AURKA Overexpression Is Driven by FOXM1 and MAPK/ERK Activation in Melanoma Cells Harboring BRAF or NRAS Mutations: Impact on Melanoma Prognosis and Therapy
The cell cycle-related genes AURKA and FOXM1 are overexpressed in melanoma. We show here that AURKA overexpression is associated with poor prognosis in three independent cohorts of melanoma patients and correlates with the presence of genomic amplification of AURKA locus and BRAFV600E mutation. AURKA overexpression may also be driven by increased promoter activation through elements such as ETS and FOXM1 found within the 5' proximal promoter region. Activated MAPK/ERK signaling pathway mediates robust AURKA promoter activation, thereby knockdown of BRAFV600E and ERK inhibition results in reduced AURKA transcription and expression. We show a positive correlation between FOXM1 and AURKA expression in three independent cohorts of melanoma patients. FOXM1 silencing decreases expression of AURKA and late cell cycle genes in melanoma cells. We further found that FOXM1 expression levels are significantly higher in tumors carrying the BRAFV600E mutation compared with the wild-type BRAF (BRAFwt). Accordingly, the knockdown of BRAFV600E also reduces the expression of FOXM1 in BRAFV600E cells. Moreover, Aurora kinase A and FOXM1 inhibition by either genetic knockdown or pharmacologic inhibitors impair melanoma growth and survival both in culture and in vivo, underscoring their therapeutic value for melanoma patients who fail to benefit from BRAF/MEK signaling inhibition. https://www.ncbi.nlm.nih.gov/pubmed/28188776
Understanding the contribution of the ugly duckling sign (a nevus that is obviously different from the others in a given individual) in intrapatient comparative analysis (IPCA) of nevi may help improve the detection of melanoma.
To assess the agreement of dermatologists on identification of the ugly duckling sign and estimate the contribution of IPCA to the diagnosis of melanoma.
Design, Setting, and Participants:
The same 2089 digital images of the nevi of a sample of 80 patients (mean age, 42 years [range, 19-80 years]; 33 men and 47 women), as well as 766 dermoscopic images from a subset of 30 patients (mean age, 40 years [range, 21-75 years]; 12 men and 18 women), were randomly presented to the same 9 dermatologists for blinded assessment from September 22, 2011, to April 1, 2013. The first experiment was designed to mimic an IPCA situation, with images of all nevi of each patient shown to the dermatologists, who were asked to identify ugly duckling nevi (UDN). The second experiment was designed to mimic a lesion-focused analysis to identify morphologically suspicious nevi. Data analysis was conducted from November 1, 2012, to June 1, 2013.
Main Outcomes and Measures:
Number of nevi labeled UDN and morphologically suspicious nevi, specificity of lesion-focused analysis and IPCA, and number of nevi identified for biopsy.
Of the 2089 clinical images of nevi from 80 patients (median number of nevi per patient, 26 [range, 8-81]) and 766 dermoscopic images (median number of nevi per patient, 19 [range, 8-81]), all melanomas were labeled UDN and as morphologically suspicious nevi by the 9 dermatologists. The median number of UDN detected per patient was 0.8 among the clinical images of nevi (mean, 1.0; range, 0.48-2.03) and 1.26 among the dermoscopic images (mean, 1.4; range, 1.00-2.06). The propensity to consider more or fewer nevi as having ugly duckling signs was independent of the presentation (clinical or dermoscopic). The agreement among the dermatologists regarding UDN was lower with dermoscopic images (mean pairwise agreement, 0.53 for clinical images and 0.50 for dermoscopic images). The specificity of IPCA was 0.96 for clinical images and 0.95 for dermoscopic images vs 0.88 and 0.85, respectively, for lesion-focused analysis. When both IPCA and lesion-focused analyses were used, the number of nevi considered for biopsy was reduced by a factor of 6.9 compared with lesion-focused analysis alone.
Conclusions and Relevance:
Intrapatient comparative analysis is of major importance to the effectiveness of the diagnosis of melanoma. Introducing IPCA using the ugly duckling sign in computer-assisted diagnosis systems would be expected to improve performance.
Standardizing dermatological imaging is important to improve monitoring of skin lesions and skin conditions, ensure the availability of high-quality images for teledermatology, and contribute to the development of a robust archive of skin images to be used for research.
To provide guidelines for the clinical application of the Standards for Dermatological Imaging set forward by the ISIC.
The ISIC recommendations were developed through a hybrid Delphi methodology. The methods for achieving consensus have been described previously. The practical application of these recommendations was evaluated by 2 clinical photographers with expertise in skin imaging. Images corresponding to each recommendation were taken by a clinical photographer and provided as visual examples of how these recommendations can be implemented in clinical practice.
The Standards for Dermatological Imaging developed by the ISIC members could be followed in the clinical setting. Images showing appropriate lighting, background color, field of view, image orientation, focus and depth of field, resolution, and scale and color calibration were obtained by the clinical photographer, by following the detailed recommendations for regional, close-up and dermoscopic images.
Conclusions and Relevance:
Adhering to the recommendations is both feasible and achievable in practice. Adopting these Standards is the first step in achieving international standardization of skin imaging, with the potential to improve clinical outcomes and research activities. https://www.ncbi.nlm.nih.gov/pubmed/28241182