The role of oncostatin M receptor gene polymorphisms in bladder cancer

Cancer of the bladder is a frequently encountered malignancy. It is associated with a poor quality of life. According to the 2012 World Health Organization statistics, the number of new bladder cancer cases was approximately 429,000 worldwide, which ranks ninth in the incidence of malignant tumors. The number of deaths attributed to bladder cancer was approximately 165,000, ranking thirteenth among all malignant tumors [1]. In USA, an estimated 74,690 cases of bladder cancer occurred in 2014, including 65,390 males and 18,300 females [2]. In China, the incidence of bladder cancer was the tenth highest among malignant tumors, with increased death rate over the years 1991 to 2005 [3]. Bladder cancer comprises of muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). Furthermore, during the initial diagnosis, most cases of bladder cancer belong to NMIBC, constituting nearly 70%, while MIBC accounts for approximately 25% [4]. After transurethral resection of bladder tumor (TURBT) combined with postoperative perfusion of chemotherapy, some patients will undergo tumor relapse, and nearly 10% of the NMIBC patients will progress to MIBC and even distant metastasis [5]. MIBC patients' experience low 5-year survival rates at 69%, with metastasis lowering this survival rate rapidly to 6% [4]. Early diagnosis and treatment of malignant tumors has a significant impact on the prognosis of patients. Tajuddin SM et al. found that if bladder cancer patients received the early diagnosis and treated at an early stage, the 5-year survival rate was nearly three times higher than the late stage [6].Until now, early diagnosis of bladder cancer has been accomplished using cystoscopy, imaging, and urinary cytology. Cystoscopy and pathological biopsy represent the gold standard for the diagnosis of bladder cancer. However, the disadvantages include high cost, trauma, pain, and the inability of these approaches to predict the treatment outcomes.

Bladder cancer has a complex etiology, which may be closely associated with chromosomal aberrations, gene mutations, lifestyles, and environmental factors. It is a pathological process mediated by multiple genes and affected by multiple factors. The study found that smoking or long-term exposure to chemical carcinogens are high risk factors leading to carcinogenesis of urothelial mucosa. However, only a small proportion of individuals exposed to these high risk factors eventually develop bladder cancer, highlighting the crucial contributions of genetic differences to the development of this disease [7]. Today, the role of genetic factors in the incidence of bladder cancer has attracted widespread attention and several genes are currently associated with the incidence of bladder cancer, including CD44, CRCC1, and PDCD6 [8‐10]. However, none of these genes were recommended for bladder cancer detection and the study of other gene combination with existing genes might improve its clinical value to predict the occurrence and prognosis of bladder cancer.

Oncostatin M (OSM) is first discovered in1986 by Zarling et al. and is a member of interleukin-6 family [11, 12]. As a well-known multifunctional cytokine, OSM has multiple effects and functions, which are important in controlling immune responses, inflammation, cell proliferation, and tumor formation [13]. Current research indicates that there are two types of receptors for OSM, LIF binding protein and OSM-specific receptor (OSMR) [12]. OSMR receptor plays a key role in signal recognition. When OSM binds to OSMR, Janus protein tyrosine kinase (JAK) can be activated followed by activation of the mitogen-activated protein kinase (MAPK) as well as the signal transducer and activator of transcription (STAT, mainly STAT3) [14‐16]. OSMR is active in a wide range of solid tumor cell lines, including breast tumor, colorectal cancer, bone carcinoma, and so on. West N et al. found that high OSMR was associated with reduced estrogen receptor alpha (ER), which could reduce the risk of tumor progression in breast tumor. Besides, patients with invasive breast cancer who had high OSMR expressions were previously observed to experience shorter overall survival and disease-free periods [17]. An investigation of OSMR gene methylation by Hibi K et al. in colorectal cancer patients revealed that OSMR methylation may prevent the tumorigenesis, progression in non-invasive colorectal cancer [18]. Stacey L et al. demonstrated that OSMR expression stimulated tumor angiogenesis and pro-invasive tumor activity in osteosarcoma cell lines, while David E et al. found OSMR is a growth factor for Ewing sarcoma [13, 19]. Recently, several gene polymorphisms (SNPs) were detected in the promoters regions of the OSMR gene and showed that the gene polymorphisms were associated with tumor, chronic inflammation [20, 21]. Unfortunately, studies have yet to delineate the relationship between OSMR SNPs and the initiation, progression, and prognosis of cancer of the bladder.

Gene polymorphism may be an adaptive manifestation in humans to the various risk factors during evolution, suggesting that similar diseases may have different clinical manifestations and similar treatment may possibly with varying efficacy in individuals. A serial of studies demonstrate that the onset and progression of bladder cancer are closely associated with multiple gene polymorphisms including CD44, XRCC1, and PDCD6 [8‐10]. In this study, no association were found between bladder cancer patients and controls with respect to the genotypic and allelic frequencies of OSMR gene polymorphisms (rs2278329 and rs2292016). However, further analysis showed the rs2292016 was associated with clinicopathologic characteristics, such as higher tumor grade and recurrence. In addition, multivariate analysis indicated that recurrence-free survival was strongly linked to the rs2278329 genotype while overall survival depended on the presence of a rs2292016 genotype. Our study is the first of its kind to report a relationship between the OSMR gene and bladder cancer.

According to the tumor number, size, recurrence status, concomitant CIS or not, and tumor grade, NMIBC was divided into three risk groups based on the European Organization for Research and Treatment of Cancer (EORTC) [22]. Patient-derived data indicates that patients in the high-risk group may face high incidence of tumor recurrence and progression possibly because of the different pathophysiologic mechanism. Bladder tumor has a high possibility of postoperative recurrence, necessitating careful long-term clinical follow-up. Although cystoscopy, ultrasonic examination, urine cytology, etc. are useful tools to assess and monitor the relapses of bladder tumor, not all examination techniques are perfect. For example, cystoscopy is invasive thus unacceptable to many patients [23] while urine cytology is less sensitive especially for the low-grade bladder tumors [24]. With the gradual improvement of the diagnostic value of biological tests, serology, and molecular biology, serum tumor markers could be a new way to monitor tumor relapse. Nuclear Matrix Protein 22 (NMP22), bladder tumor antigen (BTA), and HA are among a few examples of bladder tumor markers. However, there are still many shortcomings of tumor markers, requiring the combination of other methods in order to provide an adequately sensitive and specific means for early diagnosis and postoperative surveillance [25, 26]. The results showed a close relationship between SNP rs2292016 and relapse. In this study, we found that rs2292016 T allele and GT/TT genotype in the dominant model were risk factors for recurrence and careful follow-up was needed in these patients.

Although the prognosis is generally good for most NMIBC patients, about 30–80% of patients may suffer a relapse and approximately 1–45% patients progress to MIBC in 5 years [22, 27, 28]. The treatment options of the NMIBC patients with high tumor grade have long been a contentious issue, especially the T1G3. For instance, Denzinger et al. found that T1G3 patients who received early cystectomy had a better 10-year CSS (78%) compared to those who received deferred cystectomy (51%) [29]. Similar conclusions were concluded from Herr et al. and Hautmann RE et al. [30, 31]. There are several potential explanations for this phenomenon. The repeated use of TUR in the NMIBC may improve the tumor staging and deferred cystectomy has been associated with increase in the prevalence of lymph node metastases (LNMs) [32]. In a retrospective study of 866 bladder tumor patients, Wiesner C et al. found that 8% of patients who had undergone a single TUR had LNMs, and the statistic increased threefold to 24% in those who had undergone 2–4 TURs [33]. In the overdominant model of this study, high-grade bladder cancers were more likely to be GT heterozygotes of the rs2292016 genotype rather than the homozygote genotype (GG/TT), indicating that patients with this specific genotype should consider undergoing early cystectomy.

OSM–OSMR signaling is a significant mediator of inflammatory disease, cell development, and is also considered an important mechanism in tumor progression [16]. Studies showed that OSMR is expressed by multiple neoplastic cells and tumor tissues, but the exact OSM‐OSMR mechanisms seem to be influenced by cell-type and tumor types. In AIDS-related Kaposi’s sarcoma, OSM promoted the tumor proliferation and protein synthesis [34]. A similar phenomenon was observed in myeloma and human prostate cancer cells [35, 36]. In contrast, Hibi K et al. found OSMR to be more methylated in non-invasive colorectal cancer compared to invasive colorectal cancer. The highlights the tumor-suppressive role of OSMR in colorectal carcinoma [18]. Survivin, Mcl-1, and VEGF are examples of tumor-related factors whose expressions are thought to be regulated by STAT3. As stated before, OSMR was associated with activation of STAT3 signal transduction pathway. These all reveal that OSMR plays a role in tumor metabolism and possibly affects the chances of survival. Our study showed that rs2278329 and rs2292016 were associated with recurrence-free survival and overall survival in NMIBC patients. rs2278329 GA heterozygotes might have shorter durations of recurrence-free survival, while T alleles of rs2292016 was associated with increased survival. Patients with (TT/GT) genotype had a lower risk of death compared to those with the GG homozygote genotype. Based on the evidence above, we can draw a conclusion that OSMR decreases survival rate for bladder cancer.

Our study shows a significant association between OSMR gene polymorphism and bladder cancer that potentially impacts tumor grade, recurrence, and overall survival. This is a first report of the association between bladder cancer and OSMR gene polymorphisms, to the best of our knowledge. However, this study still has its limitations. First, multiple genes have emerged as potentially having links with the occurrence, progression, and prognosis of bladder cancer. However, this study only evaluated the OSMR gene and there could be other genes that could synergistically affect the survival. Secondly, the tumors caused by genetic polymorphisms occur across different races, whereas the study participants represented only the Han residents of Sichuan province. Therefore, the study findings cannot be generalized or applicable to all the races. Furthermore, the study sample size was small, suggesting the need for larger studies to corroborate the results.