Abstract
STAT3 plays an important role in various complex and sometimes contradictory pathways such as proliferation, differentiation, migration, inflammation, and apoptosis. The transcriptional activity of the STAT3 gene is controlled by a transcription factor called ZNF341. There is insufficient data on radiation sensitivity and post-radiation DNA repair in STAT3- loss-of-function (LOF) patients. We aimed to investigate the radiosensitivity in patients with STAT3-LOF and ZNF341 deficiency. Twelve patients with STAT3-LOF and four ZNF341-deficiency patients were recruited from three clinical immunology centers in Turkey and evaluated for radiosensitivity by the Comet assay, comparing to 14 age- and sex-matched healthy controls. The tail length (TL) (μm), percentage of DNA in the tail (TDNA%), and olive tail moment (OTM) (arbitrary units) were evaluated at the same time for baseline (spontaneous), initial (immediately after 2 Gy irradiation), and recovery (2 h after irradiation) periods by using a computerized image-analysis system, estimating DNA damage. Except for a patient with ZNF341 deficiency who developed nasal cell primitive neuroendocrine tumor and papillary thyroid cancer during the follow-up, there was no cancer in both groups. During the recovery period of irradiation, TL, TDNA%, and OTM values of healthy controls decreased rapidly toward the baseline, while these values of patients with STAT3-LOF and ZNF341 deficiency continued to increase, implying impaired DNA repair mechanisms. Increased radiosensitivity and impaired DNA repair were demonstrated in patients diagnosed with STAT3-LOF and ZNF341 deficiency, potentially explaining the susceptibility to malignant transformation.
Keywords: STAT3-LOF, ZNF-341 deficiency, radiosensitivity, DNA repair, Comet assay
This study demonstrates for the first time that patients with STAT3-LOF and ZNF341 deficiency had increased radiation sensitivity and DNA repair defects compared with healthy controls. Our results highlight the need for close monitoring of these patients for the development of malignancy.
Graphical Abstract
Graphical Abstract.
Introduction
The transcription factor signal transducer and activator of transcription 3 (STAT3) mediate the actions of many cytokines involved in mounting innate and adaptive immune responses, whereby drive many critical cellular processes, including growth and apoptosis [1, 2]. Dominant-negative, heterozygous STAT3-loss-of-function (LOF) germline mutations cause autosomal dominant hyper immunoglobulin (Ig) E syndrome (HIES) characterized by eczematoid dermatitis, recurrent skin and sinopulmonary infections, and high IgE levels [1–3]. STAT3-HIES patients usually display normal serum IgE levels, except for IgE, and most of them exhibit insufficient antigen-specific antibody responses after immunization with T-cell-dependent antigens [4]. STAT3 regulates DNA damage response signaling pathway by modifying ataxia-telangiectasia mutated-Serine/threonine-protein kinase Chk1, and dysregulated STAT3 can become a potent oncogene that licenses many human cancers’ development [5, 6].
The zinc finger (ZNF) domains are small protein motifs that coordinate various biological functions, including gene transcription, translation, mRNA trafficking, cytoskeletal organization, protein folding, and chromatin remodeling [7]. ZNF341 is a transcription factor that controls the transcription of the STAT3 gene. Biallelic nonsense mutations encoding truncated forms of ZNF341 are responsible for the STAT3-like hyper-IgE phenotype [8, 9].
Although the role of STAT3 in the process of DNA repair has been well defined, there is insufficient data on DNA repair status in patients diagnosed with STAT3-LOF disease. We recently reported impaired DNA repair processing in a patient with ZNF341 deficiency, highlighting the role of STAT3 in cancer development, and questioned whether the exact mechanism could also be linked to STAT3-LOF disease [10].
The Comet assay was first developed by Ostling and Johansson [11]. It is a technique for measuring DNA-strand breaks and repairing at the level of a single cell [12, 13]. In the last two decades, Comet assay has become one of the most common tests to evaluate DNA damage and repair [14].
Herein, we aimed to investigate radiation sensitivity and DNA repair status after irradiation in patients with STAT3-LOF and ZNF341 deficiency by Comet assay.
Materials and methods
Patients and controls
Twelve patients with STAT3-LOF and four with ZNF341 deficiency genetically confirmed from three tertiary clinical immunology centers in Turkey were included in the study. The control group consisted of 14 healthy individuals who were mates in gender and age and did not have cancer in themselves and their relatives.
For the positive control of the comet test, three patients with Ataxia telangiectasia (AT) and two healthy controls were included in the study.
Comet assay
The comet assay was applied to peripheral blood leucocytes of the patients to determine DNA repair problems causing radiosensitivity. The alkaline version of the comet assay was used as it allows to detection of DNA damages induced by clinically relevant doses of radiation [15]. White blood cells of age- and sex-matched healthy blood donors were used as control. The extents of spontaneous (0 Gy), initial (immediately after 2 Gy irradiation), and residual (2 h after irradiation) DNA damage were evaluated by quantifying the tail length (TL) (μm), the percentage of DNA in the tail (TDNA%), and olive tail moment (OTM) (arbitrary units) parameters under an epifluorescence microscope using a computer-based image analysis system (Kameram Komet Module, Micro System Ltd., Turkey). Experiments were performed in triplicate for each subject.
Statistical analysis
Categorical data were expressed as frequencies and percentages, and continuous data as mean ± standard deviation (SD). The size of the differences between the group means was calculated by considering the effect size (ES) of Cohen’s d. The ES values were evaluated as 0.2 is low, 0.5 is medium, 0.8 is high, and 1.3 is very high. Statistical analysis was performed using the statistical package SPSS 23 (IBM corp.).
Results
The demographic and clinical features of the patients
STAT3-LOF
The female/male ratio of the patients was 1.4 (7/5), and the median age was 16.1 years (min: 3.9 to max: 39.9 years). No history of malignancy was present in all cases with STAT3-LOF or in their first-degree relatives. None of them had a chronic viral infection. The clinical and laboratory features of the patients were summarized in Supplementary Table S1. It was observed that the effect size of the difference between the mean initial TDNA% measurement of STAT3-LOF and control groups was moderate, and the size of the difference between the groups in other parameters was thoroughly high and vastly significant (Table 1, Figure 1).
Table 1:
Comet assay results of patients with STAT3- LOF (n = 12) and controls (n = 10)
| Number of tested cells | Mean ± standard deviation | ES | ||||
|---|---|---|---|---|---|---|
| STAT3-LOF | Controls | STAT3-LOF | Controls | |||
| TL | Spontaneous | 1200 | 1000 | 12.4 ± 4.5 | 8.7 ± 3.1 | 0.97 |
| Initial | 1200 | 1000 | 37.3 ± 13.4 | 19.5 ± 5.9 | >1.30 | |
| Residual | 1200 | 1000 | 50.5 ± 18.6 | 16.0 ± 5.6 | >1.30 | |
| TDNA% | Spontaneous | 1200 | 1000 | 22.3 ± 13 | 13.5 ± 8 | 0.82 |
| Initial | 1200 | 999 | 41.1 ± 13.8 | 35.5 ± 11.7 | 0.44 | |
| Residual | 1199 | 1000 | 61.4 ± 16.8 | 28.1 ± 8.8 | >1.30 | |
| OTM | Spontaneous | 1200 | 1000 | 3.5 ± 2.3 | 1.9 ± 0.9 | 0.92 |
| Initial | 1199 | 1000 | 12.7 ± 5.9 | 7.1 ± 3 | >1.30 | |
| Residual | 1200 | 1000 | 20.4 ± 8.4 | 5.2 ± 2.4 | >1.30 | |
Effect size (ES): 0.2 low, 0.5 moderate, 0.8 high, 1.3 very high.
DNA: deoxyribonucleic acid.
TL: tail length, TDNA%: the percentage of DNA in the tail, OTM: olive tail moment.
Figure 1:
Radiation-induced DNA damage in leukocytes of patients with STAT3-LOF and controls. (A) Representative fluorescent microscope images of DNA comets and (B) boxplots of the evaluated comet parameters (tail length, tail % DNA, and olive tail moment).
ZNF341 deficiency
Four previously reported ZNF341-deficient patients from two distinct families were included in the study [8, 9]. Three biological siblings belonging to one family, aged 21.6, 34.8, and 40.2 years, had a mutation in exon 8 of the ZNF341 gene (c.1156C>T, p.R386*), and the other patient, aged 27, from a different family, had c.1062delG deletion (p.K355fs). These two variants were detected by whole-exome sequencing, and there was no additional variant contributing to the defective DNA repairing. Only the oldest patient developed nasal cell primitive neuroendocrine tumor and secondary papillary thyroid cancer [10]. Malignancy in the family history was not present. None of them had a chronic viral infection that could lead to malignancy. The clinical and laboratory characteristics of the patients are shown in Supplementary Table S1.
It was determined that TL, TDNA%, and OTM parameters of patients with ZNF341 deficiency were higher in all measurements than controls; moreover, the effect size of this difference was substantially high. (Table 2, Figure 2).
Table 2.
: Comet assay results of patients with ZNF341 deficiencies (n = 4) and controls (n = 4)
| Number of tested cells | Mean ± standard deviation | ES | ||||
|---|---|---|---|---|---|---|
| Patients | Controls | Patients | Controls | |||
| TL | Spontaneous | 400 | 400 | 11.78 ± 2.06 | 7.49 ± 2.49 | >1.30 |
| Initial | 400 | 400 | 36.73 ± 5.53 | 19.37 ± 3.78 | >1.30 | |
| Residual | 400 | 400 | 53.59 ± 6.00 | 13.81 ± 3.52 | >1.30 | |
| TDNA% | Spontaneous | 400 | 400 | 20.43 ± 2.00 | 10.19 ± 2.01 | >1.30 |
| Initial | 400 | 400 | 41.42 ± 5.23 | 31.53 ± 3.56 | >1.30 | |
| Residual | 400 | 400 | 58.38 ± 6.78 | 26.05 ± 2.75 | >1.30 | |
| OTM | Spontaneous | 400 | 400 | 3.29 ± 0.51 | 1.48 ± 0.41 | >1.30 |
| Initial | 400 | 400 | 11.35 ± 1.70 | 6.82 ± 1.17 | >1.30 | |
| Residual | 400 | 400 | 20.91 ± 3.67 | 4.04 ± 0.81 | >1.30 | |
Effect size (ES): 0.2 low, 0.5 moderate, 0.8 high, 1.3 very high.
DNA: deoxyribonucleic acid.
TL: tail length, TDNA%: the percentage of DNA in the tail, OTM: olive tail moment.
Figure 2:
Radiation-induced DNA damage in leukocytes of patients with ZNF341 deficiency and controls. (A) Representative fluorescent microscope images of DNA comets and (B) boxplots of the evaluated comet parameters (tail length, percentage of DNA in the tail, and olive tail moment).
No pathogenic variants were found in all exons of hereditary cancer susceptibility genes (MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, TM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1) and in all exons of cancer susceptibility genes (CDKN2A, FANCL, XRCC2, FANCA, FANCC, FANCB, FANCE, MLH1, PALB2, FANCG, FANCF, RAD50, APC, ERCC3, ERCC4, WT1, ERCC1, ERCC2, ATM, ERCC5, NOP10, BMPR1A) in patients with ZNF341 deficiency who developed malignancy.
It was observed that DNA scattering decreased in the parents’ leukocytes 2 h after irradiation, unlike their ZNF341-deficient children.
Ataxia telangiectasia
The TL, TDNA%, and OTM values at all stages of the comet test were higher in AT patients than in controls (Table 3).
Table 3:
Comet assay results of patients with Ataxia Telangiectasia (n = 3) and controls (n = 2)
| Number of tested cells | Mean ± standard deviation | ES | ||||
|---|---|---|---|---|---|---|
| Patients | Controls | Patients | Controls | |||
| TL | Spontaneous | 300 | 200 | 15.8 ± 4.7 | 7.2 ± 1.7 | >1.30 |
| Initial | 300 | 200 | 33.7 ± 9.1 | 15.2 ± 4.7 | >1.30 | |
| Residual | 300 | 200 | 49.1 ± 12.3 | 13.5 ± 5.05 | >1.30 | |
| TDNA% | Spontaneous | 300 | 200 | 28.2 ± 8 | 10.1 ± 6.1 | >1.30 |
| Initial | 300 | 200 | 43.4 ± 13.2 | 27.8 ± 8.7 | >1.30 | |
| Residual | 300 | 200 | 69 ± 16.5 | 19.9 ± 6.45 | >1.30 | |
| OTM | Spontaneous | 300 | 200 | 5.1 ± 2.1 | 1.65 ± 0.8 | >1.30 |
| Initial | 300 | 200 | 14.1 ± 5.1 | 4.5 ± 1.7 | >1.30 | |
| Residual | 300 | 200 | 22.1 ± 6.5 | 3.2 ± 1.4 | >1.30 | |
Effect size (ES): 0.2 low, 0.5 moderate, 0.8 high, 1.3 very high.
DNA: deoxyribonucleic acid.
TL: tail length, TDNA%: the percentage of DNA in the tail, OTM: olive tail moment.
Discussion
This study demonstrates for the first time that patients with STAT3-LOF and ZNF341 deficiency had increased radiation sensitivity and DNA repair defects compared with healthy controls. Our results highlight the need for close monitoring of these patients for the development of malignancy.
Circulating white blood cells can be used to reflect the overall body exposures to carcinogens and DNA repair activity in target tissues even if they are not the primary target cancer cells [16–19]. Thus, peripheral blood leukocytes are commonly used as surrogates to predict radiosensitivity based on DNA repair ability in healthy subjects and patients with or at risk of cancer. In this study, peripheral blood leucocytes of patients and controls were irradiated in the Comet test and the changes were examined.
STAT3 is a member of the STAT family that mediates signal transduction from the plasma membrane to the nucleus and plays a role in various cellular activities [20]. It plays an important role in various complex and sometimes contradictory pathways such as proliferation, differentiation, migration, inflammation, and apoptosis [2]. The normal function of endogenous STAT3 is critical for reprogramming human somatic cells [21]. Although dysregulated STAT3 is known as a potent oncogene for many human cancers, it can act as both a potent tumor promoter and tumor suppressor factor [5, 22, 23]. It is well known that somatic activating gain-of-function (GOF) mutations in the STAT3 gene are associated with different hematological malignancies [24, 25]. Despite this association between somatic STAT3 GOF mutations and malignancy, cancer has been reported only in two patients [26]. It has been shown that hematological malignancies can also develop in patients with STAT3-LOF-mutations [27]. It was reported in the French National Survey that four (7%) of 60 STAT3-LOF patients developed non-Hodgkin lymphoma [28]. In another study involving 12 patients with STAT3-LOF, a case (8.3%) developed B-cell lymphoma [29]. Moreover, a case report shows the development of diffuse large B-cell lymphoma in a patient diagnosed with STAT3-LOF [30]. In our study, no malignancy has developed in our cases diagnosed with STAT3-LOF so far.
Ionizing radiation damages DNA directly and indirectly by increasing free radical species, especially OH radicals [31, 32]. STAT3 contributes to radioresistance in many cancer types by various mechanisms [31]. Therefore, STAT3 has become a promising target for the radiosensitization of cancer [31]. Pharmacological inhibition of STAT3 has increased radiosensitivity in various tumor types [33–35]. Additionally, STAT3 has a cytoprotective effect against oxidative stress and is required to efficiently repair damaged DNA [36, 37]. This is the first study to investigate radiation sensitivity in patients diagnosed with STAT3-LOF, the natural model of STAT3 deficiency, and our results showed that these patients had increased radiation sensitivity and insufficient DNA repair.
Human ZNF341 is essential for the STAT3 transcription-dependent auto-induction and sustained activity of STAT3, which appears to be necessary for the efficient repair of DNA damage [2]. The STAT3 error caused by the ZNF341 deficiency can facilitate cancer development by causing reduced resistance to radiation and DNA repair defects. In a recently published study, low expression levels of ZNF341 were associated with increased radiosensitivity in breast cancer [38]. In the Comet assay, as with STAT3 deficiency, patients with ZNF341 deficiency were found to have impaired DNA repair after radiation.
The number of patients diagnosed with ZNF341 is very low all over the world. Currently, 18 cases with ZNF341 deficiency have been reported in the literature, and cancer was detected in only one of them [8, 9]. As a risk factor, this patient had repeating X-ray imaging to demonstrate recurrent pulmonary infections and sinusitis. No documented chronic viremia or familial predisposition to cancer was found. In this patient, the absence of pathogenic variants in all exons of hereditary cancer susceptibility genes strengthens the possibility that malignancy (especially secondary cancer) development is associated with underlying genetic defect (ZNF341 deficiency) and radiation exposure.
Parents of patients with ZNF341 deficiency were also included in the study to understand whether post-radiation changes in the Comet test were due to a possible familial cancer tendency condition. However, DNA scattering tended to decrease at the second hour after irradiation, unlike their ZNF341-deficient children in parents. Therefore, this experiment supports the idea that there was no other familial pathology that led to radiosensitivity and impaired DNA repair.
The comet test has previously been shown to be a valid technique for measuring DNA damage in patients with AT [39]. It was also abnormal in the leukocytes of patients with AT, who were studied as positive controls in our study.
Our study has some limitations. ZNF341 deficiency and STAT3-LOF are rare inborn errors of immunity; as a result, we conducted it with a small number of patients. We think that longer follow-up is required to observe whether malignancy develops in patients. The development of malignancy occurs as a result of various mechanisms and complex events in primary immunodeficiencies. Although radiation sensitivity and disruption of DNA repair after irradiation are some of these mechanisms, they may not be sufficient alone to explain the development of cancer in these patients.
In conclusion, our study is the first to show radiation sensitivity with the comet test in cases with STAT3-LOF and ZNF341 deficiencies. The data obtained from the Comet assay revealed a high level of radiation-induced DNA damage and deficiency in the repair process in all analyzed patient cells. The susceptibility to malignancy in these patients may be due to defects in DNA repair mechanisms. Closely monitoring patients with STAT3-LOF and ZNF341 deficiency for malignancies and protecting them from radiation exposure as much as possible would provide longer life expectancy and better outcomes. Further studies are needed to fully explain the pathogenesis of cancer development in these patients and to disclose whether the Comet test will be predictive on this issue.
Supplementary Material
Acknowledgements
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Glossary
Abbreviations
- DNA
deoxyribonucleic acid
- STAT3
signal transducer and activator of transcription 3
- STAT3-LOF
STAT3-loss of function
- ZNF341
zinc finger 341
- TL
tail length
- TDNA%
tail DNA (%)
- OTM
olive tail moment
- AT
ataxia telangiectasia
- SD
standard deviation
- GOF
gain of function
Contributor Information
Sukru Cekic, Division of Pediatric Immunology, Bursa Uludag University Faculty of Medicine, Bursa, Turkey.
Huzeyfe Huriyet, Cell Culture and Genetic Toxicology Laboratory, Department of Biology, Faculty of Sciences and Arts, Bursa Uludag University, Bursa, Turkey.
Melika Hortoglu, Cell Culture and Genetic Toxicology Laboratory, Department of Biology, Faculty of Sciences and Arts, Bursa Uludag University, Bursa, Turkey.
Nurhan Kasap, Division of Pediatric Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey.
Ahmet Ozen, Division of Pediatric Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Barlan Center for Translational Medicine, Istanbul, Turkey.
Elif Karakoc-Aydiner, Division of Pediatric Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Barlan Center for Translational Medicine, Istanbul, Turkey.
Ayse Metin, Division of Pediatric Allergy and Immunology, University of Health Sciences/Ankara City Hospital/Children’s Hospital, Ankara, Turkey.
Gokhan Ocakoglu, Department of Biostatistics, Bursa Uludag University Faculty of Medicine, Bursa, Turkey.
Candan Demiroz Abakay, Department of Radiation Oncology, Bursa Uludag University Faculty of Medicine, Bursa, Turkey.
Sehime G Temel, Department of Medical Genetics, Bursa Uludag University Faculty of Medicine, Bursa, Turkey.
Sebnem Ozemri Sag, Department of Medical Genetics, Bursa Uludag University Faculty of Medicine, Bursa, Turkey.
Safa Baris, Division of Pediatric Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Barlan Center for Translational Medicine, Istanbul, Turkey.
Tolga Cavas, Cell Culture and Genetic Toxicology Laboratory, Department of Biology, Faculty of Sciences and Arts, Bursa Uludag University, Bursa, Turkey.
Sara Sebnem Kilic, Division of Pediatric Immunology, Bursa Uludag University Faculty of Medicine, Bursa, Turkey; Translational Medicine, Bursa Uludag University, Translational Medicine, Bursa, Turkey.
Funding
The authors received no specific funding for this study.
Conflict of interests
All authors declare that they have no competing interests.
Author contributions
S.C., T.C., and S.S.K. contributed to the study conception and design. Material preparation, data collection, and analysis were performed by S.C., H.H., M.H., N.K., G.O., A.O., E.K.A., A.M., C.D.A., S.G.T., S.O.S., S.B., T.C., and S.S.K. The first draft of the manuscript was written by S.C. and S.S.K., and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Ethical approval
Ethical approval was obtained from the Uludag University Faculty of Medicine Medical Research Ethics Committee for the study.
Patient consent
The informed consent form was obtained from participants.
Data availability
The data that support the study findings are available from the corresponding author upon reasonable request.
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Associated Data
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Supplementary Materials
Data Availability Statement
The data that support the study findings are available from the corresponding author upon reasonable request.