Introduction
The three most common cancers of the female reproductive system are cervical cancer, endometrial cancer, and ovarian cancer. Globally, in 2020, cervical cancer was the fourth most common cancer among women, with approximately 604,000 new cases and 342,000 associated deaths, endometrial cancer was the second most common malignant cancer of the female reproductive system, with approximately 417,367 new cases and 97,370 deaths, and ovarian cancer ranked at the top among malignant tumors of the female reproductive system, with approximately 313,959 new cases and 207,252 deaths [1].
In recent years, there has been a significant increase in cancer incidence and mortality rate among patients with autoimmune diseases, attracting considerable attention [2–7]. The increased risk of cancer may be attributed to the autoimmune system, medication, age, sex, and other heterogeneous factors. An autoimmune disease, systemic lupus erythematosus (SLE) is a complex, chronic, and systemic, that affects multiple organ systems to varying degrees. Malignant tumors are one of the primary causes of death in patients with SLE and a major concern in its long-term management [3, 4, 8–10]. An increasing number of observational studies over the past decade have supported the association between SLE and the occurrence and development of cancers, indicating that patients with SLE have a higher incidence of malignant tumors than the general population, with an increase in the risk of certain types of malignancies, such as lymphoma and thyroid cancer, being an issue of concern among patients with SLE [8–10]. SLE mainly affects women, with the male-to-female ratio being as high as 1:10 [11]. The most common types of malignant tumors, such as breast, cervical, ovarian, and endometrial cancer, in patients with SLE are those commonly found in women in the general population. Despite this, less attention has been paid to cancers related to women. Therefore, in this study, the causal relationship was explored between SLE and common malignant tumors of the female reproductive system, including cervical, endometrial, and ovarian cancers.
Several earlier observational studies have found higher risk of certain types of malignant tumors in SLE, often showing a positive association with hematologic malignancies (such as non-Hodgkin's lymphoma) and thyroid cancer, and a negative association with hormone-sensitive tumors (including endometrial, breast, ovarian, and prostate cancer) [12–15]. However, a few results from other observational studies are inconsistent. One meta-analysis conducted by Clarke et al. in 2021evaluated the risk of more than 40 types of malignant cancers in SLE, and reported an 18% increase in comprehensive risk of all malignant tumors in patients with SLE compared to that in the general population. That study identified 24 site-specific malignant tumors with increased risk, including cancers of female reproductive system such as cervical, vulvar, and vaginal cancer, and four malignant tumors with reduced risk, including endometrial cancer; for the remaining 11 malignant tumors, including ovarian cancer, no evidence of an increased risk in SLE patients was observed [9]. Some observational studies contradict these findings; for example, a cohort study in China reported an increased risk of endometrial cancer in patients with SLE, and an increased incidence of ovarian cancer in populations in Asia [16] and Europe [17]. According to some scholars, SLE and immune system activation or dysregulation render malignant tumors more susceptible [18]. Some researchers have discovered that medications used to treat SLE can lead to cancer [19], while others believe that patients with SLE may harbor other, including genetic susceptibility and lifestyle-related risk factors, factors that increase susceptibility to cancer [20]. Thus, the potential causal relationship between the genetic susceptibility to SLE and the risk of common cancers of the female reproductive system is not yet clear.
These observational studies may be limited by sample size and potential confounding factors, with occasionally inconsistent results. Compared to classical observational studies, Mendelian randomization (MR) analysis is a new epidemiological research approach that uses genetic variants as instrumental variables (IVs) to examine the causal effects of exposures on outcomes [20]. Single nucleotide polymorphisms (SNPs) are the most commonly used genetic variants as IVs in MR analysis. In this approach different individuals are randomly assigned with different SNPs, allowing MR to remain unaffected by traditional confounding factors, overcoming biases, and being less influenced by reverse causality, achieving effects similar to those of random allocation. For MR studies, genome-wide association studies (GWAS) provide powerful and reliable IVs [21]. Therefore, in the absence of high-quality randomized controlled trials (RCTs), MR analysis can serve as an important approach for inferring causal relationships.
This study aimed to employ through MR analysis and explore any potential causal relationship between the genetic susceptibility of SLE and common cancers of the female reproductive system, including cervical, endometrial, and ovarian cancers, beyond other factors, such as a decline in autoimmunity and medication effects. The aim of this study was to help us make informed decisions about the need for early intervention or treatment for patients with SLE in a clinical setting.
Methods
Data sources
Exposure variables for SLE and outcome variables for cervical, endometrial, and ovarian cancer were obtained by searching the GWAS summary data. Summary data for patients with SLE were obtained from the public GWAS summary dataset ebi-a-GCST003156 (https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST003156/). Finally, 14,267 samples (5,201 cases and 9,066 controls) were included. Data for cervical cancer were obtained from the public GWAS summary dataset ukb-b-8777 of UK Biobank (https://gwas.mrcieu.ac.uk/datasets/ukb-b-8777/), comprising 462,933 samples (1,889 cases and 461,044 controls). The datasets for endometrial cancer come from the public GWAS abstracts ebi-a-GCST90018838 dataset (https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST90018838/) and ebi-a-GCST006464 dataset (https://gwas.mrcieu.ac.uk/datasets/ebi-a-GCST006464/). The datasets included 240,027 samples (2,188 cases and 237,839 controls) and 121,885 samples (12,906 cases and 108,979 controls). The dataset for ovarian cancer was sourced from the public GWAS summary ieu-a-1120 dataset (https://gwas.mrcieu.ac.uk/datasets/ieu-a-1120/) and comprised 66,450 samples (25,509 cases and 40,941 controls). Potential biases due to population stratification were minimized by limiting the databases for SLE and common cancers in females to individuals of European ancestry. Detailed information about these data is summarized in Table 1.
Table 1. The summary of GWAS data in this MR study
Exposure/ outcome | Race | Sample | Case/control | SNP | Years | Author |
---|---|---|---|---|---|---|
SLE | European population | 14,267 | 5201/9066 | 7,071,163 | 2015 | Bentham J |
Cervical cancer | European population | 462,933 | 1,889/461,044 | 9,851,867 | 2018 | Ben Elsworth |
Endometrial cancer | European population | 240,027 | 2188/237,839 | 24,135,295 | 2021 | Sakaue S |
Endometrial cancer | European population | 121,885 | 12,906/108,979 | 9,470,555 | 2018 | O’Mara TA |
Ovarian cancer | European population | 66,450 | 25,509/40,941 | 15,594,303 | 2017 | Phelan |
Study design
A two-sample MR analysis was conducted employing the GWAS database to assess the causal relationship between the genetic susceptibility of SLE and the risk of common female reproductive tract cancers. SNPs were selected as IVs for the two-sample randomization analysis. An overview of the study design is presented in Fig. 1. The entire process was according to the three primary assumptions of classical MR, that: 1. IVs directly affect the exposure (SLE), 2. IVs are independent of confounding factors, and 3. IVs influence the outcome only through exposure and not through other pathways [21, 22].
Fig. 1 [Images not available. See PDF.]
Mendelian Randomization Study Design Flowchart
Selection of instrumental variables
In the MR analysis, significant SNPs with genome-wide significance associated with SLE were selected as IVs through the GWAS database, through strict selection criteria (P < 5 × 10–8). To minimize linkage disequilibrium (LD)-affected biases on the distribution of random alleles, LD parameters were set to r2 < 0.01 and kb = 10,000, ensuring a that the IVs had a certain degree of independence. The obtained sensitive SNPs were analyzed in the GWAS databases for cervical cancer, endometrial cancer, and ovarian cancer, and any missing SNPs were excluded. Finally, the F-value for each IV was determined, and SNPs with F > 10 were included, while those with F < 10 were considered weak instruments and were not included in subsequent analysis [22, 23].
Two-sample Mendelian randomization analysis
This inverse variance weighted method (IVW) of the random effects model was primarily utilized to investigate the potential causal relationship between SLE and common female reproductive system cancers (cervical, endometrial, and ovarian cancer). Additionally, supplementary analyses, such as the weighted median method (WM), MR-Egger regression, and simple and weighted mode-based estimations, were employed to assess the causal relationship between the two. The results of the MR analysis were presented as odds ratios (OR) and their 95% confidence interval (CI). An OR > 1 indicated a positive correlation, and an OR < 1 indicated a negative correlation. For statistical significance, a P-value of < 0.05 was considered. To ensure robustness, the Bonferroni correction method was used to define the significance level (0.05/3 cancer types = 0.017); results having a P-value < 0.017 were deemed as significant evidence, and results with 0.017 < P < 0.05 were deemed suggestive, indicating that they did not reach the significance level after Bonferroni correction, although they did achieve the traditional 0.05 level [21].
Sensitivity analysis
Heterogeneity testing was performed employing Cochran's Q test to examine the heterogeneity among the causal inferences of all IVs in the IVW and MR-Egger methods, that assessed the heterogeneity of individual genetic variations. The Cochran's Q value was calculated to quantitatively assess the heterogeneity of SNPs. Pheterogeneity < 0.05 indicated the presence of heterogeneity, and represented the influence of confounding factors on the exposure and outcome relationship. The horizontal pleiotropy was detected using MR-Egger intercept method and funnel plot. The MR-Egger intercept method estimated any significant effect of genetic variation on the outcome through pathways other than exposure. Ppleiotropy < 0.05 indicated the existence of horizontal pleiotropy, meaning that the selected IVs significantly affected the outcome via pathways other than exposure. Additionally, stability was assessed by drawing a funnel plot to observe symmetry. An asymmetrical funnel plot indicated the presence of horizontal pleiotropy. Finally, a leave-one-out sensitivity test was conducted to assess whether the MR results were effective and stable. For this, individual SNPs were gradually removed, and the remaining SNPs were used to estimate the causal effect. The results of the leave-one-out test were presented using a forest plot.
All analyses in this study were performed using the R4.1.2 software and the "TwoSampleMR" and "MendelianRandomization" packages in RStudio (version 1.2.5019). The ggplot2" package was used to generate scatter, forest, and funnel plots. The study did not involve ethical approval issues as the data used in this study were derived from public summary data.
Results
Determination of instrumental variables
Using R software, genetic variation SNP loci with SLE-related genome-wide significance (P < 5 × 10–8) were selected for aggregation. The linkage disequilibrium parameters were set to r2 > 0.001 and kb = 10,000, and non-compliant SNPs were removed; finally, 45 independent SNPs were screened. From publicly available databases for cervical, endometrial, and ovarian cancers, 20, 42, and 31 SNPs, respectively, that simultaneously satisfied hypotheses 1, 2, and 3 were extracted (Tables 3, 4, 5 in the appendix). The F-statistic values for all IVs were > 10, indicating that the IVs included in this MR analysis possessed sufficient strength, confirming the reliability of the results.
The results of Mendelian randomization analysis
The IVW method of the random effects model was employed to analyze the findings from the two-sample MR study. The results indicated no significant causal association between SLE and cervical cancer (OR = 0.999 974 2, 95% CI [0.999 752 0–1.000 197], P = 0.820), nor with endometrial cancer (OR = 0.976 316 9, 95% CI [0.948 392 7–1.005 063], P = 0.105), or ovarian cancer (OR = 0.987 893 9, 95% CI [0.966 647 1–1.009 608], P = 0.272). Although the odds ratios for both endometrial and ovarian cancers were less than 1, their p-values exceeded the significance threshold of 0.05.
The analysis methods, including MR-Egger, weighted median, simple mode, and weighted mode yielded results consistent with the main IVW analysis method, further proving no significant causal relationship between SLE and cervical, endometrial, and ovarian cancers (all P-values > 0.05). In addition, we analyzed another GWAS data and found a causal relationship between SLE and endometrial cancer (OR = 0.96, 95%CI [0.94–0.99], P = 0.004). The results of the above-mentioned five common MR analysis methods are mentioned in Table 2 and Fig. 2.
Table 2. MR analysis results, heterogeneity test, and pleiotropy test results of the common malignant tumors in the female reproductive system with SLE
Outcome | MR method | SNPs | OR | 95%CI | P | Heterogeneity P-value Pheterogeneity | Global test P-value Ppleiotropy |
---|---|---|---|---|---|---|---|
cervical cancer | MR Egger | 20 | 0.9999674 | 0.9994036–1.000532 | 0.9111910 | 0.8708548 | 0.9797716 |
Weighted median | 20 | 0.9999489 | 0.9996401–1.000258 | 0.7396628 | |||
IVW | 20 | 0.9999742 | 0.9997520–1.000197 | 0.8203584 | 0.9049602 | ||
Simple mode | 20 | 0.9999755 | 0.9994363–1.000515 | 0.9227421 | |||
Weighted mode | 20 | 0.9999569 | 0.9996159–1.000298 | 0.8112230 | |||
endometrial cancer | MR Egger | 42 | 0.9858688 | 0.9272318–1.048214 | 0.6516376 | 0.5363098 | 0.7257479 |
Weighted median | 42 | 0.9645530 | 0.9230065–1.007970 | 0.0888895 | |||
IVW | 42 | 0.9763169 | 0.9483927–1.005063 | 0.1054741 | 0.5751958 | ||
Simple mode | 42 | 0.9692011 | 0.8924385–1.052566 | 0.3968641 | |||
Weighted mode | 42 | 0.9692011 | 0.9178899–1.023381 | 0.2707590 | |||
ovarian cancer | MR Egger | 31 | 1.0270407 | 0.9671607–1.090628 | 0.3911492 | 0.4025248 | 0.6346761 |
Weighted median | 31 | 0.9905470 | 0.9645862–1.027502 | 0.4925948 | |||
IVW | 31 | 0.9878039 | 0.9666491–1.009608 | 0.2722005 | 0.4372107 | ||
Simple mode | 31 | 1.0084270 | 0.9593472–1.060018 | 0.7439524 | |||
Weighted mode | 31 | 0.9939198 | 0.9531501–1.036433 | 0.6154643 |
Fig. 2 [Images not available. See PDF.]
Scatter plot results of MR analysis of SLE and common malignant tumors in the female reproductive system
Sensitivity analysis
The IVW method was used to calculate the heterogeneity of the MR analysis results of the relationship between SLE and common cancers of female reproductive system, the following heterogeneity results were obtained: for SLE and cervical cancer, Pheterogeneity = 0.905; for SLE and endometrial cancer, Pheterogeneity = 0.575; for SLE and ovarian cancer, Pheterogeneity = 0.437. All P-values were > 0.05, indicating no significant heterogeneity. The results of horizontal pleiotropy test obtained using the MR Egger intercept method showed Ppleiotropy values = 0.979 for SLE and cervical cancer, 0.726 for SLE and endometrial cancer, and 0.635 for SLE and ovarian cancer. All P-values were > 0.05, suggesting that IVs did not significantly affect the outcome in terms of confounding factors or other pathways other than exposure.
A sensitivity analysis the leave-one-out approach was conducted, which indicated that the results of the MR analysis for cervical, endometrial, and ovarian cancers did not fluctuate when individual SNPs were excluded, as shown in Fig. 3. Finally, the funnel plot demonstrated a symmetrical distribution, that the causal effects between SLE and cervical, endometrial, and ovarian cancers were stable and reliable. This is depicted in Fig. 4.
Fig. 3 [Images not available. See PDF.]
Leave-one-out sensitivity analysis plot of SLE and common malignant tumors in the female reproductive system. Black points represent the log odds ratio (OR) for SLE per standard deviation (SD) increase in cervical cancer, endometrial cancer and ovarian cancer, which is produced by using each SNP selected as a separate instrument. Red points show the combined causal estimate using all SNPs together as a single instrument, using the inverse‐variance weighted estimate (IVW) method. Horizontal line segments denote 95% confidence intervals of the estimate
Fig. 4 [Images not available. See PDF.]
Funnel plot of two-sample MR analysis results. The blue line represents the inverse‐variance weighted estimate (IVW), and the dark blue line represents the Mendelian randomization‐Egger (MR Egger) estimate
Discussion
There is evidence for a relationship between SLE and cancer is growing, including multiple observational studies and meta-analyses, but due to flaws in study design, the causal effect of this relationship has not yet been elucidated. This study is the first to employ the MR method based on GWAS summary database statistics to assess and detect the causal relationship between SLE and the risk of common cancers of the female reproductive system in the European population. Unfortunately, this study reveals no obvious causal relationship between SLE and the occurrence of cervical, endometrial, and ovarian cancers in European populations.
Earlier reports by the observational studies on the incidence of cervical cancer in patients with SLE have been conflicting. Most studies believe that the incidence of cervical cancer is increased in women with SLE, with those receiving immunosuppressants being at the highest risk [18, 23–26]. On the contrary, some studies have found similar incidence of cervical cancer to that of the normal population [14, 27]. In fact, one large study from the California Cancer Registry in the United States showed that compared with the general population, there is a significantly reduced risk of cervical cancer in women with SLE [28]. Considering the mechanism by which SLE leads to an increased incidence of cervical cancer, a cross-sectional analysis in Brazil reported that patients with SLE had an increased rate of HPV infection compared with controls (OR = 7.2) [29]. The increased risk of malignancy may be related to impaired HPV clearance in patients with SLE [18]. Most studies support this and belief that the long-term use of immunosuppressants, especially cyclophosphamide, by patients with SLE may lead to cervical dysplasia and an increase in human papillomavirus (HPV) infection rates, leading to increased rate of occurrence of cervical tumors [24, 30, 31]. However, some studies also hypothesize on the contrary. Even though the incidence of cervical cancer in patients with SLE is significantly increased, there is no correlation between the use of immunosuppressants and glucocorticoids and the increased frequency of cervical abnormalities [26, 29, 32, 33].
Several large-sample epidemiological studies have reported a reduced risk of endometrial cancer in patients with SLE [13, 14, 34]. In an international multicenter (30 centers) prospective cohort study, 16,409 SLE patients were followed up for a total of 121,283 times; among these patients, the risk of endometrial cancer was reduced (standardized incidence rate [SIR] = 0.44; 95% CI 0.23–0.77) [34]. Furthermore, in a meta-analysis of five large SLE cohorts involving 47,325 patients with SLE, including 42,171 female patients with SLE, the data strongly supported the protective effect of SLE against the endometrial cancer against cancer (SIR = 0.71, 95% CI [0.55–0.91] [13]. While most studies support a reduced risk of endometrial cancer in patients with SLE, the opposite findings were noted in a Chinese cohort study [7] As a result, SLE patients in this study had an increased risk of endometrial cancer (SIR 5.38, 95% CI [1.97–11.71]). Currently, the mechanism of SLE-mediated decrease in the risk of endometrial cancer is not clear. Some scholars opine that long-term administration of oral immunosuppressants to patients with SLE may cause reduced endogenous estrogen exposure, thereby minimizing the occurrence of estrogen-dependent endometrial cancer [13, 35]. Some scholars also believe that the immune surveillance ability of hormone-dependent cancers important in SLE are more active in patients [5].
Ovarian cancer is rare in SLE, and its incidence is reported to account for only 0.1% of patients with SLE [4]. Previous observational studies have also had different results. Most studies propose that patients with SLE have a reduced risk of ovarian cancer. Some scholars believe that SLE can reduce the risk of hormone-sensitive cancers such as endometrial and ovarian cancers. This is due to changes in estrogen or other female hormone metabolism in SLE patients, which delays the occurrence of hormone-sensitive cancers [4, 6]. In addition, some other studies have proposed that the presence of a nuclear lupus autoantibody in patients with SLE may help prevent the mechanism of DNA repair in ovarian cancer related to breast cancer gene 2 (BRCA2) mutations [36–38]. Nonetheless, the results of most observational studies are contrary. In a large nationwide cohort study in South Korea, including 763 patients with SLE and 2667 control subjects, the prevalence of ovarian cancer in patients with SLE was higher than that in the general population (OR 1.79; 95% CI [1.186–2.636]; P = 0.0035) [15]. In another nationwide cohort study in Denmark, the risk of ovarian cancer increased 2–4 times in patients with SLE (SIR 2.22, 95% CI [0.89–4.58]) [16].
Therefore, previous observational studies on the risk of SLE and common cancers of the female reproductive system such as cervical, endometrial, and ovarian cancers have obtained inconsistent results, and the design and analysis of causal associations in observational studies may be affected by confounding bias and sample size. Thus, to explore the causal relationship better, this study used MR analysis to examine the relationship between SLE and common cancers of the female reproductive system (cervical, endometrial, and ovarian cancers) risk. The results of this study do not align with the results of some previous cohort studies. In the MR analysis of this study, there was no obvious causal relationship between SLE and the risk of cervical, endometrial, and ovarian cancer in the European population, with the P-values being > 0.05. Therefore, the apparent causal relationship in previous observational studies may be attributed to confounding factors affecting the disease onset rather than the genetics of the disease itself. In many observational studies, the increased incidence of cervical cancer in patients with SLE may be related to the long-term use of immunosuppressants and their high HPV infection rate. Although this study does not support a genetic causal relationship between SLE and cervical cancer, considering the high HPV infection rate it may lead to, strengthening HPV and cytological screening for cervical cancer and administering HPV vaccines to these patients may reduce the incidence of cervical cancer in this population. This concept is also currently employed by several research centers [24, 39, 40]. Most previous cohort studies suggested that patients with SLE have a reduced risk of endometrial cancer, in this study, in MR analysis, although no statistically significant causal effect was observed, the risk of endometrial cancer was reduced. The P-value was close to 0.1 and the OR value was 0.976, suggesting SLE as a protective factor for endometrial cancer.
This study has the following advantages: first and primarily, when high-quality RCT studies cannot be conducted, MR design can help in inferring the causal relationship between the two diseases. Through MR analysis, the influence of confounding factors and reverse causation can be avoided. Second, this study is the first to elucidate the association between SLE and common cancers of female reproductive system, providing a directional reference for subsequent research. This study simultaneously used the GWAS database to study a large sample size of the population, and the exposure and results obtained from different database datasets, which reduce interference from overlapping samples. In addition, the IVs used in this study are strongly correlated SNPs, and sensitivity analysis includes three methods: heterogeneity, pleiotropy, and leave-one-out detection. Hence, the exposure and outcome samples in this study are more comparable, with more convincing conclusions.
Nonetheless, the current MR analysis had several limitations. First, all samples in this study were from European populations, although, this avoids racial bias caused by population heterogeneity. However, whether the results of this study can yield the same results in other populations is unknown. More research is needed to verify the applicability of these findings to other populations and races. Second, cervical cancer may be HPV-related and non-HPV-related, endometrial cancer may be estrogen-dependent and non-estrogen-dependent, and the mechanism of ovarian cancer differentiation is also unclear. Likewise, different cancers may have different incidence rates in patients with SLE; however, due to limitations of the original data, subgroup analysis could not be performed, and the relationship between patients with SLE and common female reproductive system cancers could not be fully evaluated.
In summary, two-sample MR was used to analyze the causal association between SLE and the risk of common cancers of the female reproductive system, such as cervical, endometrial, and ovarian cancers. The current results do not yet support a causal relationship between SLE and cervical cancer, endometrial cancer, and ovarian cancer, but there may be a potential protective effect on endometrial cancer. Thus, it is necessary to explore the potential mechanism of the relationship further between SLE and the incidence of cervical, endometrial, and ovarian cancers. Considering the risk of cervical cancer, based on previous research findings, there is a need to strengthen cervical cancer screening and HPV vaccination for the population with SLE.
Acknowledgements
Not applicable.
Author contributions
Cheng Sirong and Wang Zanhong, designed the study, collected data and wrote the manuscript. Kun Zhang, Yinxia Yang, Yuxuan Zhong and Pengyu Sun supervised the study, provided language help and writing assistance. All authors reviewed and commented on the manuscript. All authors approved the final version of the manuscript.
Funding
This study was supported by Shanxi Provincial Central Government guides local projects (grant Nos. YDZJSX2022B012).
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
1. Sung, H; Ferlay, J; Siegel, RL et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin; 2021; 71,
2. GBD 2017 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet; 2017; 392,
3. Song, L; Wang, Y; Zhang, J et al. The risks of cancer development in systemic lupus erythematosus (SLE) patients: a systematic review and meta-analysis. Arthritis Res Ther; 2018; 20, 270. [DOI: https://dx.doi.org/10.1186/s13075-018-1760-3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30522515][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282326]
4. Cao, L; Tong, H; Xu, G et al. Systemic lupus erythematous and malignancy risk: a meta-analysis. PLoS ONE; 2015; 10, [DOI: https://dx.doi.org/10.1371/journal.pone.0122964] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25885411][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401738]
5. Pol, J; Paillet, J; Plantureux, C et al. Beneficial autoimmunity and maladaptive inflammation shape epidemiological links between cancer and immune-inflammatory diseases. Oncoimmunology; 2022; 11, 2029299. [DOI: https://dx.doi.org/10.1080/2162402X.2022.2029299] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35070497][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773133]
6. Yu, KH; Kuo, CF; Huang, LH et al. Cancer risk in patients with inflammatory systemic autoimmune rheumatic diseases. A nationwide population-based dynamic cohort study in Taiwan. Medicine; 2016; 95,[COI: 1:CAS:528:DC%2BC28Xns1alu74%3D] [DOI: https://dx.doi.org/10.1097/MD.0000000000003540] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27149461][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863778]
7. Zhou, Z; Liu, H; Yang, Y et al. The five major autoimmune diseases increase the risk of cancer: epidemiological data from a large-scale cohort study in China. Cancer Commun (Lond); 2022; 42,
8. Kiss, E; Kovacs, L; Szodoray, P. Malignancies in systemic lupus erythematosus. Autoimmun Rev; 2010; 9,
9. Clarke, AE; Pooley, N; Marjenberg, Z et al. Risk of malignancy in patients with systemic lupus erythematosus: systematic review and meta-analysis. Semin Arthritis Rheum; 2021; 51,
10. Bernatsky, S; Boivin, J; Manzi, S et al. Mortality in systemic lupus erythematosus. Arthritis Rheum; 2006; 54, pp. 2550-2557.[COI: 1:STN:280:DC%2BD28rgvFOrtw%3D%3D] [DOI: https://dx.doi.org/10.1002/art.21955] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16868977]
11. Justiz Vaillant, AA; Goyal, A; Varacallo, M. Systemic lupus erythematosus; 2022; Treasure Island, StatPearls Publishing Copyright:
12. Bjornadal, L; Lofstrom, B; Yin, L et al. Increased cancer incidence in a Swedish cohort of patients with systemic lupus erythematosus. Scand J Rheum; 2002; 31, pp. 66-71. [DOI: https://dx.doi.org/10.1080/03009740252937568] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12109649]
13. Bernatsky, S; Ramsey-Goldman, R; Foulkes, W et al. Breast, ovarian, and endometrial malignancies in systemic lupus erythematosus: a meta-analysis. Br J Cancer; 2011; 104, pp. 1478-1481.[COI: 1:STN:280:DC%2BC3MvmvFSguw%3D%3D] [DOI: https://dx.doi.org/10.1038/bjc.2011.115] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21487409][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101932]
14. Bernatsky, S; Ramsey-Goldman, R; Labrecque, J et al. Cancer risk in systemic lupus: an updated international multi-centre cohort study. J Autoimmun; 2013; 42, pp. 130-135. [DOI: https://dx.doi.org/10.1016/j.jaut.2012.12.009] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23410586][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646904]
15. Hang, J; Huang, J; Zhou, S; Wu, L; Zhu, Y; Zhu, L; Zhou, H; Xu, K; Jiang, H; Yang, X. The clinical implication of CD45RA+ naïve T cells and CD45RO+ memory T cells in advanced pancreatic cancer: a proxy for tumor biology and outcome prediction. Cancer Med; 2019; 8,
16. Bae, EH; Lim, SY; Han, KD et al. Systemic lupus erythematosus is a risk factor for cancer: a nationwide population-based study in Korea. Lupus; 2019; 28, pp. 317-323.[COI: 1:STN:280:DC%2BB3cjotlKjsw%3D%3D] [DOI: https://dx.doi.org/10.1177/0961203319826672] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30712493]
17. Westermann, R; Zobbe, K; Cordtz, R et al. Increased cancer risk in patients with cutaneous lupus erythematosus and systemic lupus erythematosus compared with the general population: a Danish nationwide cohort study. Lupus; 2021; 30, pp. 752-761.[COI: 1:CAS:528:DC%2BB3MXnvFKqsb0%3D] [DOI: https://dx.doi.org/10.1177/0961203321990106] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33497306]
18. Bernatsky, S; Ramsey-Goldman, R; Joseph, L et al. Lymphoma risk in systemic lupus: effects of disease activity versus treatment. Ann Rheum Dis; 2014; 73, pp. 138-142.[COI: 1:CAS:528:DC%2BC2cXitVaksrs%3D] [DOI: https://dx.doi.org/10.1136/annrheumdis-2012-202099] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23303389]
19. Dreyer, L; Faurschou, M; Mogensen, M et al. High incidence of potentially virus-induced malignancies in systemic lupus erythematosus: a long-term follow-up study in a Danish cohort. Arthritis Rheum; 2011; 63, pp. 3032-3037. [DOI: https://dx.doi.org/10.1002/art.30483] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21953088]
20. Goobie, GC; Bernatsky, S; Ramsey-Goldman, R et al. Malignancies in systemic lupus erythematosus—a 2015 update. Curr Opin Rheumatol; 2015; 27, pp. 454-460.[COI: 1:CAS:528:DC%2BC2MXht1Ohur7K] [DOI: https://dx.doi.org/10.1097/BOR.0000000000000202] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26125105][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562287]
21. Smith, GD; Ebrahim, S. “Mendelian Randomization”: can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol; 2003; 32,
22. Zheng, J; Baird, D; Borges, MC et al. Recent developments in mendelian randomization studies. Curr Epidemiol Rep; 2017; 4,
23. Hemani, G; Zheng, J; Elsworth, B et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife; 2018; 7, [DOI: https://dx.doi.org/10.7554/eLife.34408] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29846171][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976434]
24. Cader, RA; Mei Yee, AK; Yassin, A et al. Malignancy in systemic lupus erythematosus (SLE) patients. Asian Pac J Cancer Prev; 2018; 19,
25. Wadström, H; Arkema, EV; Sjöwall, C et al. Cervical neoplasia in systemic lupus erythematosus: a nationwide study. Rheumatology (Oxford); 2017; 56,
26. Zard, E; Arnaud, L; Mathian, A et al. Increased risk of high grade cervical squamous cell intraepithelial lesions in systemic lupus erythematosus: a meta-analysis of the literature. Autoimmun Rev; 2014; 13, pp. 730-735. [DOI: https://dx.doi.org/10.1016/j.autrev.2014.03.001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24657969]
27. Skare, TL; da Rocha, BV. Câncer cervical e de mama em pacientes com lúpus eritematoso sistêmico [Breast and cervical cancer in patients with systemic lupus erythematosus]. Rev Bras Ginecol Obstet; 2014; 36,
28. Cibere, J; Sibley, J; Haga, M. Systemic lupus erythematosus and the risk of malignancy. Lupus; 2001; 10,
29. Parikh-Patel, A; White, R; Allen, M et al. Cancer risk in a cohort of patients with systemic lupus erythematosus (SLE) in California. Cancer Causes Control; 2008; 19, pp. 887-894. [DOI: https://dx.doi.org/10.1007/s10552-008-9151-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18386139][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357418]
30. Lyrio, LDC; Grassi, MFR; Santana, IU et al. Prevalence of cervical human papillomavirus infection in women with systemic lupus erythematosus. Rheumatol Int; 2013; 33, pp. 335-340.[COI: 1:CAS:528:DC%2BC3sXhvV2mu7c%3D] [DOI: https://dx.doi.org/10.1007/s00296-012-2426-0] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22451033]
31. Tam, LS; Chan, AY; Chan, PK et al. Increased prevalence of squamous intraepithelial lesions in systemic lupus erythematosus: association with human papillomavirus infection. Arthritis Rheum; 2004; 50,
32. Tam, L-S; Chan, PKS; Ho, SC et al. Risk factors for squamous intraepithelial lesions in systemic lupus erythematosus: a prospective cohort study. Arthritis Care Res; 2011; 63, pp. 269-276. [DOI: https://dx.doi.org/10.1002/acr.20367]
33. Wang, Y; Fan, P; Feng, Y; Yao, X; Peng, Y et al. Clinical implication of naive and memory T cells in locally advanced cervical cancer: a proxy for tumor biology and short-term response prediction. Biocell; 2023; 47,
34. Kim, SC; Glynn, RJ; Giovannucci, E et al. Risk of high-grade cervical dysplasia and cervical cancer in women with systemic inflammatory diseases: a population-based cohort study. Ann Rheum Dis; 2015; 74,
35. Ladouceur, A; Tessier-Cloutier, B; Clarke, AE et al. Cancer and systemic lupus erythematosus. Rheum Dis Clin North Am; 2020; 46,
36. Ji, J; Liu, X; Sundquist, K; Sundquist, J. Survival of cancer in patients with rheumatoid arthritis: a follow-up study in Sweden of patients hospitalized with rheumatoid arthritis 1 year before diagnosis of cancer. Rheumatology (Oxford); 2011; 50, pp. 1513-1518. [DOI: https://dx.doi.org/10.1093/rheumatology/ker143] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21498553]
37. Noble, PW; Young, MR; Bernatsky, S et al. A nucleolytic lupus autoantibody is toxic to BRCA2-deficient cancer cells. Sci Rep; 2014; 4, 5958.[COI: 1:CAS:528:DC%2BC2MXktlKqtr4%3D] [DOI: https://dx.doi.org/10.1038/srep05958] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25091037][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380011]
38. Hansen, JE; Chan, G; Liu, Y et al. Targeting cancer with a lupus antibody. Sci Transl Med.; 2012; 4, [DOI: https://dx.doi.org/10.1126/scitranslmed.3004385] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23100628][PubMedCentral: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713477]
39. Wu, J; Liao, Q; Zhang, LI; Wu, S; Liu, Z. TGF-β-regulated different iron metabolism processes in the development and cisplatin resistance of ovarian cancer. Oncol Res; 2023; 32,
40. Bruera, S; Lei, X; Zogala, R et al. Cervical cancer screening in women with systemic lupus erythematosus. Arthritis Care Res (Hoboken); 2021; 73,
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Abstract
Lymphocytes are important for protective immunity against infections and cancers, and dysregulation of the immune system may lead to systemic lupus erythematosus (SLE). Metabolic adaptation regulates the fate of lymphocytes. The immune microenvironment is vital role in both SLE and gynecological malignancies. The disruption of the immune microenvironment in SLE is one of the key factors leading to disease occurrence. Overactive autoimmunity indices the body to attack its own tissues, leading to the formation of immune complexes that further trigger tissue damage and inflammation. This imbalance in the immune microenvironment affects the progression of SLE and may also indirectly affect the occurrence of gynecological cancers. For gynecological cancers, immune cells, cytokines, and chemokines in the tumor microenvironment jointly comprise a complex network, and their interactions determine cancer growth, invasion, and metastasis. Mendelian randomization analysis revealed that SLE does not have a statistically significant causal effect on the risk of common cancers of the female reproductive system such as cervical, endometrial, and ovarian cancers in the European population. However, the odds ratio < 1 in the inverse variance weighted results suggest the potential of SLE as a protective factor for endometrial cancer.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
Details
1 Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Department of Obstetrics and Gynecology, Shanxi Bethune Hospital, Taiyuan, China (GRID:grid.470966.a)
2 Shanxi Provincial People’s Hospital, Department of Surgical Oncology of Gastrointestinal Pancreatic Tumors, Taiyuan, China (GRID:grid.440288.2) (ISNI:0000 0004 1758 0451)