Telomere Shortening and p16-Associated Senescence in Myofibromas

The goal of this study was to explore the biological mechanisms that may influence the development of myofibromas, noninvasive soft tissue tumors with a variable clinical course. Although solitary lesions are usually benign, multicentric infantile myofibromatosis can range from indolent disease with spontaneous regression to severe forms with visceral involvement and life-threatening complications.

We analyzed senescence markers, DNA damage, and telomere biology in 33 tumor samples from 28 patients with myofibroma, including both solitary and multicentric forms. DNA damage and senescence markers (53BP1 and p16) were quantified by immunofluorescence and immunohistochemistry, whereas telomere length and maintenance mechanisms were assessed using telomere-specific fluorescence in situ hybridization. ATRX expression was evaluated, and sequencing data were reviewed for chromatin regulator mutations.

Tumor tissues exhibited significant p16 overexpression compared with matched normal tissues. DNA damage, reflected by an increased number of 53BP1 nuclear foci, was also significantly higher in tumors, whereas telomere dysfunction-induced foci, measuring telomere-associated DNA damage, showed no notable difference between groups. Telomere length analysis revealed significantly shorter telomeres in tumors, without evidence of an active telomere maintenance mechanism, such as alternative lengthening of telomeres or telomerase reactivation. Loss or downregulation of ATRX protein was frequently observed. Variants in ATRX or DAXX were identified in a subset of cases, including 1 large somatic ATRX deletion and 1 likely pathogenic germline ATRX variant. No significant difference was observed between isolated and multicentric lesions.

Our findings suggest that cellular senescence, characterized by p16 upregulation, increased DNA damage, and telomere shortening, may underlie the spontaneous regression observed in myofibromas. Alterations in ATRX and DAXX may further contribute to chromatin instability. These insights shed light on a possible protective mechanism limiting tumor growth and progression, offering a new perspective on the biology of benign pediatric tumors. Article History.