KLF9-dependent ROS regulate melanoma progression in stage-specific manner.

Although antioxidants promote melanoma metastasis, the role of reactive oxygen species (ROS) in other stages of melanoma progression is controversial. Moreover, genes regulating ROS have not been functionally characterized throughout the entire tumor progression in mouse models of cancer. To address this question, we crossed mice-bearing knock-out of Klf9, an ubiquitous transcriptional regulator of oxidative stress, with two conditional melanocytic mouse models: Braf mice, where Braf causes premalignant melanocytic hyperplasia, and Braf/Pten mice, where Braf and loss of Pten induce primary melanomas and metastases.

The triennial International Pigment Cell Conference (IPCC).

The International Federation of Pigment Cell Societies (IFPCS) held its XXIII triennial International Pigment Cell Conference (IPCC) in Denver, Colorado in August 2017. The goal of the summit was to provide a venue promoting a vibrant interchange among leading basic and clinical researchers working on leading-edge aspects of melanocyte biology and disease. The philosophy of the meeting, entitled Breakthroughs in Pigment Cell and Melanoma Research, was to deliver a comprehensive program in an inclusive environment fostering scientific exchange and building new academic bridges.

Frontiers in pigment cell and melanoma research.

In this perspective, we identify emerging frontiers in clinical and basic research of melanocyte biology and its associated biomedical disciplines. We describe challenges and opportunities in clinical and basic research of normal and diseased melanocytes that impact current approaches to research in melanoma and the dermatological sciences. We focus on four themes: (1) clinical melanoma research, (2) basic melanoma research, (3) clinical dermatology, and (4) basic pigment cell research, with the goal of outlining current highlights, challenges, and frontiers associated with pigmentation and melanocyte biology.

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease.

Trajectories of Nevus Development From Age 3 to 16 Years in the Colorado Kids Sun Care Program Cohort.

Importance: Nevi are a risk factor for melanoma and other forms of skin cancer, and many of the same factors confer risk for both. Understanding childhood nevus development may provide clues to possible causes and prevention of melanoma.

Objectives: To describe nevus acquisition from the ages of 3 to 16 years among white youths and evaluate variation by sex, Hispanic ethnicity, and body sites that are chronically vs intermittently exposed to the sun.

FOXQ1 controls the induced differentiation of melanocytic cells.

Oncogenic transcription factor FOXQ1 has been implicated in promotion of multiple transformed phenotypes in carcinoma cells. Recently, we have characterized FOXQ1 as a melanoma tumor suppressor that acts via repression of N-cadherin gene, and invasion and metastasis. Here we report that FOXQ1 induces differentiation in normal and transformed melanocytic cells at least partially via direct transcriptional activation of MITF gene, melanocytic lineage-specific regulator of differentiation.

Portable equipment for taking dramatic sun-damage revealing photos at skin cancer prevention outreach events.

In recent years, appearance-based interventions have gained popularity as a means to improve public awareness about skin cancer and sun protective behaviors. Although numerous reports discuss the use of ultraviolet (UV) camera devices for this purpose,studies on the use of portable imaging devices in community outreach events do not presently exist. In this report, we discuss how we successfully utilize portable imaging devices at community outreach events.

Whole-exome sequencing identifies recurrent SF3B1 R625 mutation and comutation of NF1 and KIT in mucosal melanoma.

Mucosal melanomas are a rare subtype of melanoma, arising in mucosal tissues, which have a very poor prognosis due to the lack of effective targeted therapies. This study aimed to better understand the molecular landscape of these cancers and find potential new therapeutic targets. Whole-exome sequencing was performed on mucosal melanomas from 19 patients and 135 sun-exposed cutaneous melanomas, with matched peripheral blood samples when available.

Senescence-Like Phenotypes in Human Nevi.

Cellular senescence is an irreversible arrest of cell proliferation at the G1 stage of the cell cycle in which cells become refractory to growth stimuli. Senescence is a critical and potent defense mechanism that mammalian cells use to suppress tumors. While there are many ways to induce a senescence response, oncogene-induced senescence (OIS) remains the key to inhibiting progression of cells that have acquired oncogenic mutations.

Interactions between ultraviolet light and MC1R and OCA2 variants are determinants of childhood nevus and freckle phenotypes.

Background: Melanocytic nevi (moles) and freckles are well known biomarkers of melanoma risk, and they are influenced by similar UV light exposures and genetic susceptibilities to those that increase melanoma risk. Nevertheless, the selective interactions between UV exposures and nevus and freckling genes remain largely undescribed.

Methods: We conducted a longitudinal study from ages 6 through 10 years in 477 Colorado children who had annual information collected for sun exposure, sun protection behaviors, and full body skin exams.

A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.

The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene.

Parents' perceptions of skin cancer threat and children's physical activity.

Introduction: Sun exposure is a major risk factor for skin cancer, but without physical activity, children are at risk of childhood obesity. The objective of this study was to explore relationships between parental perceptions of skin cancer threat, sun protection behaviors, physical activity, and body mass index (BMI) in children.

Methods: This is a cross-sectional analysis nested within the Colorado Kids Sun Care Program sun safety intervention trial.

Sun damage in ultraviolet photographs correlates with phenotypic melanoma risk factors in 12-year-old children.

Background: Ultraviolet (UV) photography has been used to motivate sun safety in behavioral interventions. The relationship between sun damage shown in UV photographs and melanoma risk has not been systematically investigated.

Objective: To examine the relationship between severity of sun damage in UV photographs and phenotypic melanoma risk factors in children.

Modelling melanoma in mice.

Phenotypic and molecular heterogeneity in human melanoma has impaired efforts to explain many of the clinically important features of melanoma. For example, many of the underlying mechanisms that might predict age-of-onset, time to metastasis and other key elements in melanoma progression remain unknown. Furthermore, melanoma staging used to predict outcome and treatment has not yet moved beyond a basic phenotypic classification.

Rpl27a mutation in the sooty foot ataxia mouse phenocopies high p53 mouse models.

Ribosomal stress is an important, yet poorly understood, mechanism that results in activation of the p53 tumour suppressor. We present a mutation in the ribosomal protein Rpl27a gene (sooty foot ataxia mice), isolated through a sensitized N-ethyl-N-nitrosourea (ENU) mutagenesis screen for p53 pathway defects, that shares striking phenotypic similarities with high p53 mouse models, including cerebellar ataxia, pancytopenia and epidermal hyperpigmentation. This phenocopy is rescued in a haploinsufficient p53 background.

p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation.

p53 is the central member of a critical tumor suppressor pathway in virtually all tumor types, where it is silenced mainly by missense mutations. In melanoma, p53 predominantly remains wild type, thus its role has been neglected. To study the effect of p53 on melanocyte function and melanomagenesis, we crossed the ‘high-p53’Mdm4+/− mouse to the well-established TP-ras0/+ murine melanoma progression model.

Tanning and increased nevus development in very-light-skinned children without red hair.

Objective: To examine the relationship between tanning and nevus development in very-light-skinned children.

Design: Prospective cohort nested within a randomized controlled trial. Skin examinations in 3 consecutive years (2004, 2005, and 2006) included full-body counts of nevi, skin color and tanning measurement using colorimetry, and hair and eye color evaluation by comparison with charts.

The role of p53 in pigmentation, tanning and melanoma.

p53 has a central role in skin pigmentation and may impact on melanoma at all stages, however, as it's mutation frequency in melanoma is low, it's role has been somewhat under-appreciated. During normal skin function, p53 in the keratinocyte is a transducer of the skin tanning signal and an essential component of what is effectively a keratinocyte-melanocyte signaling cycle that regulates skin pigmentation. It is clear that this cycle functions optimally in skin of dark pigmentation.

Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development.

The tumor suppressor p53 is inactivated by multiple mechanisms that include mutations of the p53 gene itself and increased levels of the p53 inhibitors MDM2 and MDM4. Mice lacking Mdm2 or Mdm4 exhibit embryo-lethal phenotypes that are completely rescued by concomitant deletion of p53. Here we show that Mdm2 and Mdm4 haploinsufficiency leads to increased p53 activity, exhibited as increased sensitivity to DNA damage and decreased transformation potential.