR = 0.62, CI95%:0.5-0.75) and lung squamous cell carcinoma (n = 675), P = 0.0015 (HR = 0.42, IC95%:0.24-0.73).

Conclusion: Although DDIT4 structural alterations are infrequent, its dysregulation impact in the clinical outcome in several types of cancer. DDIT4 is an attractive target to improve the therapeutic strategies, mainly those related with mTOR inhibition.

Citation Format: Joseph A. Pinto, Christian Rolfo, Leny Bravo, Williams Fajardo, Zaida D. Morante, Silvia Neciosup, Luis Mas, Alfredo Aguilar, Carlos Castañeda, Luis Pinillos, Carlos Vallejos, Henry Gomez. In silico evaluation of DNA-damage-inducible transcript 4 gene (DDIT4) in the outcome of several malignant tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 115.