Next Article in Journal
Antibodies Specific to Rheumatologic and Neurologic Pathologies Found in Patient with Long COVID
Previous Article in Journal
Reducing Diagnostic Delay in Axial Spondyloarthritis: Could Lipocalin 2 Biomarkers Help?
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Rheumato
Volume 4
Issue 4
10.3390/rheumato4040017
rheumato-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Pathogenesis, Epidemiology, and Risk Factors of Malignant Tumors in Systemic Lupus Erythematosus

by
Dominika Blachut
*,
Brygida Przywara-Chowaniec
and
Andrzej Tomasik
2nd Department of Cardiology, Medical University of Silesia in Katowice, 41-800 Zabrze, Poland
*
Author to whom correspondence should be addressed.
Rheumato 2024, 4(4), 209-221; https://doi.org/10.3390/rheumato4040017
Submission received: 20 October 2024 / Revised: 14 December 2024 / Accepted: 18 December 2024 / Published: 23 December 2024
Browse Figure
Versions Notes

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease with a complex pathogenesis, primarily affecting women. SLE is associated with the presence of autoantibodies, chronic inflammation, and multi-organ dysfunction. Increasing evidence suggests that SLE is linked to a higher risk of malignancies, compared to the general population, though the mechanism behind this phenomenon remains unclear. Malignant tumors are the fourth most common cause of death in SLE patients. SLE is associated with an elevated risk of hematological cancers, as well as cancers of the lungs, thyroid, liver, and bile ducts. The aim of this paper is to review the latest literature on the pathogenesis, epidemiology, and risk factors for malignancies in SLE patients. The mechanisms of oncogenesis in SLE are still not fully understood, and the pathophysiology includes such risk factors as chronic inflammation, immune disorders, therapies used, overlap syndromes of connective tissue diseases, viral infections, and traditional cancer risk factors. Evaluating these factors and understanding the process of oncogenesis are crucial for prevention. Systemic lupus erythematosus may be an independent risk factor for the development of malignancies. It is important to raise awareness among SLE patients about the increased risk of malignancies. Further research is needed to establish guidelines for prevention, including screening recommendations.

1. Introduction

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease with a complex pathogenesis, primarily affecting women. SLE is associated with the presence of autoantibodies, chronic inflammation, and multi-organ dysfunction. Long-term therapy is related to the prolonged use of immunosuppressive drugs, which significantly influences the course of treatment and prognosis. Increasing evidence suggests that SLE is linked to a higher risk of malignancies compared to the general population, though the mechanism remains unclear. Numerous studies show that SLE is characterized by an altered cancer risk profile. In recent years, the association between SLE and a higher risk of malignancies, which may be up to 20% higher [1,2,3,4,5], has been emphasized. Although survival in SLE has significantly improved in recent years, mortality remains high, compared to the general population [6]. Malignant tumors are a common cause of death among patients with SLE and may account for as much as 30% of deaths [7]. SLE is likely associated with an increased risk of hematological cancers, as well as cancers of the lungs, thyroid, liver, and bile ducts. There is also a noted lower risk of breast, uterine, ovarian, or prostate cancer [6]. The overall risk of carcinogenesis may be up to 1.5 times higher, compared to the general population [4].
Malignant tumors are associated with genetic disturbances that lead to the activation of oncogenes and the simultaneous deactivation of tumor suppressor genes. Therefore, cell and tissue damage due to chronic inflammation may indirectly contribute to cancerous transformation. Additionally, the presence of specific inflammatory cells may modulate the immune response, thereby promoting oncogenesis [8,9,10,11]. The risk of oncogenesis in SLE may be closely linked to immunological pathways, genetics, and the use of immunosuppressive drugs. Immunological disorders characteristic of SLE may potentially contribute to an increased cancer risk. Immunosuppressive therapy used in SLE is related to the dysregulation of the immune system and may be a potential factor in oncogenesis. Mutational genes associated with the risk of malignancies have also been identified. Moreover, the disease itself, due to chronic inflammation, may contribute to oxidative stress, cytokine overexpression, impaired gene repair, and DNA damage [6,12,13]. However, the mechanisms behind the increased risk of malignancies are not yet fully understood.
The aim of this paper was to review the latest literature and present the most significant findings on the pathogenesis, epidemiology, and risk factors for malignancies in systemic lupus erythematosus. Databases were searched for the terms “systemic lupus erythematosus” and “malignant tumors”. The literature review was conducted based on publications indexed in the PubMed, Embase, Scopus, and Web of Science databases from the last 5 years, with a search extended to 10 years in cases where data were insufficient.

2. Pathogenesis

The mechanisms of oncogenesis in SLE remain unclear, and the pathophysiology involves risk factors such as chronic inflammation, immune disorders, disease activity, oxidative stress, the presence of antibodies, therapies used, overlap syndromes of connective tissue diseases (e.g., the overlap of SLE with Sjogren’s syndrome), viral infections, and traditional cancer risk factors (e.g., smoking and lung cancer) [1,2]. The process of oncogenesis is closely linked to genetic alterations that disrupt the apoptosis of abnormal cells. Although the body is protected by numerous mechanisms against the growth of cancerous cells, such as the elimination of mutated cells by NK cells, the release of pro-inflammatory chemokines and cytokines, and the differentiation of T cells, at some point, these defenses fail, leading to uncontrolled cancer cell growth. In autoimmune diseases such as systemic lupus erythematosus, there is improper activation of the immune system. The immune system, through the production of autoantibodies by plasma cells, activation of CD4+ T cells by reactive T cells, and aberrations in control proteins, leads to chronic inflammation [14,15,16,17,18,19,20,21,22,23,24,25,26].
Transforming growth factor-beta (TGF-β) promotes cancer progression by arresting the cell cycle, activating the PI3K/AKT/mTOR pathway and fibroblast growth factor (bFGF), and enhancing inflammation via NF-κB signaling [27,28,29,30,31]. NF-κB signaling is associated with immune dysfunction in autoimmune diseases. The NF-κB p50/p65 signaling cascade can activate other cells, such as T cells, B cells, toll-like receptors (TLR), and pro-inflammatory cytokines [32,33,34]. Chronic inflammation is associated with the excessive production of pro-inflammatory cytokines (e.g., tumor necrosis factor α (TNF-α), interleukin-6, interleukin-10), which may secondarily increase cancer risk [35]. Interferon-gamma (IFN-γ) promotes oncogenesis by impairing immunity, promoting apoptosis, decreasing BCL-2 expression, increasing programmed death-ligand 1 (PD-L1) expression, and inhibiting Th1 cell differentiation. However, IFN-γ can also inhibit tumor growth [36,37,38,39,40,41].
Epigenetic regulation disorders associated with SLE may be related to cancer, particularly through processes such as DNA methylation, mRNA activation, expression of a proliferation-inducing ligand (APRIL), and cytokine expression related to TNF [42]. In breast cancer pathogenesis in SLE, dendritic cells, NK cells, and CD8+ T cells are involved [43]. Autoantibodies associated with SLE can disrupt DNA repair, leading to DNA damage and subsequently increasing the risk of oncogenesis [44]. Anti-3E10 antibodies, poly (ADP-ribose) polymerase 1 (PARP-1), DNA ligase IV, and the ligase IV/XRCC4 complex are anti-DNA antibodies, and their dysfunction in SLE can lead to alterations in key DNA repair pathways, indirectly contributing to a higher cancer risk [45]. In many malignancies associated with SLE, genes linked to monocytes, such as IFI30, BLVRA, and RIN2, are strongly expressed. These genes are involved in interferon-related signaling pathways and are linked to monocyte-dependent immune responses. These three important genes could serve as potential biomarkers for cancers in SLE [12].
Abnormal cytokine expression can lead to excessive stimulation and apoptosis dysfunction, particularly in B cells. APRIL may help B lymphocytes avoid apoptosis, thus increasing cancer risk. Currently, cytokine expression disorders are associated with a higher risk of hematological cancers [42,46,47,48]. Overexpression of the AGRN gene is higher in cancer tissues in SLE, and it participates in T cell activation by binding to the α-DG protein. AGRN has been identified as a risk factor for the development of breast cancer, liver hepatocellular carcinoma, pancreatic adenocarcinoma, and prostate cancer and may be a potential prognostic biomarker [48]. The dysregulation associated with SLE and cancer is illustrated in Figure 1.
Research has shown that antibodies related to systemic lupus erythematosus may be associated with DNA repair disorders, which could indirectly lead to tumor formation [44]. Additionally, the presence of antiphospholipid antibodies (aPLA) increases the risk of both hematologic and solid tumors [13,42]. On the other hand, autoantibodies present in SLE may be linked to a reduced risk of certain hormone-dependent cancers, such as breast cancer. This is attributed to nucleolytic autoantibody anti-5C6, which is associated with impaired DNA repair mechanisms in hormone-dependent cancers related to BRCA2 mutations [44,49]. It is important to note that the immunological dysregulation in SLE leads to increased lymphocyte proliferation, raising the risk of developing hematologic cancers [35].
Environmental factors also play a role in oncogenesis. One such factor is smoking, which is a well-known cause of lung cancer [50]. The question remains whether the risk is comparable to that of the general population, higher, or related to disease monitoring. Another factor is reduced endogenous and/or exogenous exposure to sex hormones, leading to a lower risk of hormone-dependent malignancies (such as endometrial, breast, or prostate cancer) [13]. This is likely associated with delayed menarche and early menopause in women with SLE and hypoandrogenemia in men [2,13]. Due to the increased risk of thrombosis and lupus flare-ups, oral hormone therapy is often avoided in these patients, which may act as a protective measure. Immunosuppressive therapy significantly reduces hormone synthesis, resulting in lower estrogen exposure [51,52]. Another factor involves oncogenic viruses, such as human papillomavirus (HPV), Epstein–Barr virus (EBV), hepatitis B virus (HBV), and hepatitis C virus (HCV) [13,53,54]. Increased susceptibility to oncogenic viral infections may result from immune system dysfunction. However, the role of these viruses in SLE-related oncogenesis remains unclear.
Moreover, the use of immunomodulatory drugs, immune system disorders, and genetic factors may contribute to a shared mechanism associated with the increased cancer risk in SLE. Immunosuppressive therapy could theoretically cause mutagenesis and cytotoxicity. Additionally, due to the use of glucocorticoids and immunosuppressive drugs, SLE patients are more susceptible to oncogenic viruses [55]. A potential link is seen between the use of these therapies and an increased risk of malignancies, particularly with methotrexate, cyclophosphamide, azathioprine, or mycophenolate mofetil [1,56]. It is important to remember that some drugs are administered only briefly during flare-ups, making it difficult to establish an oncogenic link in SLE. Cyclophosphamide may have oncogenic potential, which increases with prolonged use, but available data are inconsistent. Cancers associated with cyclophosphamide therapy include bladder cancer, skin cancers, and leukemia [56,57,58]. Azathioprine has been linked to a sevenfold increase in the risk of hematologic cancers [59]. Long-term use of glucocorticosteroids and immunosuppressive drugs may increase the risk of prostate cancer [60,61,62]. Data on this issue are conflicting, with some researchers finding no link to carcinogenesis [55,63,64,65,66], while others suggest an increased risk [56,67,68]. A potential mechanism could be related to DNA damage processes [68]. SLE patients have an increased risk of developing liver cancer, which is associated with the presence of HBV and HCV [69].

3. Epidemiology

In recent years, numerous studies have highlighted the connection between systemic lupus erythematosus and a higher risk of malignant tumors, compared to the general population, with an increase of up to 20% [1,2]. Current data are conflicting regarding the timing of cancer development in SLE, with some reporting occurrences within the first year, between 1 and 9 years, or even after 10 years following the diagnosis of SLE. Cancer may affect as many as one in ten individuals with SLE [2,42,49,50]. The highest risk of developing cancer pertains to women with SLE under the age of 65 [70,71]. SLE is associated with an elevated risk of hematologic cancers, as well as cancers of the lungs, thyroid, pancreas, cervix, vulva and vagina, liver, and bile ducts [1,46,47,58,72,73].
Interestingly, SLE also shows a reduced risk, compared to the general population, for certain malignant cancers, such as breast cancer, melanoma, prostate cancer, and renal cell carcinoma [11,47,72,74]. The highest incidence rates in SLE are observed for breast, gynecological, and hematologic cancers [50,71,75]. According to literature, the cancers most frequently leading to death in SLE are, in women, breast cancer, colorectal cancer, and lung cancer and in men, lung cancer, colorectal cancer, and prostate cancer [49]. The overall mortality rate from malignant cancer in SLE ranges from 1.1 to 1.9 [4]. The standardized morbidity rates (SMR) for SLE in relation to all malignant cancers is 0.8 (0.6–1.0; 95% CI), and the standardized incidence ratio (SIR) is higher for most organ systems [49]. Table 1 presents the incidences of malignant cancers in SLE and the associated risk compared to the general population.
In cases of malignant hematological cancers in SLE, non-Hodgkin lymphoma (NHL) occurs at a frequency four times higher than in the general population, with the most common subtype being diffuse large B-cell lymphoma (DLBCL). Studies have demonstrated a connection between the pathophysiology of SLE and DLBCL, chronic inflammation through the activated NF-κB pathway, or the presence of antiphospholipid antibodies. In both diseases, genes such as CD177, CEACAM1, CDK1, KIF23, GPR84, IFIT3, PSMB10, PSMB4, TAF10, NFΚBI, and miR-155 are active, along with the expressions of B cell-related cytokines, B cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL), which could serve as potential diagnostic markers for DLBCL in SLE. These genes are strongly linked to inflammatory responses and immune pathways. Lower expression levels of GPR84 and IFIT3 are associated with greater sensitivity to immunotherapy and better overall survival in DLBCL patients [1,2,54,78,86,87]. Possible mechanisms are also related to B and T cell activation [88]. SLE patients are also at increased risk of Hodgkin’s lymphoma and leukemia [53,56,83], with a connection found between the telomerase reverse transcriptase (TERT) gene and chronic lymphocytic leukemia [89]. There is also evidence of an increased risk of multiple myeloma [53,90], though some studies have not confirmed this [50,75,91].
SLE patients have an increased risk of lung cancer, which is the second most common malignancy in this patient group [69,92]. A strong association with traditional lung cancer risk factors, such as smoking [93,94] and lung fibrosis [95], has been identified. There is no clear link between lung cancer risk and SLE treatments [1]. Scientific reports on SPOCK2 have mainly focused on its role in tumorigenesis and cancer progression. Reduced expression of SPOCK2 significantly inhibits the proliferation and invasion of cancer cells while promoting their apoptosis. In patients with SLE and lung adenocarcinoma, decreased expression of SPOCK2 is observed, which is partly due to its association with immune cells infiltrating the tumor. Studies have shown that genetic mutations in components associated with the basement membrane, such as SPOC1 and SPOC2 proteins, can lead to the development of disease phenotypes in patients, manifesting in various organs, such as the kidneys and blood vessels. These proteins, which are part of the basement membrane, are also targets of autoantibodies in autoimmune diseases [48,96].
SLE patients are at an increased risk for kidney and bladder cancers [69]. The risk of bladder cancer in SLE is highest with cyclophosphamide use, particularly when the daily dose exceeds 6 g [97,98].
It has been shown that SLE patients have an increased risk of developing squamous intraepithelial lesions, which can lead to cervical cancer [84]. It is worth considering whether appropriate preventive measures (such as Pap smears) and access to these services play a role in the higher detection of precancerous and cancerous lesions. Researchers are investigating a possible link between the higher incidence of oncogenic HPV in SLE and cancers associated with this virus [79,99]. It is also worth considering whether chronic immunosuppression contributes to the frequency of HPV infections. In SLE, lower estrogen levels are likely, as evidenced by the later onset of menstruation in women with SLE, which may be linked to the lower incidence of hormone-dependent cancers, such as ovarian, uterine, or breast cancer in SLE [2,52,81]. The SPOC1 (PHF13) protein has been linked to the development of ovarian cancer, as it is responsible for repairing DNA damage and regulating chromatin structure [48,100]. It should be noted that in the case of SLE, common cancer markers such as CA125 or CA19-9 are not necessarily associated with cancer. These markers are found to correlate with disease activity, as research indicates that inflammation increases CA19-9 expression [101]. In the case of prostate cancer, it is suspected that genetic factors may link it to SLE. Androgens play a key role in the proliferation of prostate tissue cells, and testosterone levels in men with SLE are lower, which reduces the risk of developing prostate cancer [60,102,103]. There is a hypothesis that immunosuppressive drugs may significantly increase the risk of prostate cancer development in SLE [60].
An increased risk of nonmelanoma skin cancer but a decreased risk of melanoma in SLE has been confirmed in a large meta-analysis [53]. The association between skin cancer and SLE is thought to be linked to cyclophosphamide use and chronic immunotherapy [50]. Due to the exacerbation of skin lesions in SLE after sun exposure, patients tend to avoid sun exposure and use UV filters, which may indirectly contribute to the reduced risk of melanoma in this group.
There are few studies showing an increased incidence of thyroid cancer. It is possible that the presence of antibodies (anti-thyroglobulin and anti-thyroid peroxidase) is associated with both SLE and coexisting thyroid cancer [46].
An increased risk of soft tissue sarcoma has been demonstrated in only one publication [75]. This may be a chance finding. Anti-neutrophil cytoplasmic antibodies (ANCAs) are linked to poorer prognosis in Ewing’s sarcoma [104].
Breast cancer is associated with chronic inflammation, which plays a role in the pathogenesis of SLE [5]. Links have been found between the increased expression of genes such as TOP2A, RACGAP1, KIF15, TTK, and HMMR in breast cancer. These genes are involved in mitochondrial dysfunction, cell modification and proliferation, and promoting metastasis [105,106,107,108,109]. IFI35 and EIF2AK2 genes were also expressed in the group with active SLE [43]. IRF7, a regulator of the interferon-α pathway and indirectly of NK cells and CD8+ T lymphocytes, may act as a tumor suppressor in breast cancer. Reduced IRF7 activity may accelerate bone metastasis [110,111]. The mRNA levels of STAT1 and OAS1 were increased in breast cancer but reduced in SLE. However, the mRNA levels of OASL and PML were elevated in both SLE and breast cancer. According to the analysis, changes in components of the IFN-JAK-STAT pathway were observed in both SLE and breast cancer [18,112,113]. A study by Ding et al. demonstrated a reduced expression of membrane metalloendopeptidase (MME) in breast cancer, which may correlate positively with SLE. This could serve as a potential biomarker for breast cancer. The PI3K/AKT/FOXO signaling pathway may be dysregulated, reducing the risk of breast cancer in SLE patients [61,101].

4. Protective Factors of Malignant Tumors Associated with SLE

The likely reduced risk of hormone-dependent cancers in SLE, such as breast and prostate cancers, is thought to be related to the presence of autoantibodies and decreased protein expression in SLE [46]. There is evidence suggesting that anti-dsDNA antibodies may play a role in inhibiting cancer cells by inducing programmed cell death [45,114,115]. Hydroxychloroquine may serve as a protective factor [42,65,68]. It is suggested that antimalarial drugs reduce the risk of breast cancer and non-melanoma skin cancer [65,67,116]. The mechanisms responsible for these processes may include promoting phagocytosis, inhibiting the replicative potential of cancer cells by suppressing telomerase activity, and increasing the synthesis of the TP53 protein, which is linked to carcinogenesis [117,118,119].
It is recommended to vaccinate against HPV and conduct annual Pap smears for the prevention of cervical, vulvar, or anal cancer [97]. Due to the exacerbation of skin lesions after sun exposure, SLE patients tend to avoid external factors that worsen the disease. Since melanoma is strongly associated with sun exposure, attributing its lower occurrence in SLE to this factor is an oversimplification. It is unclear whether increased monitoring of SLE patients leads to better cancer screening and earlier detection of precancerous lesions, which may contribute to reduced cancer incidence. A summary is presented in Table 2.
The main limitation of the review is the small number of studies and publications in recent years. Despite advances in medicine, the field of autoimmune diseases remains in the research phase. Many aspects, including pathogenesis, remain unexplained.

5. Conclusions

Assessment of risk factors associated with malignancy in systemic lupus erythematosus and understanding the oncogenesis process are important aspects of prevention. Systemic lupus erythematosus may be an independent risk factor for malignancy. The awareness of patients with SLE of the increased risk of malignancy should be increased. Further studies are needed to define guidelines for prevention, including screening.

Author Contributions

Conceptualization, D.B. and B.P.-C.; methodology, A.T.; formal analysis, A.T.; investigation, D.B.; resources, B.P.-C.; data curation, D.B.; writing—original draft preparation, D.B. and B.P-C.; writing—review and editing, A.T.; supervision, A.T.; project administration, D.B.; funding acquisition, D.B. and B.P.-C. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Medical University of Silesia in Katowice, grant number PCN-191/N/1/K and PCN-1-182/K/0/K.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Ladouceur, A.; Tessier-Cloutier, B.; Clarke, A.E.; Ramsey-Goldman, R.; Gordon, C.; Hansen, J.E.; Bernatsky, S. Cancer and Systemic Lupus Erythematosus. Rheum. Dis. Clin. N. Am. 2020, 46, 533–550. [Google Scholar] [CrossRef] [PubMed]
  2. Clarke, A.E.; Pooley, N.; Marjenberg, Z.; Langham, J.; Nicholson, L.; Langham, S.; Embleton, N.; Wang, X.; Desta, B.; Barut, V.; et al. Risk of Malignancy in Patients with Systemic Lupus Erythematosus: Systematic Review and Meta-Analysis. Semin. Arthritis Rheum. 2021, 51, 1230–1241. [Google Scholar] [CrossRef] [PubMed]
  3. Tselios, K.; Gladman, D.D.; Sheane, B.J.; Su, J.; Urowitz, M. All-Cause, Cause-Specific and Age-Specific Standardised Mortality Ratios of Patients with Systemic Lupus Erythematosus in Ontario, Canada over 43 Years (1971–2013). Ann. Rheum. Dis. 2019, 78, 802–806. [Google Scholar] [CrossRef] [PubMed]
  4. Kariniemi, S.; Rantalaiho, V.; Virta, L.J.; Kautiainen, H.; Puolakka, K.; Elfving, P. Malignancies among Newly Diagnosed Systemic Lupus Erythematosus Patients and Their Survival. Lupus 2022, 31, 1750–1758. [Google Scholar] [CrossRef] [PubMed]
  5. Li, W.; Wang, R.; Wang, W. Exploring the Causality and Pathogenesis of Systemic Lupus Erythematosus in Breast Cancer Based on Mendelian Randomization and Transcriptome Data Analyses. Front. Immunol. 2023, 13, 1029884. [Google Scholar] [CrossRef]
  6. Han, J.Y.; Kim, H.; Jung, S.Y.; Jang, E.J.; Cho, S.K.; Sung, Y.K. Increased Risk of Malignancy in Patients with Systemic Lupus Erythematosus: Population-Based Cohort Study in Korea. Arthritis Res. Ther. 2021, 23, 270. [Google Scholar] [CrossRef]
  7. Zen, M.; Salmaso, L.; Barbiellini Amidei, C.; Fedeli, U.; Bellio, S.; Iaccarino, L.; Doria, A.; Saia, M. Mortality and Causes of Death in Systemic Lupus Erythematosus over the Last Decade: Data from a Large Population-Based Study. Eur. J. Intern. Med. 2023, 112, 45–51. [Google Scholar] [CrossRef]
  8. López-Otín, C.; Kroemer, G. Hallmarks of Health. Cell 2021, 184, 33–63. [Google Scholar] [CrossRef] [PubMed]
  9. Galluzzi, L.; Chan, T.A.; Kroemer, G.; Wolchok, J.D.; López-Soto, A. The Hallmarks of Successful Anticancer Immunotherapy. Sci. Transl. Med. 2018, 10, eaat7807. [Google Scholar] [CrossRef]
  10. Lahouel, K.; Younes, L.; Danilova, L.; Giardiello, F.M.; Hruban, R.H.; Groopman, J.; Kinzler, K.W.; Vogelstein, B.; Geman, D.; Tomasetti, C. Revisiting the Tumorigenesis Timeline with a Data-Driven Generative Model. Proc. Natl. Acad. Sci. USA 2020, 117, 857–864. [Google Scholar] [CrossRef]
  11. Pol, J.; Paillet, J.; Plantureux, C.; Kroemer, G. Beneficial Autoimmunity and Maladaptive Inflammation Shape Epidemiological Links between Cancer and Immune-Inflammatory Diseases. Oncoimmunology 2022, 11, 11–13. [Google Scholar] [CrossRef] [PubMed]
  12. Chen, H.; He, J.; Wang, L.; Lin, Y.; Mou, Z.; Huang, X.; Chen, L. Identification of Monocyte-Associated Biomarkers in Systemic Lupus Erythematosus and Their Pan-Cancer Analysis. Lupus 2023, 32, 1369–1380. [Google Scholar] [CrossRef]
  13. Choi, M.Y.; Flood, K.; Bernatsky, S.; Ramsey-Goldman, R.; Clarke, A.E. A Review on SLE and Malignancy. Best Pract. Res. Clin. Rheumatol. 2017, 31, 373–396. [Google Scholar] [CrossRef] [PubMed]
  14. Wang, Z.; Strasser, A.; Kelly, G.L. Should Mutant TP53 Be Targeted for Cancer Therapy? Cell Death Differ. 2022, 29, 911–920. [Google Scholar] [CrossRef] [PubMed]
  15. Böttcher, J.P.; Bonavita, E.; Chakravarty, P.; Blees, H.; Cabeza-Cabrerizo, M.; Sammicheli, S.; Rogers, N.C.; Sahai, E.; Zelenay, S.; Reis e Sousa, C. NK Cells Stimulate Recruitment of CDC1 into the Tumor Microenvironment Promoting Cancer Immune Control. Cell 2018, 172, 1022–1037.e14. [Google Scholar] [CrossRef]
  16. Markmann, C.; Bhoj, V.G. On the Road to Eliminating Long-Lived Plasma Cells—"are We There Yet?”. Immunol. Rev. 2021, 303, 154–167. [Google Scholar] [CrossRef]
  17. Schultheiß, C.; Steinmann, S.; Lohse, A.W.; Binder, M. B Cells in Autoimmune Hepatitis: Bystanders or Central Players? Semin. Immunopathol. 2022, 44, 411–427. [Google Scholar] [CrossRef] [PubMed]
  18. Sui, Y.; Li, S.; Fu, X.Q.; Zhao, Z.J.; Xing, S. Bioinformatics Analyses of Combined Databases Identify Shared Differentially Expressed Genes in Cancer and Autoimmune Disease. J. Transl. Med. 2023, 21, 109. [Google Scholar] [CrossRef] [PubMed]
  19. Gonzalez, H.; Hagerling, C.; Werb, Z. Roles of the Immune System in Cancer: From Tumor Initiation to Metastatic Progression. Genes Dev. 2018, 32, 1267–1284. [Google Scholar] [CrossRef] [PubMed]
  20. Finisguerra, V.; Di Conza, G.; Di Matteo, M.; Serneels, J.; Costa, S.; Thompson, A.A.R.; Wauters, E.; Walmsley, S.; Prenen, H.; Granot, Z.; et al. MET Is Required for the Recruitment of Anti-Tumoural Neutrophils. Nature 2015, 522, 349–353. [Google Scholar] [CrossRef] [PubMed]
  21. Showalter, A.; Limaye, A.; Oyer, J.L.; Igarashi, R.; Kittipatarin, C.; Copik, A.J.; Khaled, A.R. Cytokines in Immunogenic Cell Death: Applications for Cancer Immunotherapy. Cytokine 2017, 97, 123–132. [Google Scholar] [CrossRef] [PubMed]
  22. Durcan, L.; O’Dwyer, T.; Petri, M. Management Strategies and Future Directions for Systemic Lupus Erythematosus in Adults. Lancet 2019, 393, 2332–2343. [Google Scholar] [CrossRef] [PubMed]
  23. Soto, M.; Delatorre, N.; Hurst, C.; Rodgers, K.E. Targeting the Protective Arm of the Renin-Angiotensin System to Reduce Systemic Lupus Erythematosus Related Pathologies in MRL-Lpr Mice. Front. Immunol. 2020, 11, 1572. [Google Scholar] [CrossRef]
  24. Krovi, S.H.; Kuchroo, V.K. Activation Pathways That Drive CD4+ T Cells to Break Tolerance in Autoimmune Diseases. Immunol. Rev. 2022, 307, 161–190. [Google Scholar] [CrossRef]
  25. Hoffmann, C.; Noel, F.; Grandclaudon, M.; Massenet-Regad, L.; Michea, P.; Sirven, P.; Faucheux, L.; Surun, A.; Lantz, O.; Bohec, M.; et al. PD-L1 and ICOSL Discriminate Human Secretory and Helper Dendritic Cells in Cancer, Allergy and Autoimmunity. Nat. Commun. 2022, 13, 1983. [Google Scholar] [CrossRef] [PubMed]
  26. Policheni, A.N.; Teh, C.E.; Robbins, A.; Tuzlak, S.; Strasser, A.; Gray, D.H.D. PD-1 Cooperates with AIRE-Mediated Tolerance to Prevent Lethal Autoimmune Disease. Proc. Natl. Acad. Sci. USA 2022, 119, e2120149119. [Google Scholar] [CrossRef]
  27. Thien, A.; Prentzell, M.T.; Holzwarth, B.; Kläsener, K.; Kuper, I.; Boehlke, C.; Sonntag, A.G.; Ruf, S.; Maerz, L.; Nitschke, R.; et al. TSC1 Activates TGF-β-Smad2/3 Signaling in Growth Arrest and Epithelial-to-Mesenchymal Transition. Dev. Cell 2015, 32, 617–630. [Google Scholar] [CrossRef] [PubMed]
  28. Cho, J.-H.; Oh, A.-Y.; Park, S.; Kang, S.-M.; Yoon, M.-H.; Woo, T.-G.; Hong, S.-D.; Hwang, J.; Ha, N.-C.; Lee, H.-Y.; et al. Loss of NF2 Induces TGFβ Receptor 1-Mediated Noncanonical and Oncogenic TGFβ Signaling: Implication of the Therapeutic Effect of TGFβ Receptor 1 Inhibitor on NF2 Syndrome. Mol. Cancer Ther. 2018, 17, 2271–2284. [Google Scholar] [CrossRef]
  29. Freudlsperger, C.; Bian, Y.; Contag Wise, S.; Burnett, J.; Coupar, J.; Yang, X.; Chen, Z.; Van Waes, C. TGF-β and NF-ΚB Signal Pathway Cross-Talk Is Mediated through TAK1 and SMAD7 in a Subset of Head and Neck Cancers. Oncogene 2013, 32, 1549–1559. [Google Scholar] [CrossRef] [PubMed]
  30. Chan, M.K.-K.; Chung, J.Y.-F.; Tang, P.C.-T.; Chan, A.S.-W.; Ho, J.Y.-Y.; Lin, T.P.-T.; Chen, J.; Leung, K.-T.; To, K.-F.; Lan, H.-Y.; et al. TGF-β Signaling Networks in the Tumor Microenvironment. Cancer Lett. 2022, 550, 215925. [Google Scholar] [CrossRef]
  31. Wang, Q.-M.; Tang, P.M.-K.; Lian, G.-Y.; Li, C.; Li, J.; Huang, X.-R.; To, K.-F.; Lan, H.-Y. Enhanced Cancer Immunotherapy with Smad3-Silenced NK-92 Cells. Cancer Immunol. Res. 2018, 6, 965–977. [Google Scholar] [CrossRef]
  32. Xia, L.; Tan, S.; Zhou, Y.; Lin, J.; Wang, H.; Oyang, L.; Tian, Y.; Liu, L.; Su, M.; Wang, H.; et al. Role of the NFκB-Signaling Pathway in Cancer. OncoTargets Ther. 2018, 11, 2063–2073. [Google Scholar] [CrossRef]
  33. Gaptulbarova, K.A.; Tsyganov, M.M.; Pevzner, A.M.; Ibragimova, M.K.; Litviakov, N.V. NF-KB as a Potential Prognostic Marker and a Candidate for Targeted Therapy of Cancer. Exp. Oncol. 2020, 42, 263–269. [Google Scholar] [CrossRef] [PubMed]
  34. Verzella, D.; Pescatore, A.; Capece, D.; Vecchiotti, D.; Ursini, M.V.; Franzoso, G.; Alesse, E.; Zazzeroni, F. Life, Death, and Autophagy in Cancer: NF-ΚB Turns up Everywhere. Cell Death Dis. 2020, 11, 210. [Google Scholar] [CrossRef]
  35. Ott, G.; Rosenwald, A. Molecular Pathogenesis of Follicular Lymphoma. Haematologica 2008, 93, 1773–1776. [Google Scholar] [CrossRef] [PubMed]
  36. von Locquenghien, M.; Rozalén, C.; Celià-Terrassa, T. Interferons in Cancer Immunoediting: Sculpting Metastasis and Immunotherapy Response. J. Clin. Investig. 2021, 131, e143296. [Google Scholar] [CrossRef]
  37. Yu, R.; Zhu, B.; Chen, D. Type I Interferon-Mediated Tumor Immunity and Its Role in Immunotherapy. Cell. Mol. Life Sci. 2022, 79, 191. [Google Scholar] [CrossRef] [PubMed]
  38. Gocher, A.M.; Workman, C.J.; Vignali, D.A.A. Interferon-γ: Teammate or Opponent in the Tumour Microenvironment? Nat. Rev. Immunol. 2022, 22, 158–172. [Google Scholar] [CrossRef] [PubMed]
  39. Vilmen, G.; Glon, D.; Siracusano, G.; Lussignol, M.; Shao, Z.; Hernandez, E.; Perdiz, D.; Quignon, F.; Mouna, L.; Poüs, C.; et al. BHRF1, a BCL2 Viral Homolog, Disturbs Mitochondrial Dynamics and Stimulates Mitophagy to Dampen Type I IFN Induction. Autophagy 2021, 17, 1296–1315. [Google Scholar] [CrossRef]
  40. Rackov, G.; Tavakoli Zaniani, P.; Colomo del Pino, S.; Shokri, R.; Monserrat, J.; Alvarez-Mon, M.; Martinez-A, C.; Balomenos, D. Mitochondrial Reactive Oxygen Is Critical for IL-12/IL-18-Induced IFN-γ Production by CD4+ T Cells and Is Regulated by Fas/FasL Signaling. Cell Death Dis. 2022, 13, 531. [Google Scholar] [CrossRef]
  41. Haymaker, C.; Johnson, D.H.; Murthy, R.; Bentebibel, S.E.; Uemura, M.I.; Hudgens, C.W.; Safa, H.; James, M.; Andtbacka, R.H.I.; Johnson, D.B.; et al. Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti–Pd-1 Refractory Melanoma. Cancer Discov. 2021, 11, 1996–2013. [Google Scholar] [CrossRef]
  42. Cader, R.A.; Yee, A.K.M.; Yassin, A.; Ahmad, I.; Haron, S.N. Malignancy in Systemic Lupus Erythematosus (SLE) Patients. Asian Pac. J. Cancer Prev. 2018, 19, 3551–3555. [Google Scholar] [CrossRef] [PubMed]
  43. Liang, X.; Peng, Z.; Lin, Z.; Lin, X.; Lin, W.; Deng, Y.; Yang, S.; Wei, S. Identification of Prognostic Genes for Breast Cancer Related to Systemic Lupus Erythematosus by Integrated Analysis and Machine Learning. Immunobiology 2023, 228, 152730. [Google Scholar] [CrossRef] [PubMed]
  44. Noble, P.W.; Bernatsky, S.; Clarke, A.E.; Isenberg, D.A.; Ramsey-Goldman, R.; Hansen, J.E. DNA-Damaging Autoantibodies and Cancer: The Lupus Butterfly Theory. Nat. Rev. Rheumatol. 2016, 12, 429–434. [Google Scholar] [CrossRef]
  45. Hansen, J.E.; Chan, G.; Liu, Y.; Hegan, D.C.; Dalal, S.; Dray, E.; Kwon, Y.; Xu, Y.; Xu, X.; Peterson-Roth, E.; et al. Targeting Cancer with a Lupus Autoantibody. Sci. Transl. Med. 2012, 4, 157ra142. [Google Scholar] [CrossRef]
  46. Ladouceur, A.; Clarke, A.E.; Ramsey-Goldman, R.; Bernatsky, S. Malignancies in Systemic Lupus Erythematosus: An Update. Curr. Opin. Rheumatol. 2019, 31, 678–681. [Google Scholar] [CrossRef]
  47. Hardenbergh, D.; Molina, E.; Naik, R.; Geetha, D.; Chaturvedi, S.; Timlin, H. Factors Mediating Cancer Risk in Systemic Lupus Erythematosus. Lupus 2022, 31, 1285–1295. [Google Scholar] [CrossRef]
  48. Lv, R.; Duan, L.; Gao, J.; Si, J.; Feng, C.; Hu, J.; Zheng, X. Bioinformatics-Based Analysis of the Roles of Basement Membrane-Related Gene AGRN in Systemic Lupus Erythematosus and Pan-Cancer Development. Front. Immunol. 2023, 14, 1231611. [Google Scholar] [CrossRef] [PubMed]
  49. Cobo-Ibáñez, T.; Urruticoechea-Arana, A.; Rúa-Figueroa, I.; Martín-Martínez, M.A.; Ovalles-Bonilla, J.G.; Galindo, M.; Calvo-Alén, J.; Olivé, A.; Fernández-Nebro, A.; Menor-Almagro, R.; et al. Hormonal Dependence and Cancer in Systemic Lupus Erythematosus. Arthritis Care Res. 2020, 72, 216–224. [Google Scholar] [CrossRef] [PubMed]
  50. Bernatsky, S.; Ramsey-Goldman, R.; Labrecque, J.; Joseph, L.; Boivin, J.F.; Petri, M.; Zoma, A.; Manzi, S.; Urowitz, M.B.; Gladman, D.; et al. Cancer Risk in Systemic Lupus: An Updated International Multi-Centre Cohort Study. J. Autoimmun. 2013, 42, 130–135. [Google Scholar] [CrossRef] [PubMed]
  51. Zhu, T.; Ding, Y.; Xu, X.; Zhang, L.; Zhang, X.; Cui, Y.; Liu, L. Trans-Ethnic Mendelian Randomization Study of Systemic Lupus Erythematosus and Common Female Hormone-Dependent Malignancies. Chin. Med. J. 2023, 136, 2609–2620. [Google Scholar] [CrossRef] [PubMed]
  52. Bernatsky, S.; Ramsey-Goldman, R.; Foulkes, W.D.; Gordon, C.; Clarke, A.E. Breast, Ovarian, and Endometrial Malignancies in Systemic Lupus Erythematosus: A Meta-Analysis. Br. J. Cancer 2011, 104, 1478–1481. [Google Scholar] [CrossRef] [PubMed]
  53. Song, L.; Wang, Y.; Zhang, J.; Song, N.; Xu, X.; Lu, Y. The Risks of Cancer Development in Systemic Lupus Erythematosus (SLE) Patients: A Systematic Review and Meta-Analysis. Arthritis Res. Ther. 2018, 20, 270. [Google Scholar] [CrossRef]
  54. Zhu, Q.Y. Bioinformatics Analysis of the Pathogenic Link between Epstein-Barr Virus Infection, Systemic Lupus Erythematosus and Diffuse Large B Cell Lymphoma. Sci. Rep. 2023, 13, 6310. [Google Scholar] [CrossRef] [PubMed]
  55. Zhao, Q.; Liu, H.; Yang, W.; Zhou, Z.; Yang, Y.; Jiang, X.; Yang, H.; Zhang, F. Cancer Occurrence after SLE: Effects of Medication-Related Factors, Disease-Related Factors and Survival from an Observational Study. Rheumatology 2023, 62, 659–667. [Google Scholar] [CrossRef]
  56. Bernatsky, S.; Ramsey-Goldman, R.; Joseph, L.; Boivin, J.F.; Costenbader, K.H.; Urowitz, M.B.; Gladman, D.D.; Fortin, P.R.; Nived, O.; Petri, M.A.; et al. Lymphoma Risk in Systemic Lupus: Effects of Disease Activity versus Treatment. Ann. Rheum. Dis. 2014, 73, 138–142. [Google Scholar] [CrossRef]
  57. Kang, K.Y.; Kim, H.O.; Yoon, H.S.; Lee, J.; Lee, W.C.; Ko, H.J.; Ju, J.H.; Cho, C.S.; Kim, H.Y.; Park, S.H. Incidence of Cancer among Female Patients with Systemic Lupus Erythematosus in Korea. Clin. Rheumatol. 2010, 29, 381–388. [Google Scholar] [CrossRef]
  58. Westermann, R.; Zobbe, K.; Cordtz, R.; Haugaard, J.H.; Dreyer, L. 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, 752–761. [Google Scholar] [CrossRef]
  59. Ertz-Archambault, N.; Kosiorek, H.; Taylor, G.E.; Kelemen, K.; Dueck, A.; Castro, J.; Marino, R.; Gauthier, S.; Finn, L.; Sproat, L.Z.; et al. Association of Therapy for Autoimmune Disease with Myelodysplastic Syndromes and Acute Myeloid Leukemia. JAMA Oncol. 2017, 3, 936–943. [Google Scholar] [CrossRef] [PubMed]
  60. Ou, J.; Zhen, K.; Wu, Y.; Xue, Z.; Fang, Y.; Zhang, Q.; Bi, H.; Tian, X.; Ma, L.; Liu, C. Systemic Lupus Erythematosus and Prostate Cancer Risk: A Pool of Cohort Studies and Mendelian Randomization Analysis. J. Cancer Res. Clin. Oncol. 2023, 149, 9517–9528. [Google Scholar] [CrossRef]
  61. Takada, A.; Ohmori, K.; Yoneda, T.; Tsuyuoka, K.; Hasegawa, A.; Kiso, M.; Kannagi, R. Contribution of Carbohydrate Antigens Sialyl Lewis A and Sialyl Lewis X to Adhesion of Human Cancer Cells to Vascular Endothelium. Cancer Res. 1993, 53, 354–361. [Google Scholar] [PubMed]
  62. Xu, F.; Chen, Z. Causal Associations of Hyperthyroidism with Prostate Cancer, Colon Cancer, and Leukemia: A Mendelian Randomization Study. Front. Endocrinol. 2023, 14, 1162224. [Google Scholar] [CrossRef] [PubMed]
  63. Raymond, W.D.; Preen, D.B.; Keen, H.I.; Inderjeeth, C.A.; Nossent, J.C. Cancer Development in Patients Hospitalized with Systemic Lupus Erythematosus: A Population-Level Data Linkage Study. Int. J. Rheum. Dis. 2023, 26, 1557–1570. [Google Scholar] [CrossRef]
  64. Löfström, B.; Backlin, C.; Sundström, C.; Hellström-Lindberg, E.; Ekbom, A.; Lundberg, I.E. Myeloid Leukaemia in Systemic Lupus Erythematosus—A Nested Case-Control Study Based on Swedish Registers. Rheumatology 2009, 48, 1222–1226. [Google Scholar] [CrossRef] [PubMed]
  65. Guo, J.; Ren, Z.; Li, J.; Li, T.; Liu, S.; Yu, Z. The Relationship between Cancer and Medication Exposure in Patients with Systemic Lupus Erythematosus: A Nested Case-Control Study. Arthritis Res. Ther. 2020, 22, 159. [Google Scholar] [CrossRef]
  66. Ichinose, K.; Sato, S.; Igawa, T.; Okamoto, M.; Takatani, A.; Endo, Y.; Tsuji, S.; Shimizu, T.; Sumiyoshi, R.; Koga, T.; et al. Evaluating the Safety Profile of Calcineurin Inhibitors: Cancer Risk in Patients with Systemic Lupus Erythematosus from the LUNA Registry—A Historical Cohort Study. Arthritis Res. Ther. 2024, 26, 48. [Google Scholar] [CrossRef]
  67. Bernatsky, S.; Ramsey-Goldman, R.; Urowitz, M.B.; Hanly, J.G.; Gordon, C.; Petri, M.A.; Ginzler, E.M.; Wallace, D.J.; Bae, S.C.; Romero-Diaz, J.; et al. Cancer Risk in a Large Inception Systemic Lupus Erythematosus Cohort: Effects of Demographic Characteristics, Smoking, and Medications. Arthritis Care Res. 2021, 73, 1789–1795. [Google Scholar] [CrossRef]
  68. Hsu, C.Y.; Lin, M.S.; Su, Y.J.; Cheng, T.T.; Lin, Y.S.; Chen, Y.C.; Chiu, W.C.; Chen, T.H. Cumulative Immunosuppressant Exposure Is Associated with Diversified Cancer Risk among 14 832 Patients with Systemic Lupus Erythematosus: A Nested Case-Control Study. Rheumatology 2017, 56, 620–628. [Google Scholar] [CrossRef] [PubMed]
  69. Ni, J.; Qiu, L.-J.; Hu, L.-F.; Cen, H.; Zhang, M.; Wen, P.-F.; Wang, X.-S.; Pan, H.-F.; Ye, D.-Q. Lung, Liver, Prostate, Bladder Malignancies Risk in Systemic Lupus Erythematosus: Evidence from a Meta-Analysis. Lupus 2014, 23, 284–292. [Google Scholar] [CrossRef] [PubMed]
  70. Yeo, J.; Seo, M.S.; Hwang, I.C.; Shim, J.Y. An Updated Meta-Analysis on the Risk of Urologic Cancer in Patients with Systemic Lupus Erythematosus. Arch. Iran. Med. 2020, 23, 614–620. [Google Scholar] [CrossRef] [PubMed]
  71. Yu, K.-H.; Kuo, C.-F.; Huang, L.H.; Huang, W.-K.; See, L.-C. Cancer Risk in Patients With Inflammatory Systemic Autoimmune Rheumatic Diseases: A Nationwide Population-Based Dynamic Cohort Study in Taiwan. Medicine 2016, 95, e3540. [Google Scholar] [CrossRef]
  72. Hardenbergh, D.; Naik, R.; Manno, R.; Azar, A.; Monroy Trujillo, J.M.; Adler, B.; Haque, U.; Timlin, H. The Cancer Risk Profile of Systemic Lupus Erythematosus Patients. J. Clin. Rheumatol. Pract. Rep. Rheum. Musculoskelet. Dis. 2022, 28, e257–e262. [Google Scholar] [CrossRef]
  73. Bae, E.H.; Lim, S.Y.; Han, K.-D.; Jung, J.-H.; Choi, H.S.; Kim, C.S.; Ma, S.K.; Kim, S.W. Systemic Lupus Erythematosus Is a Risk Factor for Cancer: A Nationwide Population-Based Study in Korea. Lupus 2019, 28, 317–323. [Google Scholar] [CrossRef]
  74. An, T.; Zhang, W. Mendelian Randomization Analysis Reveals a Protective Association between Genetically Predicted Systemic Lupus Erythematosus and Renal Cell Carcinoma. Medicine 2024, 103, E37545. [Google Scholar] [CrossRef]
  75. Tallbacka, K.R.; Pettersson, T.; Pukkala, E. Increased Incidence of Cancer in Systemic Lupus Erythematosus: A Finnish Cohort Study with More than 25 Years of Follow-Up. Scand. J. Rheumatol. 2018, 47, 461–464. [Google Scholar] [CrossRef] [PubMed]
  76. Cairns, A.P.; Filippucci, E.; McVeigh, C.M.; Grassi, W. An Electronic Logbook for Rheumatologists Performing Musculoskeletal Ultrasound. Rheumatology 2006, 45, 1042. [Google Scholar] [CrossRef] [PubMed][Green Version]
  77. Goobie, G.C.; Bernatsky, S.; Ramsey-Goldman, R.; Clarke, A.E.; Centre, H.S. HHS Public Access: Malignancies in Systemic Lupus Erythematosus—A 2015 Update. Curr Opin Rheumatol. 2015, 27, 454–460. [Google Scholar] [CrossRef] [PubMed]
  78. Peng, Z.; Liang, X.; Lin, X.; Lin, W.; Lin, Z.; Wei, S. Exploration of the Molecular Mechanisms, Shared Gene Signatures, and MicroRNAs between Systemic Lupus Erythematosus and Diffuse Large B Cell Lymphoma by Bioinformatics Analysis. Lupus 2022, 31, 1317–1327. [Google Scholar] [CrossRef] [PubMed]
  79. Shah, A.A.; Igusa, T.; Goldman, D.; Li, J.; Casciola-Rosen, L.; Rosen, A.; Petri, M. Association of Systemic Lupus Erythematosus Autoantibody Diversity with Breast Cancer Protection. Arthritis Res. Ther. 2021, 23, 64. [Google Scholar] [CrossRef]
  80. Pang, X.; Qian, J.; Jin, H.; Zhang, L.; Lin, L.; Wang, Y.; Lei, Y.; Zhou, Z.; Li, M.; Zhang, H. Durable Benefit from Immunotherapy and Accompanied Lupus Erythematosus in Pancreatic Adenocarcinoma with DNA Repair Deficiency. J. Immunother. Cancer 2020, 8, e000463. [Google Scholar] [CrossRef]
  81. Lopes Almeida Gomes, L.; Werth, A.J.; Thomas, P.; Werth, V.P. The Impact of Hormones in Autoimmune Cutaneous Diseases. J. Dermatol. Treat. 2024, 35, 2312241. [Google Scholar] [CrossRef] [PubMed]
  82. Chang, S.L.; Hsu, H.-T.; Weng, S.F.; Lin, Y.S. Impact of Head and Neck Malignancies on Risk Factors and Survival in Systemic Lupus Erythematosus. Acta Otolaryngol. 2013, 133, 1088–1095. [Google Scholar] [CrossRef]
  83. Lu, M.; Bernatsky, S.; Ramsey-Goldman, R.; Petri, M.; Manzi, S.; Urowitz, M.B.; Gladman, D.; Fortin, P.R.; Ginzler, E.M.; Yelin, E.; et al. Non-Lymphoma Hematological Malignancies in Systemic Lupus Erythematosus. Oncology 2013, 85, 235–240. [Google Scholar] [CrossRef]
  84. Wadström, H.; Arkema, E.V.; Sjöwall, C.; Askling, J.; Simard, J.F. Cervical Neoplasia in Systemic Lupus Erythematosus: A Nationwide Study. Rheumatology 2017, 56, 613–619. [Google Scholar] [CrossRef]
  85. Rodrigues, L.R.S.; Ferraz, D.L.F.; de Oliveira, C.R.G.; Evangelista, K.; Silva, M.A.G.; Silva, F.P.Y.; de Silva, B.S.F. Risk and Prevalence of Oral Cancer in Patients with Different Types of Lupus Erythematosus: A Systematic Review and Meta-Analysis. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2023, 136, 595–605. [Google Scholar] [CrossRef]
  86. Li, H.; Zhou, J.; Zhou, L.; Zhang, X.; Shang, J.; Feng, X.; Yu, L.; Fan, J.; Ren, J.; Zhang, R.; et al. Identification of the Shared Gene Signatures and Molecular Pathways in Systemic Lupus Erythematosus and Diffuse Large B-Cell Lymphoma. J. Gene Med. 2023, 25, e3558. [Google Scholar] [CrossRef]
  87. Martín-López, M.; Galindo, M.; Pego-Reigosa, J.M.; Jiménez, N.; Olivé Marqués, A.; Tomero, E.; Freire, M.; Martínez-Barrio, J.; Boteanu, A.; Salgado-Perez, E.; et al. Clinical Characteristics and Risk Factors Associated with Lymphoma in Patients with Systemic Lupus Erythematosus: A Nationwide Cohort Study. Rheumatology 2023, 62, 217–224. [Google Scholar] [CrossRef]
  88. Wang, L.H.; Wang, W.M.; Lin, S.H.; Shieh, C.C. Bidirectional Relationship between Systemic Lupus Erythematosus and Non-Hodgkin’s Lymphoma: A Nationwide Population-Based Study. Rheumatology 2019, 58, 1245–1249. [Google Scholar] [CrossRef]
  89. Din, L.; Sheikh, M.; Kosaraju, N.; Smedby, K.E.; Bernatsky, S.; Berndt, S.I.; Skibola, C.F.; Nieters, A.; Wang, S.; McKay, J.D.; et al. Genetic Overlap between Autoimmune Diseases and Non-Hodgkin Lymphoma Subtypes. Genet. Epidemiol. 2019, 43, 844–863. [Google Scholar] [CrossRef] [PubMed]
  90. Desai, R.; Devaragudi, S.; Kaur, L.; Singh, K.; Bawa, J.; Theik, N.W.Y.; Palisetti, S.; Jain, A. SLE and Multiple Myeloma: An Underlooked Link? A Review of Case Reports from the Last Decade. J. Med. Life 2024, 17, 141–146. [Google Scholar] [CrossRef]
  91. Parikh-Patel, A.; White, R.H.; Allen, M.; Cress, R. Cancer Risk in a Cohort of Patients with Systemic Lupus Erythematosus (SLE) in California. Cancer Causes Control 2008, 19, 887–894. [Google Scholar] [CrossRef] [PubMed]
  92. Bernatsky, S.; Ramsey-Goldman, R.; Petri, M.; Urowitz, M.B.; Gladman, D.D.; Fortin, P.R.; Yelin, E.H.; Ginzler, E.; Hanly, J.G.; Peschken, C.; et al. Smoking Is the Most Significant Modifiable Lung Cancer Risk Factor in Systemic Lupus Erythematosus. J. Rheumatol. 2018, 45, 393–396. [Google Scholar] [CrossRef]
  93. Cheng, H.H.; Ho, C.M.; Huang, C.J.; Hsu, S.S.; Jiann, B.P.; Chen, J.S.; Huang, J.K.; Chang, H.T.; Lo, Y.K.; Yeh, J.H.; et al. Defect in Regulation of Ca2+ Movement in Platelets from Patients with Systemic Lupus Erythematosus. Pharmacology 2005, 73, 169–174. [Google Scholar] [CrossRef]
  94. Ekblom-Kullberg, S.; Kautiainen, H.; Alha, P.; Leirisalo-Repo, M.; Julkunen, H. Smoking and the Risk of Systemic Lupus Erythematosus. Clin. Rheumatol. 2013, 32, 1219–1222. [Google Scholar] [CrossRef]
  95. Sansone, P.; Bromberg, J. Environment, Inflammation, and Cancer. Curr. Opin. Genet. Dev. 2011, 21, 80–85. [Google Scholar] [CrossRef] [PubMed]
  96. Zhao, J.; Cheng, M.; Gai, J.; Zhang, R.; Du, T.; Li, Q. SPOCK2 Serves as a Potential Prognostic Marker and Correlates with Immune Infiltration in Lung Adenocarcinoma. Front. Genet. 2020, 11, 588499. [Google Scholar] [CrossRef] [PubMed]
  97. Furer, V.; Rondaan, C.; Heijstek, M.W.; Agmon-Levin, N.; Van Assen, S.; Bijl, M.; Breedveld, F.C.; D’amelio, R.; Dougados, M.; Kapetanovic, M.C.; et al. 2019 Update of EULAR Recommendations for Vaccination in Adult Patients with Autoimmune Inflammatory Rheumatic Diseases. Ann. Rheum. Dis. 2020, 79, 39–52. [Google Scholar] [CrossRef] [PubMed]
  98. Zhou, Z.; Liu, H.; Yang, Y.; Zhou, J.; Zhao, L.; Chen, H.; Fei, Y.; Zhang, W.; Li, M.; Zhao, 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. 2022, 42, 435–446. [Google Scholar] [CrossRef]
  99. Chung, S.H.; Oshima, K.; Singleton, M.; Thomason, J.; Currier, C.; McCartney, S.; Singh, N. Determinants of Cervical Cancer Screening Patterns Among Women with Systemic Lupus Erythematosus. J. Rheumatol. 2022, 49, 1236–1241. [Google Scholar] [CrossRef] [PubMed]
  100. Mohrmann, G.; Hengstler, J.G.; Hofmann, T.G.; Endele, S.U.; Lee, B.; Stelzer, C.; Zabel, B.; Brieger, J.; Hasenclever, D.; Tanner, B.; et al. SPOC1, a Novel PHD-Finger Protein: Association with Residual Disease and Survival in Ovarian Cancer. Int. J. Cancer 2005, 116, 547–554. [Google Scholar] [CrossRef]
  101. Zhong, Y.; Liu, Z.; Ma, J.; Zhang, L.; Xue, L. Tumour-Associated Antigens in Systemic Lupus Erythematosus: Association with Clinical Manifestations and Serological Indicators. Rheumatology 2024, 63, 235–241. [Google Scholar] [CrossRef] [PubMed]
  102. Watts, E.L.; Appleby, P.N.; Perez-Cornago, A.; Bueno-de-Mesquita, H.B.; Chan, J.M.; Chen, C.; Cohn, B.A.; Cook, M.B.; Flicker, L.; Freedman, N.D.; et al. Low Free Testosterone and Prostate Cancer Risk: A Collaborative Analysis of 20 Prospective Studies. Eur. Urol. 2018, 74, 585–594. [Google Scholar] [CrossRef] [PubMed]
  103. Dobbs, R.W.; Malhotra, N.R.; Greenwald, D.T.; Wang, A.Y.; Prins, G.S.; Abern, M.R. Estrogens and Prostate Cancer. Prostate Cancer Prostatic Dis. 2019, 22, 185–194. [Google Scholar] [CrossRef] [PubMed]
  104. Scandolara, T.B.; Panis, C. Neutrophil Traps, Anti-Myeloperoxidase Antibodies and Cancer: Are They Linked? Immunol. Lett. 2020, 221, 33–38. [Google Scholar] [CrossRef] [PubMed]
  105. Ren, K.; Zhou, D.; Wang, M.; Li, E.; Hou, C.; Su, Y.; Zou, Q.; Zhou, P.; Liu, X. RACGAP1 Modulates ECT2-Dependent Mitochondrial Quality Control to Drive Breast Cancer Metastasis. Exp. Cell Res. 2021, 400, 112493. [Google Scholar] [CrossRef] [PubMed]
  106. Mateo, F.; He, Z.; Mei, L.; de Garibay, G.R.; Herranz, C.; García, N.; Lorentzian, A.; Baiges, A.; Blommaert, E.; Gómez, A.; et al. Modification of BRCA1-Associated Breast Cancer Risk by HMMR Overexpression. Nat. Commun. 2022, 13, 1895. [Google Scholar] [CrossRef] [PubMed]
  107. Zaczek, A.J.; Markiewicz, A.; Seroczynska, B.; Skokowski, J.; Jaskiewicz, J.; Pienkowski, T.; Olszewski, W.P.; Szade, J.; Rhone, P.; Welnicka-Jaskiewicz, M.; et al. Prognostic Significance of TOP2A Gene Dosage in HER-2-Negative Breast Cancer. Oncologist 2012, 17, 1246–1255. [Google Scholar] [CrossRef]
  108. King, J.L.; Zhang, B.; Li, Y.; Li, K.P.; Ni, J.J.; Saavedra, H.I.; Dong, J.-T. TTK Promotes Mesenchymal Signaling via Multiple Mechanisms in Triple Negative Breast Cancer. Oncogenesis 2018, 7, 69. [Google Scholar] [CrossRef]
  109. Gao, X.; Zhu, L.; Lu, X.; Wang, Y.; Li, R.; Jiang, G. KIF15 Contributes to Cell Proliferation and Migration in Breast Cancer. Hum. Cell 2020, 33, 1218–1228. [Google Scholar] [CrossRef] [PubMed]
  110. Li, Z.; Geng, M.; Ye, X.; Ji, Y.; Li, Y.; Zhang, X.; Xu, W. IRF7 Inhibits the Warburg Effect via Transcriptional Suppression of PKM2 in Osteosarcoma. Int. J. Biol. Sci. 2022, 18, 30–42. [Google Scholar] [CrossRef] [PubMed]
  111. Lan, Q.; Peyvandi, S.; Duffey, N.; Huang, Y.T.; Barras, D.; Held, W.; Richard, F.; Delorenzi, M.; Sotiriou, C.; Desmedt, C.; et al. Type I Interferon/IRF7 Axis Instigates Chemotherapy-Induced Immunological Dormancy in Breast Cancer. Oncogene 2019, 38, 2814–2829. [Google Scholar] [CrossRef] [PubMed]
  112. Arreal, L.; Piva, M.; Fernández, S.; Revandkar, A.; Schaub-Clerigué, A.; Villanueva, J.; Zabala-Letona, A.; Pujana, M.; Astobiza, I.; Cortazar, A.R.; et al. Targeting PML in Triple Negative Breast Cancer Elicits Growth Suppression and Senescence. Cell Death Differ. 2020, 27, 1186–1199. [Google Scholar] [CrossRef] [PubMed]
  113. Tampakaki, M.; Oraiopoulou, M.-E.; Tzamali, E.; Tzedakis, G.; Makatounakis, T.; Zacharakis, G.; Papamatheakis, J.; Sakkalis, V. PML Differentially Regulates Growth and Invasion in Brain Cancer. Int. J. Mol. Sci. 2021, 22, 6289. [Google Scholar] [CrossRef]
  114. Zhang, Y.; Li, W.; Zhang, P.; Guo, J.; Sun, J.; Lu, J.; Liu, S. Hematological Malignancies in Systemic Lupus Erythematosus: Clinical Characteristics, Risk Factors, and Prognosis—A Case-Control Study. Arthritis Res. Ther. 2022, 24, 5. [Google Scholar] [CrossRef] [PubMed]
  115. Lü, S.; Zhang, J.; Wu, H.; Zheng, X.; Chu, Y.; Xiong, S. Anti-tumor effect of anti-dsDNA autoantibodies. Zhonghua Zhong Liu Za Zhi 2005, 27, 73–76. [Google Scholar] [PubMed]
  116. Ruiz-Irastorza, G.; Ugarte, A.; Egurbide, M.V.; Garmendia, M.; Pijoan, J.I.; Martinez-Berriotxoa, A.; Aguirre, C. Antimalarials May Influence the Risk of Malignancy in Systemic Lupus Erythematosus. Ann. Rheum. Dis. 2007, 66, 815–817. [Google Scholar] [CrossRef] [PubMed]
  117. Sohn, T.A.; Bansal, R.; Su, G.H.; Murphy, K.M.; Kern, S.E. Erratum: High-Throughput Measurement of the Tp53 Response to Anticancer Drugs and Random Compounds Using a Stably Integrated Tp53-Responsive Luciferase Reporter. Carcinogenesis 2003, 24, 1713. [Google Scholar] [CrossRef]
  118. Pan, Y.; Gao, Y.; Chen, L.; Gao, G.; Dong, H.; Yang, Y.; Dong, B.; Chen, X. Targeting Autophagy Augments In Vitro and In Vivo Antimyeloma Activity of DNA-Damaging Chemotherapy. Clin. Cancer Res. 2011, 17, 3248–3258. [Google Scholar] [CrossRef]
  119. Li, J.; Yang, B.; Zhou, Q.; Wu, Y.; Shang, D.; Guo, Y.; Song, Z.; Zheng, Q.; Xiong, J. Autophagy Promotes Hepatocellular Carcinoma Cell Invasion through Activation of Epithelial-Mesenchymal Transition. Carcinogenesis 2013, 34, 1343–1351. [Google Scholar] [CrossRef] [PubMed]
  120. Seo, M.S.; Yeo, J.; Hwang, I.C.; Shim, J.Y. Risk of Pancreatic Cancer in Patients with Systemic Lupus Erythematosus: A Meta-Analysis. Clin. Rheumatol. 2019, 38, 3109–3116. [Google Scholar] [CrossRef]
Rheumato 04 00017 g001
Figure 1. Related mechanisms of oncogenesis and autoimmunity in SLE. Source: own study.
Figure 1. Related mechanisms of oncogenesis and autoimmunity in SLE. Source: own study.
Rheumato 04 00017 g001
Table 1. Incidences of malignancies in SLE.
Table 1. Incidences of malignancies in SLE.
Type of Malignant TumorSIR (95% CI)Prevalence in SLE Compared to the General
Population
Overall1.18 (1.00–1.38)1.5 to 2 times higher risk
Hematologic 3 to 4 times higher risk
Non-Hodgkin lymphoma (NHL)4.32 (3.4–5.47)4 to 5 times more often
Hodgkin lymphoma, lymphoma, leukemia, multiple myeloma2.71 (1.68–4.36)2 to 3 times higher risk
The respiratory system1.53 (1.11–2.11)
Lung1.75 (1.37–2.24)1.5 times higher risk; in case of smoking, the risk increases 7 times
Larynx4.22 (1.97–9.03)2 times higher risk
Oropharynx7.35 (1.12–48.36)Increased risk
The digestive system1.15 (0.97–1.37)
Oral2.69 (1.75–4.16)3 times higher risk
Oesophagus1.73 (1.04–2.89)Increased risk
Liver2.81 (1.72–4.59)2 times higher risk
Gallbladder1.83 (1.76–1.90)Increased risk
Hepatobiliary tract2.07 (1.37–3.12)Increased risk
Stomach1.34 (1.05–1.72)1.3 times higher risk
Pancreatic1.26 (0.97–1.63)Increased risk
Colorectal1.65 (1.23–2.22)Increased risk
Anal5.69 (1.62–19.94)
The cardiovascular systemNRNR
The musculoskeletal systemNRNR
The urogenital system3.41 (1.86–6.23)
Bladder and kidney1.80 (1.04–3.11)1,5-krotnie wyższe ryzyko
Ovarian0.86 (0.68–1.10)Reduced risk
Endometrial0.64 (0.49–0.83)Reduced risk
Cervical1.66 (1.16–2.36)1.5 times higher risk of squamous cell carcinoma and squamous intraepithelial lesions
Vulva/vagina3.63 (2.54–5.20)3 times higher risk
Prostate0.80 (0.65–0.99)Reduced risk
The nervous system and brain1.41 (1.02–1.93)1.3 times higher risk
The skin tumors
Nonmelanoma skin1.24 (0.98–1.57)Increased risk
Melanoma skin0.69 (0.53–0.90)Reduced risk
Others malignant tumors
Head and neckNRIncreased risk
Thyroid1.50 (1.34–1.68)1.5 times higher risk
Breast0.87 (0.76–1.00)Reduced risk
CI: confidence interval; min: minimum; max: maximum; NR: none reported; SIR: standardized incidence ratio. Source: own studies [2,4,13,42,55,56,63,67,70,73,76,77,78,79,80,81,82,83,84,85].
Table 2. Protective and risk factors of malignant tumors in SLE.
Table 2. Protective and risk factors of malignant tumors in SLE.
Type of Malignant TumorProtective Factors of
Malignant Tumors		Risk Factors for Malignant Tumors
Overall Immunosuppressive therapies (excluding antimalarials and steroids); cyclophosphamide; disease activity; acquired immunodeficiency syndrome (AIDS)
Hematologic Antiphospholipid antibodies (aPL); immunosuppressive therapies (excluding antimalarials and steroids); cyclophosphamide; presence of BAFF, APRIL, and 3E10 antibody; TNFAIP3 or A20 rs77191406 polymorphism; increased levels of IL-6 and IL-10; EBV;
Non-Hodgkin lymphoma (NHL) Male gender; Sjogren’s syndrome; CD40 allele rs4810485 (chromosome 20q13); HLA allele rs1270942 (chromosome 6p21.33); cyclophosphamide
Hodgkin lymphoma, lymphoma, leukemia, multiple myeloma
The respiratory system
Lung Smoking; lung fibrosis; rs13194781 and rs1270942 (chromosome 6p21-22)
The digestive systemAcetylsalicylic acidSmoking, alcohol consumption, diet, obesity, low physical activity, diabetes,
Liver HBV, HCV, nonalcoholic fatty liver disease
Stomach
PancreaticRo60/SSA antigen reduction, acetylsalicylic acid, melatonin, statins, curcumin, and flavonoids
The musculoskeletal system The presence of anti-neutrophil cytoplasmic antibodies (ANCAs)
The urogenital system
Bladder and kidney Age, diet, low physical activity, cyclophosphamide; TNFAIP3 or A20 rs77191406 polymorphism
Ovarian, Endometrialless exposure to endogenous and/or exogenous hormones
CervicalHPV vaccination and cytology every year;Immunosuppressive therapies (excluding antimalarials and steroids); HPV; cyclophosphamide
Vulva/vaginaHPV vaccinationHPV; cyclophosphamide
ProstateLow levels of heat shock protein 27, reduced testosterone levelsGlucocorticosteroids
The skin tumors
Nonmelanoma skinAntimalarialsCyclophosphamide
Melanoma skinUse of UV filter, avoiding solar radiationThe presence of anti-neutrophil cytoplasmic antibodies (ANCAs)
Others malignant tumors
Head and neck Smoking; HPV, EBV
Thyroid Thyroid antibodies
BreastLess exposure to endogenous and/or exogenous hormones; antimalarials; presence of anti-double-stranded DNA and 5C6 antibody; regulatory T cells (Tregs); low levels of heat shock protein 27rs9888739 (chromosome 16p11.2)
BAFF: B-cell activating factor, APRIL: A proliferation-inducing ligand; ANCAs: anti-neutrophil cytoplasmic antibodies; HPV: human papillomavirus; EBV: Epstein–Barr virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus. Source: own studies [2,13,42,55,56,60,67,70,73,74,76,77,78,79,80,81,82,83,84,98,104,120].
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Blachut, D.; Przywara-Chowaniec, B.; Tomasik, A. Pathogenesis, Epidemiology, and Risk Factors of Malignant Tumors in Systemic Lupus Erythematosus. Rheumato 2024, 4, 209-221. https://doi.org/10.3390/rheumato4040017

AMA Style

Blachut D, Przywara-Chowaniec B, Tomasik A. Pathogenesis, Epidemiology, and Risk Factors of Malignant Tumors in Systemic Lupus Erythematosus. Rheumato. 2024; 4(4):209-221. https://doi.org/10.3390/rheumato4040017

Chicago/Turabian Style

Blachut, Dominika, Brygida Przywara-Chowaniec, and Andrzej Tomasik. 2024. "Pathogenesis, Epidemiology, and Risk Factors of Malignant Tumors in Systemic Lupus Erythematosus" Rheumato 4, no. 4: 209-221. https://doi.org/10.3390/rheumato4040017

APA Style

Blachut, D., Przywara-Chowaniec, B., & Tomasik, A. (2024). Pathogenesis, Epidemiology, and Risk Factors of Malignant Tumors in Systemic Lupus Erythematosus. Rheumato, 4(4), 209-221. https://doi.org/10.3390/rheumato4040017

Article Metrics

Back to TopTop