Exploring the role of cancer fatalism and engagement with skin cancer genetic information in diverse primary care patients.

OBJECTIVE: To broaden the currently limited reach of genomic innovations, research is needed to understand how psychosocial and cultural factors influence reactions to genetic testing in diverse subgroups. Cancer fatalism is important in cancer prevention and deserves theoretical and empirical attention in the context of genomics and behavior change. METHODS: The current study employed data from a randomized controlled trial (N = 593) offering skin cancer genetic testing (using the melanocortin-1 receptor [MC1R] gene) in primary care in Albuquerque, New Mexico, USA. We examined interrelations of cancer fatalism with demographics, general health beliefs, perceived risk, perceived control, sun protection and skin screening behaviors and cancer worry in the skin cancer context stratified across Hispanic versus non-Hispanic ethnicity, and examined cancer fatalism as a moderator of intervention effects on study primary outcomes, including 3-month sun protection, cancer worry and perceived risk. RESULTS: Cancer fatalism was significantly related to the perception of control over skin cancer risk behaviors (ps ≤ 0.01) and demographics (ethnicity, education, health literacy; ps < 0.05), but not consistently related to general health beliefs or risk perception. Cancer fatalism did not moderate intervention effects on primary outcomes, except those with higher cancer fatalism randomized to intervention had higher levels of 3-month cancer worry (p = 0.019). CONCLUSIONS: These findings will guide future work considering the role of cancer fatalism in use of genomic technologies in the general population. This work anticipates strategies required to address cancer fatalism as translational genomics becomes more commonly available to diverse general population subgroups.

"Let's Talk about Skin Cancer": Examining Association between Family Communication about Skin Cancer, Perceived Risk, and Sun Protection Behaviors.

Family communication about skin cancer risk may motivate protective behaviors. However, it is unclear how widespread such communication might be. In this study, we describe prevalence and patterns (across environmental, personal, and behavioral factors) of family communication about skin cancer across N = 600 diverse (79% female, 48% Hispanic, 44% non-Hispanic White) primary care patients from Albuquerque, New Mexico, a geographical location with year-round sun exposure. Over half reported discussing general cancer (77%) and skin cancer risks (66%) with their families. The most frequent target of skin cancer risk communication included doctors (54%), followed by friends/coworkers (49%), spouse/partner (43%), other family members (38%), sisters (36%), mothers (36%), daughters (33%), sons (32%), father (24%), and brothers (22%). On average, participants reported having talked to three family members about skin cancer risks. The most frequently discussed content of skin cancer risk communication was the use of sun protection (89%), followed by the personal risk of skin cancer (68%), who had skin cancer in the family (60%), family risk of skin cancer (59%), time of sun exposure (57%), and skin cancer screening (57%). A family or personal history of cancer, higher perceived risk, higher health literacy, being non-Hispanic, having higher education or income, and proactive sun protective behavior were associated with greater family communication about general cancer and skin cancer risks. These study findings have implications for interventions that encourage discussions about skin cancer risk, sun protection, and skin cancer screening that lead to adoption of sun-safe behaviors.

Human genes differ by their UV sensitivity estimated through analysis of UV-induced silent mutations in melanoma.

We hypothesized that human genes differ by their sensitivity to ultraviolet (UV) exposure. We used somatic mutations detected by genome-wide screens in melanoma and reported in the Catalog Of Somatic Mutations In Cancer. As a measure of UV sensitivity, we used the number of silent mutations generated by C>T transitions in pyrimidine dimers of a given transcript divided by the number of potential sites for this type of mutations in the transcript. We found that human genes varied by UV sensitivity by two orders of magnitude. We noted that the melanoma-associated tumor suppressor gene CDKN2A was among the top five most UV-sensitive genes in the human genome. Melanoma driver genes have a higher UV-sensitivity compared with other genes in the human genome. The difference was more prominent for tumor suppressors compared with oncogene. The results of this study suggest that differential sensitivity of human transcripts to UV light may explain melanoma specificity of some driver genes. Practical significance of the study relates to the fact that differences in UV sensitivity among human genes need to be taken into consideration whereas predicting melanoma-associated genes by the number of somatic mutations detected in a given gene.

Solar UV Exposure and Mortality from Skin Tumors: An Update.

Solar UV exposure is critical and complex in the etiology and prognosis of skin cancer, particularly cutaneous malignant melanoma. Sun exposure and one of its "derivatives," vitamin D, have been implicated in protection against mortality from melanoma. However, the relationships are inconsistent. At this time, it is not possible to make clear recommendations for or against sun exposure in relationship to melanoma prognosis. However, this relationship deserves continued exploration.

Melanoma - role of the environment and genetics.

Melanoma rates have increased in populations that are mainly European. The main etiologic factor is ultraviolet radiation, from the sun as well as artificial tanning devices. Host factors such as skin color, number of nevi, hair and eye color and tanning ability are critical factors in modifying an individual's response to the sun. Genetic factors interact with host factors and environmental factors to increase risk. This review summarizes our current knowledge of environment and genetics on melanoma risk and on gene-environment interaction.

Invited Commentary: Indoor Tanning-A Melanoma Accelerator?

In this issue of the Journal, Ghiasvand et al. (Am J Epidemiol. 2017;185(3):147-156) present results from a longitudinal study of the association between indoor tanning and melanoma in a large cohort of Norwegian women. These new data further support previous findings on the damaging effects of tanning bed exposure on women, particularly young women. The authors present compelling evidence that early exposure to tanning beds advances the date of diagnosis of melanoma by at least 2 years. With a strong design and a large cohort followed for a mean of 13.7 years, this study lends additional support to previous evidence of the negative effects of tanning beds and provides further justification for stronger policy initiatives designed to reduce tanning bed use among young women.

Communication about melanoma and risk reduction after melanoma diagnosis.

BACKGROUND: Melanoma patients are advised to perform regular risk-reduction practices, including sun protection as well as skin self-examinations (SSEs) and physician-led examinations. Melanoma-specific communication regarding family risk and screening may promote such behaviors. To this end, associations between patients' melanoma-specific communication and risk reduction were examined. METHODS: Melanoma patients (N = 169) drawn from a population-based cancer registry reported their current risk-reduction practices, perceived risk of future melanoma, and communication with physicians and relatives about melanoma risk and screening. RESULTS: Patients were, on average, 56 years old and 6.7 years' post diagnosis; 51% were male, 93% reported "fair/very fair" skin color, 75% completed at least some college, and 22% reported a family history of melanoma. Patients reported varying levels of regular (always/nearly always) sun protection: sunscreen use (79%), shade seeking (60%), hat use (54%), and long-sleeve shirt use (30%). Only 28% performed thorough SSE regularly, whereas 92% reported undergoing physician-led skin examinations within the past year. Participants who were female, younger, and had a higher perceived risk of future melanoma were more likely to report past communication. In adjusted analyses, communication remained uniquely associated with increased sunscreen use and SSE. CONCLUSIONS: Encouraging melanoma patients to have a more active role in discussions concerning melanoma risk and screening with relatives and physicians alike may be a useful strategy to promote 2 key risk-reduction practices post melanoma diagnosis and treatment. Future research is needed to identify additional strategies to improve comprehensive risk reduction in long-term melanoma patients.

Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study.

Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics.

Nevus count associations with pigmentary phenotype, histopathological melanoma characteristics and survival from melanoma.

Although nevus count is an established risk factor for melanoma, relationships between nevus number and patient and tumor characteristics have not been well studied and the influence of nevus count on melanoma-specific survival is equivocal. Using data from the Genes, Environment and Melanoma (GEM) study, a large population-based study of primary cutaneous melanoma, we evaluated associations between number of nevi and patient features, including sun-sensitivity summarized in a phenotypic index, and tumor characteristics. We also assessed the association of nevus count with melanoma-specific survival. Higher nevus counts were independently and positively associated with male gender and younger age at diagnosis, and they were inversely associated with lentigo maligna histology. We observed a borderline significant trend of poorer melanoma-specific survival with increasing quartile of nevus count, but little or no association between number of nevi and pigmentary phenotypic characteristics or prognostic tumor features.

Melanoma Epidemiology and Prevention.

The epidemiology of melanoma is complex, and individual risk depends on sun exposure, host factors, and genetic factors, and in their interactions as well. Sun exposure can be classified as intermittent, chronic, or cumulative (overall) exposure, and each appears to have a different effect on type of melanoma. Other environmental factors, such as chemical exposures-either through occupation, atmosphere, or food-may increase risk for melanoma, and this area warrants further study. Host factors that are well known to be important are the numbers and types of nevi and the skin phenotype. Genetic factors are classified as high-penetrant genes, moderate-risk genes, or low-risk genetic polymorphisms. Subtypes of tumors, such as BRAF-mutated tumors, have different risk factors as well as different therapies. Prevention of melanoma has been attempted using various strategies in specific subpopulations, but to date optimal interventions to reduce incidence have not emerged.

The study of nevi in children: Principles learned and implications for melanoma diagnosis.

Melanocytic nevi are a strong phenotypic marker of cutaneous melanoma risk. Changes in nevi during childhood and adolescence make these prime periods for studying nevogenesis. Insights gained by the study of nevi in childhood have implications for melanoma detection in both adults and children. A more comprehensive understanding of the morphologic characteristics of nevi in different anatomic locations, in association with the patient's age and pigmentary phenotype may aid in the identification of melanomas. When monitoring melanocytic lesions over time, it is essential to differentiate normal from abnormal change. This review summarizes the rapidly expanding body of literature relevant to nevus phenotype, particularly in the context of our experience with the Study of Nevi in Children (SONIC) Project.

Arsenic and ultraviolet radiation exposure: melanoma in a New Mexico non-Hispanic white population.

Cases of cutaneous melanoma and controls were enrolled in a New Mexico population-based study; subjects were administered questionnaires concerning ultraviolet (UV) and inorganic arsenic (iAs) exposure. Historical iAs exposure was estimated. UV exposure estimates were also derived using geospatial methods. Drinking water samples were collected for iAs analysis. Blood samples were collected for DNA repair (Comet) and DNA repair gene polymorphism assays. Arsenic concentrations were determined in urine and toenail samples. UV exposures during the previous 90 days did not vary significantly between cases and controls. Mean (±SD) current home iAs drinking water was not significantly different for cases and controls [3.98 µg/L (±3.67) vs. 3.47 µg/L (±2.40)]. iAs exposure showed no effect on DNA repair or association with melanoma. Results did not corroborate a previously reported association between toenail As and melanoma risk. Arsenic biomarkers in urine and toenail were highly significantly correlated with iAs in drinking water. A UV-DNA repair interaction for UV exposure over the previous 7-90 days was shown; cases had higher DNA damage than controls at low UV values. This novel finding suggests that melanoma cases may be more sensitive to low-level UV exposure than are controls. A UV-APEX1 interaction was shown. Subjects with the homozygous rare APEX1 DNA repair gene allele had a higher risk of early melanoma diagnosis at low UV exposure compared with those with the homozygous wild type or the heterozygote. Notably, a UV-arsenic interaction on inhibition of DNA repair was not observed at iAs drinking water concentrations below 10 ppb (µg/L).

Inherited variation at MC1R and ASIP and association with melanoma-specific survival.

Melanocortin-1 receptor (MC1R) is a marker of melanoma risk in populations of European ancestry. However, MC1R effects on survival are much less studied. We investigated associations between variation at MC1R and survival in an international, population-based series of single primary melanoma patients enrolled into the Genes, Environment, and Melanoma study. MC1R genotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association of MC1R genotypes with melanoma-specific survival (i.e., death caused by melanoma) and overall survival using COX proportional hazards modeling, adjusting for established prognostic factors for melanoma. We also conducted stratified analyses by Breslow thickness, tumor site, phenotypic index, and age. In addition, we evaluated haplotypes involving polymorphisms near the Agouti signaling protein gene (ASIP) locus for their impacts on survival. Melanoma-specific survival was inversely associated with carriage of MC1R variants in the absence of consensus alleles compared to carriage of at least one consensus allele (hazard ratio (HR) = 0.60; 95% confidence interval (CI): 0.40, 0.90). MC1R results for overall survival were consistent with no association. We did not observe any statistical evidence of heterogeneity of effect estimates in stratified analyses. We observed increased hazard of melanoma-specific death among carriers of the risk haplotype TG near the ASIP locus (HR = 1.37; 95% CI: 0.91, 2.04) when compared to carriers of the most common GG haplotype. Similar results were noted for overall survival. Upon examining the ASIP TG/TG diplotype, we observed considerably increased hazard of melanoma-specific death (HR = 5.11; 95% CI: 1.88, 13.88) compared to carriers of the most common GG/GG diplotype. Our data suggest improved melanoma-specific survival among carriers of two inherited MC1R variants.

More skin, more sun, more tan, more melanoma.

Although personal melanoma risk factors are well established, the contribution of socioeconomic factors, including clothing styles, social norms, medical paradigms, perceptions of tanned skin, economic trends, and travel patterns, to melanoma incidence has not been fully explored. We analyzed artwork, advertisements, fashion trends, and data regarding leisure-time activities to estimate historical changes in UV skin exposure. We used data from national cancer registries to compare melanoma incidence rates with estimated skin exposure and found that they rose in parallel. Although firm conclusions about melanoma causation cannot be made in an analysis such as this, we provide a cross-disciplinary, historical framework in which to consider public health and educational measures that may ultimately help reverse melanoma incidence trends.

High sputum total adiponectin is associated with low odds for asthma.

OBJECTIVE: Adipose tissue produces adiponectin, an anti-inflammatory protein. High systemic total adiponectin is associated with a low risk for incident asthma but the association with lung adiponectin is not known. Our objective was to evaluate the association between sputum total adiponectin and asthma. METHODS: This case-control study included 44 cases with objectively-confirmed asthma and an equal number of body mass index (BMI) and sex-matched controls. Serum and sputum adiponectin were estimated by ELISA and Western Blot technique, respectively. While Fisher's exact test, t-test and Spearman's correlations were used for univariate analyses, Spearman and regression analyses were performed for multivariable analyses. RESULTS: While high-molecular-weight adiponectin was the dominant isoform in serum, medium-molecular-weight isoform was dominant in sputum. Sputum total adiponectin was not correlated with serum adiponectin or BMI. Sputum total adiponectin was lower among asthmatics than controls (p = 0.03), although individual sputum isoforms were not similarly associated. High sputum total adiponectin was associated with lower odds for asthma (OR 0.33, 95% C.I. 0.12, 0.91), even after adjustment for systemic adiposity measures including serum adiponectin. CONCLUSIONS: High sputum total adiponectin predicted lower odds for asthma, even after adjustment for serum adiponectin. Although not studied, it is possible that pharmacological modulation of sputum adiponectin may suggest new ways to prevent and/or treat asthma.

Solar ultraviolet exposure and mortality from skin tumors.

Solar UV radiation (UVR) exposure is clearly associated with increased mortality from nonmelanoma skin cancer--usually squamous cell carcinoma. However, the association with cutaneous melanoma is unclear from the evidence in ecologic studies and several analytic studies have conflicting results regarding the effect of high levels of intermittent UV exposure prior to diagnosis on mortality. Understanding this conundrum is critical to present coherent public health messages and to improve the mortality rates from melanoma.

Skin cancers are the most frequent cancers in fair-skinned populations, but we can prevent them.

Cancers of the skin are the most commonly occurring cancers in humans. In fair-skinned populations, up to 95% of keratinocyte skin cancers and 70-95% of cutaneous melanomas are caused by ultraviolet radiation and are thus theoretically preventable. Currently, however, there is no comprehensive global advice on practical steps to be taken to reduce the toll of skin cancer. To address this gap, an expert working group comprising clinicians and researchers from Africa, America, Asia, Australia, and Europe, together with learned societies (European Association of Dermato-Oncology, Euromelanoma, Euroskin, European Union of Medical Specialists, and the Melanoma World Society) reviewed the extant evidence and issued the following evidence-based recommendations for photoprotection as a strategy to prevent skin cancer. Fair skinned people, especially children, should minimise their exposure to ultraviolet radiation, and are advised to use protective measures when the UV index is forecast to reach 3 or higher. Protective measures include a combination of seeking shade, physical protection (e.g. clothing, hat, sunglasses), and applying broad-spectrum, SPF 30 + sunscreens to uncovered skin. Intentional exposure to solar ultraviolet radiation for the purpose of sunbathing and tanning is considered an unhealthy behaviour and should be avoided. Similarly, use of solaria and other artificial sources of ultraviolet radiation to encourage tanning should be strongly discouraged, through regulation if necessary. Primary prevention of skin cancer has a positive return on investment. We encourage policymakers to communicate these messages to the general public and promote their wider implementation.

A pilot study of genetic variants in dopamine regulators with indoor tanning and melanoma.

Many people frequently tan indoors despite being aware of the increased risk of melanoma. Ultraviolet radiation is hypothesized to modify biological reward pathways, for example, through the dopamine neurotransmitter system, to reinforce tanning behaviour. In this pilot study, we relied on questionnaire and DNA data from a recently completed case-control study to examine 67 single-nucleotide polymorphisms (SNPs) and related haplotypes in five dopamine receptor and drug metabolism genes in relation to indoor tanning among controls. We also examined the association between individual SNPS and likelihood of melanoma, adjusting for or stratifying on indoor tanning status. In candidate and haplotype gene analyses, variants only in the DRD2 dopamine receptor and ANKK1 signalling genes were positively associated with indoor tanning use among controls; only associations for ANKK1 remained statistically significant (P < 0.05) after adjustment. Several SNPs in ANKK1 and DRD2 associated with indoor tanning among controls were also found to be associated with increased risk of melanoma. Upon stratifying for indoor tanning status, one ANKK1 SNP was positively associated with melanoma among non-tanners, while three DRD2 SNPS were positively associated with melanoma among tanners or non-tanners, depending on the SNP. These alleles represent important genomic regions to further explore addictive tanning behaviour.

Pathway Alterations in Stage II/III Primary Melanoma.

PURPOSE: Genomic classification of melanoma has thus far focused on the mutational status of BRAF, NRAS, and NF1. The clinical utility of this classification remains limited, and the landscape of alterations in other oncogenic signaling pathways is underexplored. METHODS: Using primary samples from the InterMEL study, a retrospective cohort of cases with specimens collected from an international consortium with participating institutions throughout the United States and Australia, with oversampling of cases who ultimately died of melanoma, we examined mutual exclusivity and co-occurrence of genomic alterations in 495 stage II/III primary melanomas across 11 cancer pathways. Somatic mutation and copy number alterations were analyzed from next-generation sequencing using a clinical sequencing panel. RESULTS: Mutations in the RTK-RAS pathway were observed in 81% of cases. Other frequently occurring pathways were TP53 (31%), Cell Cycle (30%), and PI3K (18%). These frequencies are generally lower than was observed in The Cancer Genome Atlas, where the specimens analyzed were predominantly obtained from metastases. Overall, 81% of the cases had at least one targetable mutation. The RTK-RAS pathway was the only pathway that demonstrated strong and statistically significant mutual exclusivity. However, this strong mutual exclusivity signal was evident only for the three common genes in the pathway (BRAF, NRAS, and NF1). Analysis of co-occurrence of different pathways exhibited no positive significant trends. However, interestingly, a high frequency of cases with none of these pathways represented was observed, 8.4% of cases versus 4.0% expected (P < .001). A higher frequency of RTK-RAS singletons (with no other pathway alteration) was observed compared with The Cancer Genome Atlas. Clonality analyses suggest strongly that both the cell cycle and RTK-RAS pathways represent early events in melanogenesis. CONCLUSION: Our results confirm the dominance of mutations in the RTK-RAS pathway. The presence of many mutations in several well-known, actionable pathways suggests potential avenues for targeted therapy in these early-stage cases.