Increased radiosensitivity and impaired DNA repair in patients with STAT3-LOF and ZNF341 deficiency, potentially contributing to malignant transformations

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 (μm), Tail DNA (%), Olive Tail Moment (OTM) (arbitrary units) were evaluated at the same time for baseline (spontaneous), initial (immediately after 2Gy irradiation), and recovery (2h 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 towards 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.

Aggressive Pediatric Adrenal Cortical Carcinoma With a Novel Translocation t(20;22) and intergenic fusion of MN1 and ZNF341: A Case Report and Literature Review

“…On the other hand, ZNF341 is a nuclear zinc finger transcription factor that regulates the expression of the protein STAT3, which regulates human immune homeostasis [26]. Limited literature has shown that ZNF341 deficiency has been associated with impaired DNA repair mechanisms, which led to various malignancies [27]. Thus, the aberrant translocation of ZNF341 indirectly causes immunodeficiency and can be partially attributable for tumorigenesis.…”

Tailored treatments in inborn errors of immunity associated with atopy (IEIs-A) with skin involvement

“…However, patients with ZNF341 deficiency are characterized by less severe non-hematopoietic phenotypes and more severe inflammatory manifestations compared to STAT3 deficiency ( 118 ). Patients with increased radiosensitivity and subsequent increased risk of malignancy are reported ( 127 ). Furthermore, ZNF341 deficiency seems to influence several immune cells including monocytes and NK lymphocytes, which could contribute in the generation of atopic eczema.…”