Pathways to the Development of Melanoma: A Complex Issue

The investigation of nevus distribution by anatomic site has led to interesting hypotheses of divergent pathways to the development of melanoma. However, such hypotheses must be viewed in all their complexity, and the paper by Randi et al. gives additional substance to this complexity

Children’s Susceptibility to Direct DNA Damage as Compared to That of Adults

DNA damage and genetic mutations have been strongly correlated with the risk of developing certain cancers such as melanoma. It is important to assess correlations in conjunction with findings that are related to DNA damage to order to have a greater understanding of how the disease operates. Direct DNA damage happens when UV photons directly penetrate a cell’s DNA, causing base pairs to bond next to each other changing the sequence. Recent studies have begun to explore the idea that there are critical stages in one’s life where DNA is more vulnerable to direct damage. Data collected from GEM, a database of over three thousand melanoma patients of varying age, ethnicity, occupation, etc., has given us a distinct insight as to when sunburns that cause DNA damage occur. The results have shown that an overwhelming majority of sunburns had occurred during the early stages of their lives. Using the data from GEM, one can infer that children have a higher susceptibility to this form of direct DNA damage; however, to analyze this phenomenon a holistic view of the environment, physiological, bio cellular, genetic and psychological distinctions between adults and children is needed to avoid oversimplification of this complex topic. Reviewing data from these areas formulates several hypotheses as to why children may be more susceptible to direct DNA damage for future studies. Although differences in DNA damage susceptibility between adults and adolescences have not been fully explored, using data from previously published work several observations, such as melanoma risk factors during childhood, can be made to rationalize these trends. Additional examination in this area could further explain the growing number of melanoma cases, as well as reassess the protocol and initiatives for prevention

Testing the Divergent Pathway Model for Melanoma

Post hoc analysis of a large US population-based study of melanoma was carried out to test Whitemans divergent pathway model that suggests different etiologic pathways for melanoma based on (1) pattern of sun exposure, as characterized by anatomic site, and (2) host factors such as propensity for melanocyte proliferation, as characterized by nevus status. Study subjects consisted of 528 newly diagnosed cases of melanoma among Caucasian residents of Connecticut. Nurse-interviewers obtained information on age, gender, hair color, eye color, skin color, history of sun exposure, history of painful sunburns, anatomic site of melanoma, and number of nevi on both arms and the back. Age-adjusted simultaneous odds ratios with 95% confidence intervals were generated using nevus status as the dependent variable. The study found a statistically significant relationship (p\u3c0.01) exists between anatomic site of melanoma and having many nevi. This is consistent with the prediction of the divergent pathway model for different paths to melanoma formation based on pattern of sun exposure and host propensity for melanocyte proliferation. Further investigation into the biological basis for the divergent pathway is warranted so that skin cancer prevention strategies can be tailored to specific populations.\u2

Number of Nevi and Survival with Melanoma

Possession of a higher than average number of nevi has long been substantiated as one of several factors that predispose patients to malignant melanoma. Despite the relative certainty of this relationship, little is known about the relationship between the number of nevi a person possesses and risk of death from melanoma. A cohort of melanoma patients was followed prospectively to determine if a significant relationship exists between number of nevi and increased mortality from melanoma. Age at diagnosis, melanoma of the head and neck, increasing Breslow thickness and presence of mitoses all were associated with poorer survival in our multivariate analysis. Existence of a dermal nevus at the site of melanoma was also associated with poorer survival, while solar elastosis and skin awareness were associated with improved survival. Our study also suggests that having a large number of nevi increases the risk of death from melanoma more than two-fold. Further research elucidating the prognostic indications of a high number of nevi possessed by melanoma patients could potentially lead to considerable advances in the classification, diagnosis, and therapy for cutaneous melanoma

Sex-specific survival and tumor mutational burden in early stage melanoma

Introduction Tumor mutational burden (TMB) is a promising biomarker of clinical response to immune checkpoint inhibitors in metastatic cancers, and melanoma-specific survival. There are also significant gender-specific differences in TMB with men having consistently higher TMB than women. This relationship is provocative given the well-documented female melanoma survival advantage, and has not been investigated in early-stage primary tumors naïve to treatment. Approach Here we present preliminary findings on sex, survival, and tumor mutational burden from Stages II and III primary melanoma tumors, none of which have received immunotherapy using the MSK IMPACT™ next generation sequencing assay. Our team evaluated survival in 581 primary melanoma tumors procured by the parent P01 grant; 251 from patients who died with melanoma within five years (median survival, 2.4 years), and 330 from individuals who have lived at least five years (median follow up 8.5 years). Preliminary Results In the full dataset, we found the expected female survival advantage (log rank test P=0.049). After controlling for multiple comparisons using maximally selected ranked statistics7 the protective effect of high TMB on survival disappeared (HR=0.43, 95% CI=0.19 to 0.97, P=0.037). When stratified by sex, high TMB was associated with significantly improved melanoma specific survival among men (p=0.024), but not women (P=0.9). Broader Impacts Our study is the first to investigate the relationship between sex, tumor mutational burden, and mortality in an early stage primary cohort that has not received immunotherapy. In our small sample, we observed the expected protective effect of TMB on survival, but no evidence of gender differences in TMB or survival, despite the robust, consistent, and well-documented female survival advantage 5,6. Our results are an important first step to increasing our understanding of the relationship between mutational burden, survival, and biological sex. Limitations These results are exploratory and have not been adjusted for potential confounding factors such as stage, Breslow score, gender, or age

Pilot Study of Skin Cancer Risk Reduction Behaviors, Cancer Communication, and Skin Cancer Beliefs in Hispanics

Purpose: Given rising rates of deadly melanoma skin cancer in Hispanics, the study objective was to examine skin cancer-related risk reduction behaviors and beliefs to dictate content for culturally targeted skin cancer prevention strategies for Hispanics. Methods/Data Source: An anonymous survey was administered to waiting room volunteers in a primary care facility in Albuquerque, New Mexico to assess skin cancer risk reduction behaviors, screening, cancer information seeking and communication, as well as skin cancer beliefs in Hispanics (n=48) and Non-Hispanic Whites (n=36). Results: We found lower levels of sun protection clothing use among Hispanics compared to Non-Hispanic Whites, but comparable use of sunscreen and shade-seeking among these groups. Hispanic ethnicity was the most important predictor of skin cancer misconceptions, with skin cancer information overload and misconceptions reported more often in Hispanics. Conclusions: This study demonstrates the need for culturally relevant information for ethnic minority populations such as Hispanics who have shown an increased risk of presenting with later stage, more aggressive melanoma skin cancer

Tandem BRAF Mutations in Primary Invasive Melanomas

The RAS/RAF/MAPK pathway likely mediates critical cell proliferation and survival signals in melanoma. BRAF mutations have been found in a high percentage of melanoma cell lines and metastases; however, only a few studies with a limited number of specimens have focused on primary melanomas. We examined BRAF exon 15 mutational status in 37 primary invasive melanomas of varying thicknesses, which had undergone a standardized pathology review. BRAF mutational status was determined using direct manual sequencing of PCR products, followed by resequencing separately amplified DNA aliquots to confirm each mutation. BRAF exon 15 mutations were found in 17 of 37 (46%) primary melanomas. Tumor-specific tandem mutations, encoding either V599K, V599R, or V599E, were found in 5 of 17 (29%) melanomas with BRAF exon 15 mutations. Cloning of BRAF double base-pair substitutions confirmed that both base changes were on the same allele and can result in a positive charge at codon 599. BRAF mutations, including tandem mutations, were frequently found in both thin and thick primary melanomas, implying that these mutations can occur early in the progression of melanoma. The finding of tandem mutations in thin melanomas makes it more likely that they arise as a simultaneous rather than sequential event

Distance to Diagnosing Provider as a Measure of Access for Patients With Melanoma

To examine the effect of travel distance and other sociodemographic factors on access to a diagnosing provider for patients with melanoma

A design for cancer case–control studies using only incident cases: experience with the GEM study of melanoma

BACKGROUND: The population-based case-control study is not suited to the evaluation of rare genetic (or environmental) factors. The use of a novel case-control design in which cases have second primaries and controls are cancer survivors has been proposed for this purpose. METHODS: We report results from an international study of melanoma that involved population-based ascertainment of incident cases of second or subsequent primary melanoma as the 'case' group and incident cases of first primary melanoma as the 'control' group. We evaluate the validity of the study design by comparing the results obtained for phenotypic factors that have been shown consistently to be associated with melanoma in previous conventional studies with the results from a conventional case-control study conducted in Connecticut and from literature reviews. RESULTS: All but one of the known risk factors for melanoma were shown to be significantly associated with melanoma in our study, though the individual odds ratios appear to be somewhat attenuated relative to the magnitudes typically observed in the literature. CONCLUSIONS: Patients with a second or subsequent primary cancer of a single type represent a potentially valuable and under-utilized resource for the study of cancer aetiology