p15 Expression Differentiates Nevus from Melanoma

Abstract

Most melanomas are driven by BRAF(V600E)-activating mutations, while nevi harboring the same mutations have growth arrest. Although decreased p16 expression has been associated with melanoma formation, in recent work, p15 represented a primary effector of oncogene-induced senescence in nevomelanocytes that was diminished in melanomas. This study determined whether decreased p15 levels represent a general biomarker for the transition from nevus to melanoma. We performed p15 and p16 IHC analyses on a random series of nevi and melanomas. Staining was evaluated and graded for percentage and intensity to determine the H score. For real-time quantitative RT-PCR analysis of p15, RNA was extracted from FFPE sections from 14 nevus and melanoma samples via macrodissection. A two-sided t-test was used to evaluate between-group differences in mean H scores and qDCt values. p15 Expression was significantly increased in melanocytic nevi compared with melanomas (mean H scores, 254.8 versus 132.3; P < 0.001). On p15 staining, the H score differential was greater than that with p16 staining [122.5 (P < 0.001) and 64.8 (P Z 0.055), respectively]. Real-time quantitative RT-PCR analysis revealed a lower mean qDCt value in melanomas, consistent with lower p15 expression (P Z 0.018). Together, these data support the hypothesis that decreased p15 expression is a robust biomarker for distinguishing nevus from melanoma. (Am J Pathol 2016, 186: 3094e3099; http:// dx

Expression of p15 in a spectrum of spitzoid melanocytic neoplasms

“…Our study confirms an observation from prior studies, that p15 is expressed not only in melanocytes but in epithelial tissues (Figure A,C, and Figure C,F). We observed higher levels of p15 than p16 expression in epidermal keratinocytes, outer root sheath keratinocytes and adnexal epithelium in this study as well as in prior studies . Previous studies have indicated that p15 mRNA and protein expression are higher in epithelial cells than p16 under most experimental conditions .…”

“…We observed higher levels of p15 than p16 expression in epidermal keratinocytes, outer root sheath keratinocytes and adnexal epithelium in this study as well as in prior studies. 29,30 Previous studies have indicated that p15 mRNA and protein expression are higher in epithelial cells than p16 under most experimental conditions. 34,35 Therefore, the increased epidermal and adnexal epithelial staining may represent the fact that p15 is more highly expressed in epithelial cells than p16.…”

“…In melanocytes, p15 loss is now known to directly promote the transition from benign nevus to melanoma . Moreover, p15 expression has emerged as a promising diagnostic marker to distinguish benign nevi from melanomas, as p15 immunohistochemical staining is positive in most nevi and absent in many melanomas . Intriguingly, p16 is retained in some cases of melanoma in which p15 is lost, raising the possibility that immunohistochemistry labeling of p15 may be a more specific diagnostic tool than p16 .…”

“…29 Moreover, p15 expression has emerged as a promising diagnostic marker to distinguish benign nevi from melanomas, as p15 immunohistochemical staining is positive in most nevi and absent in many melanomas. 29,30 Intriguingly, p16 is retained in some cases of melanoma in which p15 is lost, raising the possibility that immunohistochemistry labeling of p15 may be a more specific diagnostic tool than p16. 29,30 In this study, we examined the utility of p15 as well as p16 immunohistochemical staining in a cohort of 77 of spitzoid melanocytic neoplasms, including Spitz nevi, atypical Spitz tumors, and spitzoid melanomas.…”

The 2018 World Health Organization Classification of Cutaneous, Mucosal, and Uveal Melanoma: Detailed Analysis of 9 Distinct Subtypes Defined by Their Evolutionary Pathway

“…This locus may be important not only because of p16, but also because it is the locus of 2 other tumor suppressors, p14 and p15, which have relevance to melanoma progression. 108 In one study, TERT promoter mutations were highly associated with fatal outcomes. 109 The sensitivity, specificity, and predictive value of these features and tests have in general not been tested and this is difficult because appropriate gold standards do not exist.…”