LBX2 expression and outcomes in patients with colon adenocarcinoma.
Authors: Sun Chenyu , Tuason John Pocholo W. , Bhan Chandur , Paudel Arpana , Ahmed Marwan K. , Kim Na Hyun , Mohammed Abdul Humaed , Gerais Yasmin A. , Prasad Apurwa , Lising Jannell F. , Siddiqui Zain I. , Tiamiyu Ayobamidele Ayisat , Abid Qurrat-ul-ain 
Published: January 2022

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Background: Colon adenocarcinoma (COAD) is one of the most common gastrointestinal cancers worldwide. Previous studies found that Ladybird homeobox 1 (LBX1) and Ladybird homeobox 2 (LBX2), were involved in the progress of several types of cancer. However, studies on their roles in cancers, such as COAD, are very limited. Thus, this study was performed to explore their roles in COAD. Methods: RNA-sequencing FPKM data and corresponding clinical information of 480 tumor tissues of COAD and 41 normal tissues were obtained from The Cancer Genome Atlas (TCGA). The ‘limma’ package was used to compare the expression differences of LBX1 and LBX2 between the normal and cancer tissues using Wilcoxon rank-sum test. Analysis of overall survival (OS), disease specific survival (DSS), and progression free interval (PFI) were conducted by Kaplan–Meier (K–M) method via ‘survminer’ package. Univariate Cox hazard regression analysis of OS was applied to five clinicopathological variables from T stage, N stage, M stage, pathologic stage, CEA level, as well as the expression level of family members of LBX that are overexpressed and associated with worsening survival outcomes, by using ‘survival’ package. Furthermore, a nomogram was also visualized by the R ‘rms’ package and ‘survival’ package to predict the 1-, 3-, and 5-year OS and individual predictors. Results: The expression of LBX2 (p = 8.1e-20) was upregulated in COAD tissues compared with normal tissues, while no statistically significant difference of expression between normal tissues and tumor was found for LBX1 (p = 0.06). Further survival analysis found that higher expression of LBX2 was associate with worse OS (HR = 2.45, 95%CI 1.62-3.71, p < 0.001), DSS (HR = 2.34, 95%CI 1.39-3.96, p = 0.001), and PFI (HR = 1.48, 95%CI 1.04-2.10, p = 0.03). Univariate Cox hazard regression analysis showed that N1, N2, N3, M1, pathologic stage III and IV, CEA level&gt;5, and high expression level of LBX2 were associated with worse OS (all p < 0.05). The nomogram based on six clinicopathological variables (T stage, N stage, M stage, pathologic stage, CEA level, and LBX2 expression level) and 1-, 3-, 5-year OS probabilities were developed, with concordance index (C-index) of 0.795(0.755-0.834), indicating its prediction value and sufficient discrimination ability, as C-index was more than 0.7. The calibration curves of 1-, 3-, and 5-year demonstrated the consistency of our results and the predictive values, indicating satisfactory performance for this nomogram. Moreover1-, 3-, 5-year AUCs of LBX2-based nomogram were 0.805, 0.831, and 0.774, showing a moderate accuracy. Conclusions: LBX2 are upregulated in COAD tumor samples, and its higher expression is associated with worsening OS, DSS, and PFI. The LBX2-based monogram developed by this study might help predict the OS possibilities for COAD patients. LBX2 can be a potential diagnostic and prognostic marker, and therapeutic marker in COAD.