Multiple outcomes of the germline p16 INK4a mutation affecting senescence and immunity in human skin

• Published in: Aging cell 2024-10, p.e14373
• Main Authors: Subramanian, Priya, Sayegh, Souraya, Laphanuwat, Phatthamon, Devine, Oliver P, Fantecelle, Carlos Henrique, Sikora, Justyna, Chambers, Emma S, Karagiannis, Sophia N, Gomes, Daniel C O, Kulkarni, Anjana, Rustin, Malcolm H A, Lacy, Katie E, Akbar, Arne N
• Format: Article
• Language: English
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.14373

The integrated behaviour of multiple senescent cell types within a single human tissue leading to the development of malignancy is unclear. Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the CDKN2A gene coding for the cyclin inhibitor p16 . Melanocytes within skin biopsies from FMS patients express significantly less p16 but express higher levels of the DNA-damage protein γH2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts in vitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types in vivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence-related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance in vivo.