Nevus Density Research Articles

Cost-effectiveness of targeted genomic risk provision to prevent skin cancer: Results of a randomized trial.

10536 Background: Many melanomas and keratinocyte cancers (KC) are preventable by reducing sun exposure and improving sun protection behaviors. Recent evidence indicates a melanoma prevention program involving personalized genomic risk information provision can reduce self-reported sunburns at 12 months in Australian adults with no history of melanoma. This was alongside genetic counselling and educational materials on skin cancer prevention and early detection. However, the economic impact of this approach was unclear. This study aimed to determine the cost-effectiveness of the program to prevent melanoma and KC. Methods: A decision-analytic Markov model was developed to simulate the lifetime cost-effectiveness of personalized genomic risk provision compared with standard prevention advice alone, from a health system perspective. We used data from the Melanoma Genomics Managing Your Risk Study Randomized Control Trial. Traditional risk was measured by a validated melanoma risk prediction model involving hair color, nevus density, history of non-melanoma skin cancer, family history of melanoma, level of sunbed sessions. Quality-adjusted life years (QALY) gained was the primary outcome measure used to estimate an incremental cost-effectiveness ratio (ICER). Both deterministic and probabilistic sensitivity analyses (PSA) were undertaken. Results: The cost of the genomic testing and risk counselling program was AUD$189 (USD$132) per participant. Genomic risk provision targeting high-traditional risk individuals was the most cost-effective lifetime strategy with an ICER of AUD$23,033 (USD$16,059) per QALY gained and an 80% probability of being cost-effective at a willingness-to-pay threshold of AUD$50,000, compared with standard preventive advice (Table). When genomic risk provision was extended to low-traditional risk groups the ICER was $43,746 (USD30,500) per QALY gained with a 45% probability of being cost-effective. Conclusions: Genomic risk provision targeted to individuals at high-traditional risk of melanoma is a cost-effective strategy for the prevention of melanoma and KCs. Long-term sustainability of the program’s effect should be examined in future research. Clinical trial information: ACTRN12617000691347. [Table: see text]

Cells to Surgery Quiz: May 2019

Cells to Surgery Quiz: May 2019

Association between Phenotypic Characteristics and Melanoma in a Large Prospective Cohort Study

To delineate causal pathways for melanoma, it is essential to derive unbiased estimates of risk. Extant knowledge derives largely from case-control studies with potential for bias. In a population-based prospective study (QSkin, n= 38,854), we assessed melanoma risks associated with pigmentation characteristics and other phenotypes, and we explored additive interactions. We fitted Cox proportional hazards models to adjust for other factors to estimate the independent effects of each characteristic on melanoma risk. During a mean follow-up of 3.5 years, 642 (1.5%) participants developed melanoma (253 invasive, 389 in situ). The characteristics most strongly associated with invasive melanoma were self-reported nevus density at age 21 years (many vs. no moles hazard ratio [95% confidence interval]= 4.91 [2.81-8.55]), inability to tan (no tan vs. deep tan, hazard ratio [95% confidence interval]= 3.39 [1.85-6.20]), and red hair color (vs. black, hazard ratio [95% confidence interval]= 3.11 [1.50-6.43]). Propensity to sunburn was not associated with melanoma after tanning inability was adjusted for. People with both high nevus density and a history of multiple keratinocyte cancers had significantly higher melanoma risks than those with only one of those traits. We infer that melanoma risk is more strongly related to nevus density and inability to tan than susceptibility to sunburn.

Abstract 228: Association analysis across different populations identifies 26 new cutaneous melanoma risk loci

Abstract Heritability of cutaneous melanoma is among the highest across cancer types and is mostly determined by common, noncoding genetic variants. Previous genome-wide association studies (GWAS), mostly including subjects from Australia and Northern European countries, had identified twenty genetic loci associated with melanoma risk. To characterize the genetic landscape of cutaneous melanoma across different populations, we conducted a new association study in Southern European countries including 6,043 melanoma cases and 10,383 controls from the MelaNostrum Consortium. Moreover, we largely expanded the analyses of melanoma cases and controls from other populations, for a total of 27,450 histologically confirmed melanoma cases and 49,888 controls from Northern Europe, Southern Europe, USA and Australia. Imputation was done using the Haplotype Reference Consortium as a reference panel. We assessed the association between cutaneous melanoma risk and single-nucleotide polymorphisms (SNPs) adjusting for country and ancestry-informative principal components. We identified 26 new genetic loci associated with melanoma risk achieving genome-wide significance. The pigmentation pathway, with TYRP1 and MITF, and the telomere-related pathway with RTEL1, TERC, and POT1 among the candidate genes, continued to show an important role for melanoma susceptibility. Additional candidate pathways emerged, including signaling (with GPRC5A and DOCK8), cell-cell junction (with CDH1), immune-related functions (with DCST2, involved in antigen processing), transcriptional regulation (with FOXD3, which represses MITF expression), or tumor-suppressor genes (TP53). Adding genotype data from 6,130 self-reported melanoma cases in a sensitivity analysis identified eight additional novel genetic loci involved in the HLA region, signaling transduction and transcription factor functions. A combined analysis of the melanoma GWAS with the GWAS of pigmentation characteristics from the UK Biobank including 500,000 UK persons, and with a GWAS of nevus density including over 52,000 persons, revealed substantial overlap across phenotypes. Although the effect size of the SNPs on melanoma risk was consistent across populations, substantial differences in minor allele frequency (MAF) were observed in pigmentation-related genes between Northern and Southern European populations; for example, MC1R, SLC45A2, and ASIP SNP MAF was 8.2, 3.1 and 14.2 in Northern and 2.6, 8.8, and 5.5 in Southern European subjects, respectively. Additional analyses based on melanoma histologic subtypes and body site distribution are ongoing. These results provide further insight into genetic susceptibility to cutaneous melanoma and provide the opportunity for genetic risk scores in risk-prediction models for early detection and targeted prevention of the disease. Citation Format: Cristina Pellegrini, Matthew Law, Mark Iles, Mitch Machiela, Alex Stratigos, Tongwu Zhang, Kevin Brown, Julia Newton-Bishop, Nick Hayward, Nick Martin, Alisa Goldstein, Rose Yang, Stephen Chanock, Florence Demenais, Susana Puig, Eduardo Nagore, Jianxin Shi, Tim Bishop, Stuart McGregor, Maria Teresa Landi, GenoMEL Consortium, MelaNostrum Consortium. Association analysis across different populations identifies 26 new cutaneous melanoma risk loci [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 228.

Cutaneous melanoma primary site is linked to nevus density.

There are at least two pathways driving cutaneous melanoma; one is linked to an inherent melanoma susceptibility to nevi development and the second to environmental cumulative ultraviolet light exposure. In this study, we examined the relation between nevus density, accrued sun damage and the site of primary melanoma excision.In a series of 888 consecutive cutaneous melanoma patients, melanomas appearing in skin areas with a high relative nevus density were most prominent in men, with an elevated nevus count, at sites without solar elastosis, but with an epidemiological history of previous sunburn.The present study associates melanoma development to sites with high nevus density. Our study supports more careful surveillance of body areas with increased nevus density in patients with high total body number of nevi, especially when they report a history of sunburns at these sites.

Development and External Validation of a Melanoma Risk Prediction Model Based on Self-assessed Risk Factors.

Identifying individuals at high risk of melanoma can optimize primary and secondary prevention strategies. To develop and externally validate a risk prediction model for incident first-primary cutaneous melanoma using self-assessed risk factors. We used unconditional logistic regression to develop a multivariable risk prediction model. Relative risk estimates from the model were combined with Australian melanoma incidence and competing mortality rates to obtain absolute risk estimates. A risk prediction model was developed using the Australian Melanoma Family Study (629 cases and 535 controls) and externally validated using 4 independent population-based studies: the Western Australia Melanoma Study (511 case-control pairs), Leeds Melanoma Case-Control Study (960 cases and 513 controls), Epigene-QSkin Study (44 544, of which 766 with melanoma), and Swedish Women's Lifestyle and Health Cohort Study (49 259 women, of which 273 had melanoma). We validated model performance internally and externally by assessing discrimination using the area under the receiver operating curve (AUC). Additionally, using the Swedish Women's Lifestyle and Health Cohort Study, we assessed model calibration and clinical usefulness. The risk prediction model included hair color, nevus density, first-degree family history of melanoma, previous nonmelanoma skin cancer, and lifetime sunbed use. On internal validation, the AUC was 0.70 (95% CI, 0.67-0.73). On external validation, the AUC was 0.66 (95% CI, 0.63-0.69) in the Western Australia Melanoma Study, 0.67 (95% CI, 0.65-0.70) in the Leeds Melanoma Case-Control Study, 0.64 (95% CI, 0.62-0.66) in the Epigene-QSkin Study, and 0.63 (95% CI, 0.60-0.67) in the Swedish Women's Lifestyle and Health Cohort Study. Model calibration showed close agreement between predicted and observed numbers of incident melanomas across all deciles of predicted risk. In the external validation setting, there was higher net benefit when using the risk prediction model to classify individuals as high risk compared with classifying all individuals as high risk. The melanoma risk prediction model performs well and may be useful in prevention interventions reliant on a risk assessment using self-assessed risk factors.

Sun Protection and Skin Examination Practices in a Setting of High Ambient Solar Radiation: A Population-Based Cohort Study.

Primary prevention and early detection are integral strategies to reduce the burden of skin cancer. To describe the prevalence of sun protection and skin examination practices in a population exposed to high levels of ambient solar radiation and to identify associated factors. Cross-sectional analyses of baseline data from a prospective cohort of 40,172 adults aged 40 through 69 years from Queensland, Australia, recruited in 2011. We obtained data on all melanoma diagnoses through 2009 via record linkage with the Queensland Cancer Registry (notifications have been mandatory since 1982). We calculated prevalence proportion ratios to compare prevalence of sun protection and skin examination practices in 3 separate groups: those with a history of melanoma (group 1), those with a self-reported history of treated actinic lesions (group 2), and those without either (group 3). We used multivariate generalized linear models to identify factors associated with each practice. Participants with a previously confirmed melanoma (group 1; n = 1433) and/or treated actinic lesions (group 2; n = 24,006) were more likely than those without (group 3; n = 14,733) to report sun protection practices, including regular use of sunscreen (53.3%, 45.1%, and 38.1%, respectively) and wearing hats (74.7%, 68.2%, and 58.2%, respectively). They were also more likely to have had a whole-body skin examination by a physician in the past 3 years (93.7%, 83.4%, and 52.1%, respectively). Within all 3 groups, the strongest association with sun protection practices was with sun-sensitive skin type. Within group 3 (no history of treated skin lesions), the strongest factor associated with clinical skin examinations was self-reported nevus density at 21 years of age, whereas a family history of melanoma was a significant factor in groups 2 and 3. In this large sample exposed to high levels of ambient solar radiation, sun protection and skin examination practices were most frequent among those with a history of treated skin lesions or sun-sensitive skin types.

Prevalence of common and atypical melanocytic nevi in young adults and its relationship with sun protection and exposure habits.

Background: The incidence of melanoma in young adults is rising. The design of appropriate preventive measures requires the analysis of risk factors, including the prevalence of common and atypical melanocytic nevi (MN) and sun protection and exposure habits. To establish the prevalence and density of common and atypical MN in young adults (18-25 yrs) and their relationship with sun exposure and protection habits. Cross-sectional descriptive study was undertaken in 535 university students from southern Spain to gather data on: the number, density, body localization, and characteristics of common and atypical nevi; phototype; sunburn history; sun protection and exposure habits; and family history of skin cancer. Means of 94.28 common MN and 0.06 atypical MN were detected; most MN were ≤2 mm in diameter; MN were more frequently detected on upper (p<0.01) and lower (p<0.0001 limbs in females versus males and on the trunk (p = 0.08) in males versus females. Nevus density was higher in females in all body areas. Sunburns (in the previous summer) were reported by 88.2% of participants, while cream with SPF ≥15 was not used by 75.8%. Mean number of atypical MN was higher in those with low phototypes and a family history of skin cancer. Mean number of common MN was elevated and atypical MN were associated with a low phototype and a family history of skin cancer. Sunburn history was significantly associated with younger age and with sun exposure between mid-day and 6 pm.

Accuracy of Self-Report of Nevus and Pigmentation Phenotype Compared to Clinical Assessment in Young Australian Adults

Abstract There is no formal community-wide melanoma screening program in Australia, but the importance of early detection and regular skin self-examination is generally well understood. It is important that individuals are able to identify key melanoma risk factors so that those at high risk can modify their sun-related behaviours and take appropriate preventative actions from a young age. Aims: 1) To evaluate the accuracy of self-reported pigmentation and nevus phenotype compared to clinical assessment, and 2) to examine agreement between clinically-measured whole-body nevus count and clinically-measured nevus count on selected anatomical regions, given that localised mole count is often used as a proxy measure. Methods: The sample included 456 cases with invasive cutaneous melanoma diagnosed between ages 18–39 years and 538 controls from the population-based Australian Melanoma Family Study. Participants completed a questionnaire regarding their pigmentation and nevus phenotype, and attended a clinical skin examination with a dermatologic trainee. Results: There was strong agreement between self-reported and clinical measurement for eye color (weighted kappa, Kw, = 0.83, 95% confidence interval (CI) 0.80–0.86); and moderate agreement for hair color (Kw = 0.52, 95% CI 0.47–0.56) There was poor agreement for skin color when using spectrophotometer-derived individual typography angle (ITA) scores as the objective measure (Kw = 0.18, 95% CI 0.14–0.22). Participants underestimated their nevus counts. The Spearman correlation was 0.43 (95% CI 0.38–0.49) when comparing clinically-measured total body nevus count (≥2 mm) with self-reported nevus density categories, and the intraclass correlation was 0.36 (95% CI 0.30–0.41) when comparing nevus counts on the back. There was good agreement between quartile distributions of clinically-measured site-specific nevus counts with total body nevus counts, particularly for the arms (Kw = 0.76 for men and 0.80 for women). Conclusions: Agreement between self-reported pigmentation and nevus phenotype compared to clinical assessment ranges from poor to excellent, depending on the measure. For studies where a full body nevus count is impractical, measuring nevus counts on the arms would be an acceptable alternative.

MITFE318K's effect on melanoma risk independent of, but modified by, other risk factors

A rare germline variant in the microphthalmia-associated transcription factor (MITF) gene, E318K, has been reported as associated with melanoma. We confirmed its independent association with melanoma [odds ratio (OR) 1.7, 95% confidence interval (CI) = 1.1, 2.7, P = 0.03]; adjusted for age, sex, center, age × sex interaction, pigmentation characteristics, family history of melanoma, and nevus density). In stratified analyses, carriage of MITF E318K was associated with melanoma more strongly in people with dark hair than fair hair (P for interaction, 0.03) and in those with no moles than some or many moles (P for interaction, <0.01). There was no evidence of interaction between MC1R 'red hair variants' and MITF E318K. Moreover, risk of melanoma among carriers with 'low risk' phenotypes was as great or greater than among those with 'at risk' phenotypes with few exceptions.

Good test–retest reproducibility for an instrument to capture self-reported melanoma risk factors

ObjectiveTo examine the test–retest reliability and validity of self-reported items capturing phenotypic characteristics and sun exposure measures in the baseline survey instrument used for a prospective study of skin cancer and melanoma. Study Design and SettingRepeatability/validity study conducted among 114 participants randomly selected from the cohort to complete the survey instrument a second time and to undergo a physician skin examination. We calculated intraclass correlation coefficients (ICCs) and kappa (κ) statistics as measures of agreement for continuous and categorical measures, respectively. ResultsMeasures of phenotypic characteristics showed moderate-to-high agreement (e.g., eye color, κ=0.87; 95% confidence interval [CI]: 0.80, 0.94). Measures of sun exposure had slightly lower estimates of agreement. The repeatability of items relating to medical and family history of skin cancer was high (e.g., the number of skin cancers removed surgically, κw=0.79; 95% CI: 0.71, 0.88). Physician counts of nevi correlated well with categorical measures of self-reported nevus density at the age of 21 years but correlated only modestly with absolute nevus counts conducted by participants (ICC, 0.38; 95% CI: 0.19, 0.54). ConclusionOur survey instrument demonstrated fair-to-good test–retest reliability for most self-reported risk factors for melanoma, indicating the suitability of these items for developing risk prediction tools in the future.

Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3.

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

Prevention of Melanoma With Regular Sunscreen Use

EVIDENCE FROM RANDOMIZED CONTROLLED TRIALS demonstrated that regular sunscreen use prevents cutaneous squamous cell carcinoma. Until now, there were no randomized controlled trial data on the effects of sunscreen use in melanoma prevention, and case-control studies yielded conflicting results. The community-based skin cancer prevention trial conducted by Green et al in the subtropical region of Nambour, Queensland, Australia, provided evidence from a randomized controlled trial that regular use of sunscreen prevents melanoma. The study included 1621 adults randomized to regular sunscreen use or to discretionary use, which included no use at all. Those randomized to regular sunscreen use were given an unlimited supply of broad-spectrum sunscreen with a sun protection factor (SPF) of 16 and asked to apply it to the head, neck, arms, and hands every morning. Reapplication was advised after heavy sweating, bathing, or long sun exposure. The regular application of a broad-spectrum sunscreen with an SPF of 16 during a 5-year treatment period reduced the incidence of new primary melanomas during a subsequent 10-year follow-up period. In the 10 years after trial cessation, 11 new primary melanomas were identified among the 812 persons assigned to the daily sunscreen group, compared with 22 melanomas among the 809 persons assigned to the discretionary group. According to the authors, this “represented a reduction of the observed rate in those randomly assigned to daily sunscreen use (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.24-1.02; P = .051).” The reduction in invasive melanomas was substantial (3 in the daily-use group vs 11 in the discretionary-use group; HR, 0.27; 95% CI, 0.08-0.97; P=.045). Dailyand discretionary-use groups were similar for known risk factors, including skin color, outdoor behavior, sunburn history, nevus density, and history of skin cancer at the start of the trial. Sun exposure and use of other forms of sun protection, such as hat wearing and shade seeking, were similar between the groups during the trial. Adherence with sunscreen use as assessed by the selfreported frequencies of application, participant diaries, and weight of returned sunscreen bottles was high among the regular sunscreen users. Approximately 75% of the regular users applied sunscreen daily; 25% of this group also applied sunscreen to nonintervention sites (trunk, lower limbs, or both). The reduction in melanomas in all body sites may reflect the tendency of participants in the daily sunscreen group to apply sunscreen to the torso and lower limbs without being asked. Since exposure to UV radiation (UVR) is the only known modifiable cause of melanoma, this study is a potential “game changer” for the primary prevention of melanoma. Patients at high risk for skin cancer because of phenotypic characteristics (fair skin, freckling, and tendency to sunburn) who live in or visit sunny climates or who have a family history of melanoma should routinely and thoroughly apply sunscreen before going outside. In the United States, this recommendation is particularly relevant to those who reside in locations with relatively high levels of ambient UVR, such as Arizona, California, and Florida, and those living in temperate climates, who often vacation in sunny places during the winter and experience seasonal variations in ambient UVR. The US Preventive Services Task Force concluded that randomized controlled trials suggest counseling can increase sun-protective behaviors and decrease indoor tanning. Counseling should consist of inquiring about at-risk individuals’ current habits of sun exposure and willingness to consider using sunscreen regularly. Instructing individuals on the proper use of sunscreens is important. Two coats or about 1 full teaspoon of sunscreen should be applied to each body part prior to going outside: head, neck, and ears; front of trunk; back of trunk; each arm, dorsum of hand, and shoulder; and each lower leg, upper leg, and dorsum of foot. The leg needs to be divided into upper and lower segments with each getting 1 teaspoon. If the person is sweating heavily or towels off after exercise or swimming, it is necessary to

Nevus density and melanoma risk in women: A pooled analysis to test the divergent pathway hypothesis

A "divergent pathway" model for the development of cutaneous melanoma has been proposed. The model hypothesizes that melanomas occurring in people with a low tendency to develop nevi will, on average, arise more commonly on habitually sun-exposed body sites such as the head and neck. In contrast, people with an inherent propensity to develop nevi will tend to develop melanomas most often on body sites with large melanocyte populations, such as on the back. We conducted a collaborative analysis to test this hypothesis using the original data from 10 case-control studies of melanoma in women (2,406 cases and 3,119 controls), with assessment of the potential confounding effects of socioeconomic, pigmentary and sun exposure-related factors. Higher nevus count on the arm was associated specifically with an increased risk of melanoma of the trunk (p for trend = 0.0004) and limbs (both upper and lower limb p for trends = 0.01), but not of the head and neck (p for trend = 0.25). The pooled odds ratios for the highest quartile of nonzero nevus count versus none were 4.6 (95% confidence interval (CI) 2.7-7.6) for melanoma of the trunk, 2.0 (95% CI 0.9-4.5) for the head and neck, 4.2 (95% CI 2.3-7.5) for the upper limbs and 3.4 (95% CI 1.5-7.9) for the lower limbs. Aggregate data from these studies suggest that high nevus counts are strongly associated with melanoma of the trunk but less so if at all of the head and neck. This finding supports different etiologic pathways of melanoma development by anatomic site.

Body‐site distribution of common acquired melanocytic nevi associated with severe sunburns among children in Lithuania

The aim of this cross-sectional study is to provide information on subsite-specific densities of melanocytic nevi by age, sex, and in relation to the history of severe sunburns. This study was conducted in Kaunas, Lithuania, on a sample of 484 children aged 1-2 years, 4-5 years, 9-10 years, and 14-15 years. The questionnaire provided information about the history of severe sunburns since birth. Site-specific numbers and densities of melanocytic nevi of all sizes and nevi 2 mm or greater were studied. We used log-linear and Poisson regression models to estimate the effects of age, sex, and severe sunburns on the nevus density. The predicted total body density of nevi shows a considerable increase up to the age of roughly 10 years. Thereafter, the density increase tapered off. Median densities of nevi were highest on the face. The median density of nevi on the upper arms is higher than on the forearms. Similarly, the median density of nevi on the thighs is higher than on the lower legs. Estimates of the relative nevus densities related to the history of severe sunburns tend to be small with the exception of the legs for nevi 2 mm or greater (relative nevus density = 2.09, 95% CI 1.49-2.93). Nevus densities are highest on maximally or intermittently sun-exposed skin areas. With the exception of the legs among women, the subsite-specific ranking of nevus densities among adolescents follows a similar ranking as the skin melanoma incidence in Lithuania.

Melanocytic Nevi and Sun Exposure in a Cohort of Colorado Children: Anatomic Distribution and Site-Specific Sunburn

Sun exposure and high prevalence of melanocytic nevi are major risk factors for melanoma, but the relationship between them is not well understood. This study examines the relationship between sun exposure (detailed by anatomic location and history of site-specific sunburns) and the presence of melanocytic nevi on 743 White children in Denver, Colorado. Parental reports of site-specific sunburns were collected annually for 2 years starting at ages 5 to 6 years. In the third year, nevi were counted and mapped by anatomic location. Nevus density was higher for boys (36.0 nevi/m2) than for girls (31.0 nevi/m2; P = 0.04). Nevus density was highest on the face, neck, and lateral forearms and was significantly higher in chronically versus intermittently sun-exposed areas (P < 0.0001). Compared with girls, boys had higher nevus density on the face, neck, and trunk, and lower nevus density on the upper arms and thighs (P < 0.01). In 2 years of reports, most subjects (69%) received at least one sunburn. The face, shoulders, and back were the most frequently sunburned areas of the body. When adjusted for host factors, total number of sunburns was significantly associated with higher total nevus prevalence (P = 0.01 for one burn). Site-specific sunburns were significantly associated with nevus prevalence on the back (P = 0.03 for three or more sunburns), but not on the face, arms, or legs. In this high-risk population, there is evidence for two pathways to nevus accumulation: by chronic sun exposure and by intermittent exposure related to sunburns.

Genome-wide search for nevus density shows linkage to two melanoma loci on chromosome 9 and identifies a new QTL on 5q31 in an adult twin cohort

The density of acquired melanocytic nevi represents an important risk factor for malignant melanoma. Total body nevus counts were collected in a cross-sectional study of 1730 healthy females from the UK Adult twin registry comprising 709 dizygous and 156 monozygous pairs. Nevus density (ND) increased up to the age of 35 years and then gradually declined. Quantitative genetic analysis showed a smaller genetic influence (36%) on ND up to 35 years, compared with after 35 years where it rose to 59%. Using a sub-sample of 1238 genotyped individuals, we performed distinct genome-wide scans for individuals above and below 35 separately. In the younger sub-sample, we confirmed a quantitative trait locus (QTL) for ND on chromosomes 9p21 (LOD=2.54), a region already linked to both familial melanoma and ND. We also observed a linkage signal on 9q21 (LOD=2.55) overlapping a recently reported susceptibility locus for ocular and cutaneous melanoma in Danish families. The strongest evidence of linkage identified a novel QTL on chromosome 5q31-32 (LOD=3.47). None of these linkages was observed in the group aged 35 years and over, which showed suggestive linkage on chromosome 2p24 (LOD=2.75). To the best of our knowledge, this is the first genome-wide search for ND in a large sample of healthy adults. The results suggest that different sets of genes are likely to influence the processes leading to the appearance of nevi and their involution. They provide both novel and replicated QTLs for nevus development, some of which might overlap with those for melanoma and warrant detailed investigation.

Etiologic factors associated with p53 immunostaining in cutaneousmalignant melanoma

Findings from a case-control study of cutaneous malignant melanoma (CMM) in Queensland, Australia, suggest that melanomas exhibiting p53 immunostaining possess different risk factors from those of other melanomas. To further explore this hypothesis, a case-only analysis of risk factors for p53 immunostaining with anti-p53 MAb DO-7 was undertaken in 523 people diagnosed with CMM in Canada and Australia. Phenotypic factors and past sun exposure were measured using a self-administered questionnaire and telephone interview. The presence of strong p53 staining (>10% of cell nuclei positively stained vs. <1% staining) was positively associated with some indicators of high cumulative sun exposure: lentigo maligna melanoma subtype (OR = 3.2 vs. superficial spreading subtype), melanoma location on the head and neck (OR = 2.8 vs. back), histopathologic evidence of solar elastosis (OR = 2.1) and previous diagnosis of nonmelanoma skin cancer (OR = 2.4). Strong staining was negatively associated with high nevus density on the back (OR = 0.2 for >25 nevi vs. 0-3 nevi) and histologic evidence of a coexisting nevus (OR = 0.3). Other factors associated with strong p53 immunostaining include greater Breslow thickness (OR = 7.4 for >4.00 vs. <0.76 mm), male sex (OR = 2.2) and dense freckling (OR = 6.6 vs. few freckles). Of these, thickness, male sex, dense freckling, low nevus density on the back, histologic subtype and history of nonmelanoma skin cancer appeared to be independently associated with strong p53 staining. Our findings are consistent with the Queensland study in suggesting that variables indicating high accumulated sun exposure are positively associated with p53 staining and that an increased number of nevi is positively associated with its absence; they may reflect etiologic and pathogenetic heterogeneity in melanoma.

Etiologic and Other Factors Predicting Nevus-Associated Cutaneous Malignant Melanoma

Cutaneous malignant melanomas with histologic evidence of an associated nevus (N+) may have a different risk factor profile from that of melanomas without it (N-). To address this question, a case-only analysis of 932 people with cutaneous malignant melanoma was done to identify etiologic and other factors associated with N+ melanoma. Evidence of an associated nevus was found in 36% of melanomas. N+ melanomas were thinner (Ptrend=0.0009) and more likely to be of the superficial spreading type than other types of melanoma. Subjects with N+ melanomas were younger (Ptrend<0.0001) and reported a higher nevus density on their skin than subjects with N- melanomas [odds ratio (OR), 3.1; 95% confidence interval (CI), 1.6-6.0, for high nevus density versus no nevi]. Indicators of high accumulated sun exposure were less prevalent among subjects with N+ melanomas (OR, 0.3; 95% CI, 0.2-0.4, for melanoma location on the head and neck versus location on trunk; OR, 0.2; 95% CI, 0.1-0.4, for severe solar elastosis adjacent to the melanoma versus no elastosis; OR, 0.2; 95% CI, 0.1-0.4, for lentigo maligna melanoma subtype versus superficial spreading subtype). With the exception of solar elastosis and age, all of the aforementioned variables remained significantly associated with N+ melanomas in multivariate analyses. No associations with self-reported measures of sun exposure, sunburn, or pigmentation phenotype were apparent. Our findings provide some support for the hypothesis of etiologically separate pathways for melanoma, with N+ melanomas appearing less likely to develop in the presence of characteristics suggesting high accumulated sun exposure than N- melanomas. However, it is possible that high UV exposure causes involution of nevi, thus reducing the density of nevi in exposed skin and thereby the probability of N+ melanoma.

Site-specific protective effect of broad-spectrum sunscreen on nevus development among white schoolchildren in a randomized trial

Melanocytic nevus density is a strong risk factor for cutaneous malignant melanoma. Reducing the number of nevi in children may reduce the risk of their developing melanoma as adults. We sought to assess the effect of sunscreen use on nevus development by anatomic sites and by nevi of different sizes for white schoolchildren in a randomized trial. We compared the new nevus count between the sunscreen intervention group (n = 145) and the control group (n = 164) by anatomic site. Children randomized to the sunscreen group had significantly fewer new nevi on the trunk than children in the control group. The differences were more pronounced among the freckled children than children with no freckles. Potential limitations to this study include relatively small numbers of enrolled children, and a follow-up period of only 3 years. Sunscreen use attenuated new nevus development on intermittently sun-exposed body sites for white schoolchildren, particularly among the freckled children.