www.aging-us.com AGING 2021, Vol. 13, No. 4 Research Paper Gene expression barcode values reveal a potential link between Parkinson’s disease and gastric cancer Suyan Tian1,2, Shishun Zhao2, Mingbo Tang3, Chi Wang4,5 1Division of Clinical Research, First Hospital of Jilin University, Changchun 130021, Jilin, P.R. China 2Center for Applied Statistical Research, School of Mathematics, Jilin University, Changchun 130012, Jilin, P.R. China 3Department of Thoracic Surgery I, First Hospital of Jilin University, Changchun 130021, Jilin, P.R. China 4Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY 40536, USA 5Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA Correspondence to: Suyan Tian, Chi Wang; email: [email protected], [email protected] Keywords: barcode values, differentially expressed genes (DEGs), gastric cancer, gene expression profiles, Parkinson's disease Received: October 12, 2020 Accepted: January 22, 2021 Published: February 16, 2021 Copyright: © 2021 Tian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Gastric cancer is a disease that develops from the lining of the stomach, whereas Parkinson’s disease is a long- term degenerative disorder of the central nervous system that mainly affects the motor system. Although these two diseases seem to be distinct from each other, increasing evidence suggests that they might be linked. To explore the linkage between these two diseases, differentially expressed genes between the diseased people and their normal controls were identified using the barcode algorithm. This algorithm transforms actual gene expression values into barcode values comprised of 1’s (expressed genes) and 0’s (silenced genes). Once the overlapped differentially expressed genes were identified, their biological relevance was investigated. Thus, using the gene expression profiles and bioinformatics methods, we demonstrate that Parkinson’s disease and gastric cancer are indeed linked. This research may serve as a pilot study, and it will stimulate more research to investigate the relationship between gastric cancer and Parkinson’s disease from the perspective of gene profiles and their functions. INTRODUCTION movements [2]. The causes of Parkinson’s disease and gastric cancer are very complicated, and increasing Gastric cancer (GC), also known as stomach cancer, evidence supports the involvement of both genetic and develops from the cells lining of the stomach. In 2018, environmental factors. more than one million new cases of gastric cancer were diagnosed, and an estimated 783,000 associated deaths It is believed that the gastrointestinal tract comprises an occurred. One out of 12 cancer deaths worldwide intrinsic nervous system — the enteric nervous system resulted from GC, making it the fifth most common (ENS). Referred to as “the second brain” [3], the ENS cancer and the third leading cause of death due to regulates the gastrointestinal tract’s motility and owns cancer [1]. Gastric cancer poses a particularly serious neuroendocrine functions. The ENS interacts bi- health problem in Eastern Asia. Parkinson’s disease is a directionally with the Central Nervous Systems (CNS), long-term degenerative disorder of the central nervous in a connection referred to as the “brain-gut axis” [4], system that mainly affects the motor system. It is which is composed of neural pathways in the CNS, currently listed as the second most prevalent autonomic nervous system, and the hypothalamic- neurodegenerative disorder after Alzheimer’s disease pituitary-adrenal axis. A large number of patients with and the most common disorder affecting body Parkinson’s disease experience constipation, abdominal www.aging-us.com 6171 AGING distension, and other gastrointestinal symptoms before Microarray and RNA-sequence techniques enable they experience motor symptoms [5]. More importantly, monitoring expression changes of thousands of genes dysbiosis of gut microbiota plays a critical role in the simultaneously. For both gastric cancer and Parkinson’s pathogenesis of Parkinson’s disease, such as [6]. On the disease, numerous microarray and RNA-Sequence other hand, gastrointestinal symptoms and microbiome experiments such as [22–32] have been conducted to dysbiosis frequently occur in patients with gastric distinguish between the diseased patients and normal cancer [7]. Especially, increased gut permeability controls, or predict the progression of the two diseases, promotes the leakage of bacteria and their products into with the aid of a variety of bioinformatics tools and the blood, leading to the maturation of antigen- statistical methods. To the best of our knowledge, no presenting cells and thus the stimulation of investigation has been carried out to explore the link inflammatory pathways that are of crucial importance in between gastric cancer and Parkinson’s disease, using these two diseases. the gene expression profiles generated through either microarray or RNA-Sequencing. The objective of this Epidemiological studies [8–12] have suggested that study is to bridge this gap by using gene expression patients with Parkinson’s disease have a reduced risk of profiles and the barcode algorithm [33] to investigate developing cancers, including gastric cancer, compared the potential association between the two diseases. to people who do not have Parkinson’s disease. Nevertheless, other studies have showed a positive RESULTS association between Parkinson’s disease and cancers, that is, an increased risk of cancers in patient with Differentially expressed genes Parkinson’s disease [13, 14]. For instance, for gastric cancer, the hazard ratio was 1.59 (95% CIs: 1.30-1.94) For gastric cancer, 2,114 differentially expressed genes by Lin et al. [14], who attributed the inconsistency to (DEGs) between the patients and the normal controls the fact that most of those epidemiological studies were were identified. Among them, 1,296 exhibited a higher carried out upon the Western population, while their expressed proportion, and 818 had a higher silenced study was performed in Taiwan. Therefore, Lin et al. proportion higher in the gastric cancer patients [14] concluded that the race or/and environmental compared to the normal controls. For Parkinson’s exposures have an interactive effect on the association disease, 36 DEGs were identified. Of them, 33 genes between cancers and Parkinson’s disease. Also, the had the propensity of being expressed higher in the Columbia Open Health Data (COHD) [15], which is disease group than that in the control group. Between based on electronic health records (EHR), indicated that the two sets of DEGs, 15 genes overlapped on each the concurrence of Parkinson’s disease and gastric other (Fisher’s exact test: p=0.033). The gene symbols cancer is significantly higher than what expected by for the 15 overlapping genes are presented in Figure 1A, chance (odds ratio=2.02, p=2.23×10-6). This implies and the odds ratios (ORs) and false discovery rates that both diseases are positively related. It is worth (FDR) stratified by the gastric cancer cohort and the noting that patients in the electronic health records may Parkinson’s disease cohort are listed in Table 1. Of not represent the general population; thus, the note, in gastric cancer, several overlapped genes had association between the two diseases may be biased. extreme ORs (either 0 or infinite), while in Parkinson’s Therefore, it is natural to speculate that Parkinson’s disease the ORs were basically moderate. disease and gastric cancer may be linked. All genes except GPX3, ZBTB16, and KCNQ1 have OR At the molecular level, studies suggest that of >1 for gastric cancer, whereas all genes have OR of neurodegenerative disorders (including Alzheimer’s >1 for Parkinson’s disease, suggesting that for a patient disease, Parkinson’s disease, and Huntington’s disease) who has either Parkinson’s disease or gastric cancer, and cancers (including lung cancer, liver cancer, and breast the status of 12 genes is highly likely to be un-silenced. cancer) are linked to each other with respect to somatic This might imply that when a person suffers from one mutations, mRNAs or microRNAs, such as [16–19]. disease, the likelihood of having the other disease tends However, only a few of the studies focused on the specific to increase, which is consistent with the results of a association between Parkinson’s disease and gastric cancer previous epidemiology study conducted in Taiwan [14] from this perspective [20, 21]. For example, Hu and and the high concurrent rate between these two colleagues [20] demonstrated that a specific miRNA, miR- diseases indicated by the COHD database [15]. 148a, is not only a potential tumor suppressor that inhibits Nevertheless, Lin’s study [14] indicated that race might gastric cancer metastasis, but is also involved in play an interactive role on the association between neurological development and functions. In particular, the Parkinson’s disease and cancers. Thus, for the Asians, expression level of miR-148a is lower in patients with this association tends to positive, but for the Parkinson’s disease compared to that in normal controls. Caucasians, this association is more likely to be www.aging-us.com 6172 AGING negative. Since no large Western gastric cancer cohort them, three enriched