A systematic review of genome-wide association studies on bladder cancer
Department of Anatomy, Faculty of Basic Medical Sciences, Bauchi State University, Gadau, PMB 65, Itas/Gadau, Nigeria
Department of Physiology, Faculty of Basic Medical Sciences, Bauchi State University, Gadau, PMB 65, Itas/Gadau, Nigeria
Department of Human Anatomy, Faculty of Basic and Allied Medical Sciences, College of Medical Sciences, Gombe State University, Gombe, Nigeria
Institute of Pathogen Genomics, Centre for Laboratory and Systems Networks, Africa Centres for Disease Control and Prevention (Africa CDC), African Union Commission, P.O.Box 3243, Addis Ababa, Ethiopia
*Correspondence: Dr. Umar Ahmad (Email: umarahmad@basug.edu.ng)Abstract
Background
Bladder cancer (BC) is the most common cancer of the urinary tract worldwide with over 550,000 new cases each year, bladder cancer has drawn relatively limited research attention and healthcare interventions despite the escalating incidence and mortality rates, particularly in Africa. Historically, the clinical handling of bladder cancer remained largely unchanged for many years. However, novel research initiatives have heralded a fresh epoch in its diagnosis and treatment, fueled by detailed probing of molecular changes.
Aim
This study aimed to identify genetic susceptibility loci associated with bladder cancer by systematically reviewing previous Genome-Wide Association Studies (GWAS).
Methods
In line with this objective, comprehensive literature searches were conducted across PubMed, Google Scholar, and relevant genetic databases, focusing on bladder cancer GWAS studies from 2000 through to November 2022. This systematic review adhered to the robust PRISMA standards. To evaluate the credibility of the studies under scrutiny, the Newcastle-Ottawa Scale was employed, further assessing any potential bias risk.
Results
The investigation identified chromosome 18q12.3 as the most vulnerable to bladder cancer, revealing four polymorphisms at this locus: rs7238033, rs10775480, rs11082469, and rs17674580. Furthermore, chromosome 5p15.3 emerged as the second most susceptible, with three noted polymorphisms: rs2736098 and two instances of rs401681.
Conclusion
Despite these findings, our understanding of genetic predisposition to bladder cancer remains rudimentary, with the majority of substantial data deriving from GWAS. No additional genetic association evidence emerged from this systematic review. Given the relatively minor influence of our current knowledge of genetic susceptibility to bladder cancer on public health, a call for larger cohort studies is necessary. These expanded studies can potentially unveil a broader range of significant polymorphisms across the genome, thereby enhancing our understanding and approach to bladder cancer.
Article notes
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This study did not receive any funding
1.0Introduction
Bladder cancer, a multifaceted disease originating from the confluence of genetic and environmental risk factors, ranks as the sixth most prevalent cancer type worldwide. Annually, it accounts for approximately 150,300 fatalities (Selvaraj et al., 2021; Wang et al., 2016). Both inherited genetic factors and environmental aspects like smoking and occupational exposure stand as major risk factors for bladder cancer (Wang et al ., 2016).Moreover, other elements such as lifestyle, medical history, fluid intake, and diet also contribute to its neogenesis(Wang et al ., 2016).
In the United States alone, an assessment in 2015 reported that bladder cancer affected 56,329 males and 17,680 females, resulting in 16,000 deaths (Nahar et al., 2011). Prevalence of bladder cancer risk is notable among Asian populations (Bau et al., 2011)(Wang et al., 2016). However, the exact factors and genes leading to this disease are yet to be fully identified. Despite most patients with bladder cancer undergoing conservative surgery, they face an exceedingly high risk of frequent recurrences. This aspect escalates the healthcare cost, making bladder cancer one of the most expensive cancers to manage in many Western countries(Nahar et al., 2011; Ye et al., 2011).
Interestingly, in Africa, bladder cancer incidence and mortality rates have been on an alarming upward trajectory. Despite the scarcity of comprehensive data compared to Asian and Western demographics, some regions in Africa report substantially high bladder cancer incidence rates, pointing to an emerging public health issue (WHO, 2022). Alarmingly, research and interventions for bladder cancer in Africa have been insufficient, further highlighted by the paucity of genetic studies and adequate healthcare services for early diagnosis and treatment. Genome wide associated studies (GWAS) is a study designed to collect and compare different type of genes in order to identify genes or genetic variant that may contribute to a particular type of disease among populations (Chang et al., 2018). Genetic polymorphism is a phenomenon in which an individual’s genes have a variety of DNA sequences. The polymorphisms of the DNA sequences, which may vary by two or more, have a role in determining the diversity of people, groups, and populations. Single nucleotide polymorphism (SNP) analyses the human genome for variations that are more prevalent in people with a certain type of disease (Verma, 2016).
In this study, a systematic reviews approach were employed to thoroughly search and identify all important published studies on bladder cancer and GWAS. The is aims to identify genetic susceptibility loci associated with bladder cancer by systematically reviewing previous GWAS studies. This approach will help further our understanding of genetic predisposition to bladder cancer, ultimately leading to enhanced preventative measures and treatment strategies.
2.0Materials and methods
2.1Protocol and registration
The Preferred Reporting standards for Systematic Reviews and Meta-Analyses (PRISMA) served as our guide for conducting this systematic review (Shamseer et al., 2015). The review protocol was registered with PROSPERO and the study ID; CRD42022351101 is obtained (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022351101).
2.2Selection criteria
The inclusion criteria for this systematic review were as follows: studies had to be published in peer-reviewed journals and be written in English. The design of the selected studies should be specifically GWAS with a focus on identifying intriguing genetic variants, particularly SNPs, related to bladder cancer. No restrictions were made based on language, demographics of the patients, or their ages. However, review is also excluded to prevent duplication of data.
2.3Search strategy and data source
Articles publish for the time period between January 1, 2000 and November 17, 2022, were retrieved from PubMed, the Cochrane Database of Systematic Reviews, ScienceDirect and the Lippincott database respectively. The searched databases, date, time of last search, search strategy employed, and the total number of results obtained in each database are described in in Table 1. Search strategies and search terms are in supplementary 1.
Our chosen search terms were tailored to suit the unique attributes of each database. For additional studies, we scrutinized the bibliographies of the studies included in our initial search, as well as the references in ISI Web of Knowledge. Our search strategy centered around keywords pertinent to Genome-Wide Association Studies (GWAS), bladder cancer, and susceptibility genes, which we merged with the MESH terms. To facilitate the review process, we employed Covidence, an online tool designed to streamline the screening and data extraction stages of systematic reviews (Kellermeyer et al., 2018). Two independent co-reviewers, Aliyu Adamu Ahmad and Umar Muhammad separately screened the downloaded articles. The screening was based on the article title, the defined keywords, and the abstract, in line with the pre-established inclusion criteria.
2.4Study selection
Upon concluding the title and abstract screening, we gathered all potentially relevant full-text reports and publications. Two independent reviewers performed a thorough assessment of these full texts. Any studies that were excluded at this stage were documented along with the reasons for their exclusion. In the event of disagreements, resolution was reached through discussion among the review team members. We have provided a detailed account of the number of records retrieved from the literature searches, the quantity of included and excluded studies, as well as the specific reasons for exclusions. This information is represented via a PRISMA flow diagram, as illustrated in Figure 1.
2.5Data extraction
A customized data extraction sheet was used to capture information about; the first authors and year of publication, country of study, study design, case and controls, methods, genetic variants (SNPs), locus, genes, alleles, p values and associations. This step was carried out by the first reviewer (Aliyu Adamu Ahmad) and the extracted data were then cross-checked by the second reviewer (Umar Muhammad).
2.6Quality assessment
Two reviewers (AAA and UM) independently assessed the quality of each included article using the Newcastle-Ottawa Scale (NOS) (Lo et al., 2014). The NOS is made out of eight components that are divided into three domains: (1) choosing study groups, (2) determining exposure and results, and (3) group comparability to gauge the caliber of observational studies. Studies received a maximum rating of nine stars, and ratings were based on a star system. Studies with less than three stars were labelled as low quality, those with four to six stars as moderate quality, and those with seven to nine stars as high quality. In order to minimize errors and reduce bias, steps in the review process were independently duplicated, especially when choosing studies and extracting data. Independent reviewers looked at both eligible and ineligible articles after the initial screening of the articles.
3.0Results
3.1Literature search
Figure 1 depicts the flow diagram outlining the procedures involved in article selection in accordance with PRISMA standard for systematic review (Shamseer et al., 2015). The search strategy generated 16,972 records after removing the duplicates. Upon collating the search results from the six electronic databases (PubMed, Google Scholar, ScienceDirect, Cochrane Library, and Lippincott), a total of 12,868 studies were ruled out. The reasons for disqualification were their irrelevance to Genome-Wide Association Studies (GWAS), lack of focus on bladder cancer in human subjects, or absence of an abstract.
Following the screening of titles and abstracts, we undertook a detailed examination of the full texts of the remaining 80 articles, evaluated against the predetermined inclusion criteria. At this stage, studies were excluded for several reasons: randomized study design (n = 13 instances), inappropriate study design (n = 38 instances), unsuitable setting (n = 9 instances), incorrect outcome focus (n = 6 instances), and inappropriate population (n = 1 instance). Upon thorough evaluation and application of the selection criteria, thirteen studies were ultimately deemed suitable for inclusion in this review. These selected studies originated from various authors and were published between the years 2009 and 2022. The comprehensive list includes studies conducted by Figueroa et al., (2015), Gu et al., (2011), Matsuda et al., (2015), Garcia-closas et al., (2011), Wang et al., (2009), Rafnar et al., (2011), Wu et al., (2012), Figueroa et al., (2014), Matsuda et al., (2015), Kiemeney et al., (2010), (Xu et al., 2020), Mamdouh et al., (2022), and Stern et al., (2009).
3.2Characteristics of the data extracted from the studies
Table 1 summarizes the main characteristics of the selected studies that identified the genetic susceptibility loci associated with bladder cancer by systematically reviewing previous genome-wide association studies (GWAS). All included studies had a case–control study design (Figure 2A). Most of these studies (62%) had ≥ 1000 participants in both the case and control groups. Six studies (46%) were conducted in America, three studies (23%) in Asia, Europe had two studies (15%), one study in Africa (8%) and, interestingly, one study (8%) was jointly conducted in America and Asia (China and USA) (Figure 2B & C). Furthermore, out of the 22 genetic susceptibility loci associated with bladder cancer identified in the included studies, the most frequently appearing SNP was 20p22.2 (seven times), followed by 18q12.3 (four times), and 3q28 and 5q15.3 appeared three times each (Figure 3A). For allele, eight different combinations were observed, with C/T appearing most frequently (nine times) and A/T appearing less frequently (one time) (Figure 3B). In addition, rs6104690, rs71052, and rs9642880 were the most appearing SNPs (appeared three times each) and rs401681 and rs1014971(appeared twice each) (Figure C). For genes, PSCA appeared more often than any other gene.
3.3Quality assessment
Twelve of the included studies (92%) were rated high quality based on the NOS assessment procedure. These studies had a total of between 8-10 stars (table 4.2) based on subject selection, comparability of the cases and controls, and exposure to experimental procedures. Only one study was rated moderate because of the absence of clear information on the selection and exposure domains (please insert citation for Chenyang Xu 2020). Therefore, all the 13 included studies had moderate to high quality and hence were included in the quantitative synthesis.
Discussion
This study presents a comprehensive overview of genetic susceptibility to bladder cancer, drawing from a meticulous systematic review of 13 Genome-Wide Association Studies (GWAS). It is worth noting that this systematic review represents one of the most extensive analyses of bladder cancer-related GWAS to date. Our objective was to synthesize the findings of these studies, shedding light on the genetic correlations between bladder cancer and associated susceptible genes. This review was necessitated by the significant public health impact of bladder cancer, which accounted for an estimated 16,000 fatalities in the United States in 2015, affecting both men and women (Wang et al., 2016).
Association between the polymorphisms and bladder cancer risk
Within the spectrum of genetic variations associated with bladder cancer, chromosome 18q12.3 emerges as particularly vulnerable, harboring four polymorphisms on the same locus. These include rs7238033, rs10775480, and rs11082469 on 18q12.3 (Garcia-closas et al., 2011), as well as rs17674580 on chromosome 18q12.3 (Xu et al., 2020). Additionally, three polymorphisms were reported on chromosome 5p15.3, with rs2736098 and rs401681 on 5p15.33 (Rafnar et al., 2011) and rs401681 on 5p15.3 (Xu et al., 2020). Among the studies, the largest GWAS, conducted by Rafnar et al., (2011), involving 4147 cases and 34988 controls, identified rs9642880 G/A and rs710521 C/T as having stronger associations with bladder cancer risk (P=0.125 and P=0.254, respectively). Figueroa et al., (2015) identified rs6104690 and rs6108803 as significantly linked to MICB risk (P ≤ 0.03). Intriguingly, when accounting for the recently discovered SNP rs6108803 in locus 20p12.2, the link for 20p12.2 rs62185668 was no longer significant (P = 0.25) (Figueroa et al., 2015).
Furthermore, Matsuda et al., (2015) identified that the SNP rs398652 on 14q21, previously associated with leukocyte telomere length, was linked to a lower risk of bladder cancer (P = 0.028771). Chromosome 15q24’s SNP also showed a significant correlation with bladder cancer (P-value of 1.22 × 10^−24) according to Matsuda et al., (2015). Wang et al., (2009) found that individuals with the GT/TT genotype of the rs9642880 G/T polymorphism had a significantly increased risk of bladder cancer compared to those with the GG genotype. Additionally, a missense mutation (rs2294008) in the PSCA gene consistently correlated with bladder cancer in US and European populations (Wu et al., 2012). Stern et al., (2009) suggested that the rs710521 A allele may increase the risk of developing low-risk urinary bladder cancers.
Association between the genes and bladder cancer risk
The genetic factors implicated in bladder cancer risk are multifaceted. For instance, Pellino homolog 2 (PELI2) was linked to the inflammatory response and cytokine production, suggesting that chronic inflammation could contribute to the relationship between rs398652 telomere length and cancer risk (Gu et al., 2011). Higher activity of the CYP1A2 gene on chromosome 15q24, which metabolizes carcinogenic compounds from tobacco, was associated with an increased risk of tobacco-related malignancies (Matsuda et al., 2015). The solute carrier family 14 member 1 gene (SLC14A1), governing urine volume and concentration in the kidney, may offer new insights into the etiology of bladder cancer (Garcia-closas et al., 2011). MYC, a multifunctional protein controlling cell division, proliferation, and apoptosis, exhibited higher mRNA and protein levels in bladder tissues of individuals with the rs9642880 GT/TT genotypes (Mamdouh et al., 2022; Wang et al., 2009). In the region of TP63 on chromosome 3q28, Rs710521 and TP53 were identified, with the A allele of rs710521 strongly associated with an increased risk of bladder cancer in the Egyptian population (Wen et al., 2019).
Conclusion
Despite this comprehensive analysis, our understanding of the genetic predisposition to bladder cancer remains incomplete, with the majority of robust data derived from GWAS. This systematic review did not yield additional genetic association evidence.
As the current knowledge of genetic susceptibility to bladder cancer has limited implications for public health, larger cohorts are imperative to identify more significant polymorphisms across the genome. Further research is essential to unravel the complex genetic underpinnings of bladder cancer and pave the way for targeted interventions and personalized treatments.
Declarations
Availability of data and material
All data associated with this study are accessible via this link: https://github.com/babasaraki/systematic-review-GWAS
Competing interests
Authors declare that there is no conflict of interests.
Funding
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Supporting information
Data Availability
All data produced are available online at https://github.com/babasaraki/systematic-review-GWAS
https://github.com/babasaraki/systematic-review-GWAS/tree/main
List of abbreviations
- (Bca/BC)
- Bladder cancer
- (GWAS)
- Genome-wide associated studies
- (SNP/SNPs)
- Single nucleotide polymorphism
- (MIBC)
- Muscular-invasive bladder cancer
- (NMIBC)
- Non-muscular invasive bladder cancer
- (UC)
- Urothelial Carcinoma
- (SCC)
- Squamous cell carcinoma
- (TCC)
- Transitional cell carcinoma