Keratinocyte (KC) apoptosis plays a critical role in regulating epidermal development and restraining carcinogenesis. Apoptosis balances proliferation to maintain epidermal thickness, contributes to stratum corneum formation and may eliminate pre-malignant cells. Apart from the normal developmental program, KC apoptosis can be triggered by UV light and other stimuli. Dysfunctional apoptosis occurs in some skin diseases, such as psoriasis and skin cancer. Here we review the current state of knowledge of KC apoptosis, with particular focus on apoptotic signaling pathways and molecular mechanisms of apoptosis control, and discuss new insights into the complex role of apoptosis in skin carcinogenesis that are emerging from mouse models.

Mutations or deletions in the cyclin-dependent kinase inhibitor p16^INK4A are associated with multiple cancer types, but are more commonly found in melanoma tumors and associated with familial melanoma predisposition. Although p16 is thought to function as a tumor suppressor by negatively regulating the cell cycle, it remains unclear why the genetic compromise of p16 predisposes to melanoma over other cancers. Here we describe a novel role for p16 in regulating oxidative stress in several cell types, including melanocytes. Expression of p16 was rapidly upregulated following ultraviolet-irradiation and in response to H₂O₂-induced oxidative stress in a p38 stress-activated protein kinase-dependent manner. Knockdown of p16 using small interfering RNA increased intracellular reactive oxygen species (ROS) and oxidative (8-oxoguanine) DNA damage, which was further enhanced by H₂O₂ treatment. Elevated ROS levels were also observed in p16-depleted human keratinocytes and in whole skin and dermal fibroblasts from Cdkn2a-deficient mice. Aberrant ROS and p38 signaling in Cdkn2a-deficient fibroblasts was normalized by expression of exogenous p16. The effect of p16 depletion on ROS was not recapitulated by the knockdown of retinoblastoma protein (Rb) and did not require Rb. Finally, p16-mediated suppression of ROS could not be attributed to the potential effects of p16 on cell cycle phase. These findings suggest a potential alternate Rb-independent tumor-suppressor function of p16 as an endogenous regulator of carcinogenic intracellular oxidative stress. Compared with keratinocytes and fibroblasts, we also found increased susceptibility of melanocytes to oxidative stress in the context of p16 depletion, which may explain why the compromise of p16 predisposes to melanoma over other cancers.

Importance Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care. Objective To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies. Evidence Review The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed. Findings The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility. Conclusions and Relevance More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.