Number Of Large Nevi Research Articles

Development and validation of a melanoma risk score based on pooled data from 16 case-control studies.

We report the development of a cutaneous melanoma risk algorithm based upon seven factors; hair color, skin type, family history, freckling, nevus count, number of large nevi, and history of sunburn, intended to form the basis of a self-assessment Web tool for the general public. Predicted odds of melanoma were estimated by analyzing a pooled dataset from 16 case-control studies using logistic random coefficients models. Risk categories were defined based on the distribution of the predicted odds in the controls from these studies. Imputation was used to estimate missing data in the pooled datasets. The 30th, 60th, and 90th centiles were used to distribute individuals into four risk groups for their age, sex, and geographic location. Cross-validation was used to test the robustness of the thresholds for each group by leaving out each study one by one. Performance of the model was assessed in an independent UK case-control study dataset. Cross-validation confirmed the robustness of the threshold estimates. Cases and controls were well discriminated in the independent dataset [area under the curve, 0.75; 95% confidence interval (CI), 0.73-0.78]. Twenty-nine percent of cases were in the highest risk group compared with 7% of controls, and 43% of controls were in the lowest risk group compared with 13% of cases. We have identified a composite score representing an estimate of relative risk and successfully validated this score in an independent dataset. This score may be a useful tool to inform members of the public about their melanoma risk.

Risk factors for melanoma development

Melanoma incidence has risen over the last 30 years; however, whether this increase is entirely genuine or caused, in part, by increased screening, needs to be addressed. A large number of nevi is the strongest risk factor for melanoma across all Caucasian populations. Number of nevi is heritable with 60% of the variation in their number attributed to additive genetic effects. Fair hair and skin is also a heritable risk factor but the magnitude of the risk is much smaller than nevi. There are different ‘at-risk’ phenotypes leading to melanoma: high number of nevi or alternatively sun damage with solar keratoses, and these two phenotypes are usually mutually exclusive. This suggests different pathways leading to melanoma. Sun exposure is linked to melanoma with an increased melanoma incidence with decreasing latitude. However, this association is very complex and is not dose dependent. Similar to all cancers, melanoma can cluster in families. Between 20 and 40% of melanoma-prone families have mutations in the tumor-suppressor gene p16 or CDKN2A. These mutations only explain a small proportion of sporadic melanomas. New common low-penetrance melanoma genes associated with pigmentation and nevi counts have recently been discovered. As for many cancers, melanoma is likely to be caused by complex interactions between environmental factors and common low-penetrance genes. Once melanoma genetic risk factors are better understood, it will be possible to further investigate genetic environment interactions and assess the role of sun exposure more accurately. Somatic mutations in p16, p53, BRAF and c-kit are found in melanoma tumors and some of these somatic mutations may be useful to offer melanoma-targeted therapy.

The Beat

The Beat

The Simultaneous Assessment of Constitutional, Behavioral, and Environmental Factors in the Development of Large Nevi

The presence of large nevi (>4 mm diameter) is the most important predictor of melanoma risk. We report on the simultaneous assessment of behavioral, constitutional, and environmental risk factors for the prevalence of large nevi in a population-based study of 33,305 individuals and compare those to risk factors for melanoma. We used self-reported data from a population-based study of twins in California, assessing the prevalence of large nevi, lifetime usual sun exposure behavior and sunburn experience, skin type and color, and birthplace and recent domicile, for which we obtained estimates of potential sun exposure. Among constitutional variables, skin type (burn rather than tan) and having blond (but not red) hair color were associated with having more than three large nevi, as was Celtic ancestry. Spending more time in the sun in adulthood was inversely associated with number of large nevi, whereas spending time in the sun during weekends in childhood increased the risk of having large nevi. We observed no latitude gradient in nevi prevalence, except among those of Mediterranean ancestry (those in the South were more likely than those in the North to report large nevi). The prevalence of large nevi was most readily explained by constitutional and then by behavioral variables in this study, rather than by independent variables describing an individual's opportunity for sun exposure. There seem to be independent relationships between nevi frequency and other melanoma risk factors, with the notable exceptions of skin color and red hair phenotype: implying that if these risk factors represent a genetic propensity to develop melanoma, that risk would seem to be unrelated to the development of nevi.

Molecular characterization of a t(9;12)(p21;q13) balanced chromosome translocation in combination with integrative genomics analysis identifies C9orf14 as a candidate tumor‐suppressor

A large number of nevi (LNN) is a high risk phenotypic trait for developing cutaneous malignant melanoma (CMM). In this study, the breakpoints of a t(9;12)(p21;q13) balanced chromosome translocation were finely mapped in a family with LNN and CMM. Molecular characterization of the 9p21 breakpoint identified a novel gene C9orf14 expressed in melanocytes disrupted by the translocation. Integrative analysis of functional genomics data was applied to determine the role of C9orf14 in CMM development. An analysis of genome-wide DNA copy number alterations in melanoma tumors revealed the loss of the C9orf14 locus, located proximal to CDKN2A, in approximately one-fourth of tumors. Analysis of gene expression data in cancer cell lines and melanoma tumors suggests a loss of C9orf14 expression in melanoma tumorigenesis. Taken together, our results indicate that C9orf14 is a candidate tumor-suppressor for nevus development and late stage melanoma at 9p21, a region frequently deleted in different types of human cancers.

Sex Differences in Numbers of Nevi on Body Sites of Young European Children: Implications for the Etiology of Cutaneous Melanoma

Abstract Background: Since 1950, the greatest increase in cutaneous melanoma incidence in fair-skinned males took place on the trunk and on the head and neck, whereas in females, it took place on the limbs, mainly on the lower limbs. We examined the influence of sex on numbers and size of nevi on different body sites in white European schoolchildren. Methods: Information about each holiday period since birth to interview was recorded from parents of six hundred twenty-eight 6- to 7-year-old children in four European cities (Brussels (Belgium), Bochum (Germany), Lyons (France), and Rome (Italy)). Number and anatomic location of small (2-4.9 mm) and large (≥5 mm) nevi and individual susceptibility to sunlight were independently assessed. Results: After adjustment for host characteristics, sun exposure, and sun protection habits, males had 7% [95% confidence interval (95% CI), −7 to 19] more small nevi than females. However, compared to females, numbers of small nevi were increased by 17% (95% CI, 1-31) on the head and neck and by 16% (95% CI, 2-27) on the trunk and shoulders. In contrast, in males, the number of small nevi on upper limbs was decreased by −5% (95% CI, −26 to 13), and on lower limbs by −8% (95% CI, −34 to 13). The number of large nevi was 6% higher in males than in females (95% CI, −26 to 30). Conclusions: The sex differences in small nevus distribution in schoolchildren reflect the sex differences in the anatomic distribution of melanoma in adults. Sex differences in sun exposure behaviors, dressing, and clothing would just add their effects to the sex-dependent inherited propensity to develop nevi on a given body site. These results reinforce the hypothesis by which childhood would be a decisive period for the occurrence of sun-induced biological events implicated in the genesis of cutaneous melanoma.

Determinants of melanoma in a case-control study of twins (United States).

To estimate the relative contribution of environmental and genetic factors disposing towards the development of melanoma. We investigated risk factors for melanoma in a case-control study conducted among 185 North American twin pairs in which one was diagnosed with melanoma and the other (the co-twin of the case) was not. We considered monozygous (MZ) and dyzygous (DZ) twins separately. While greater risk of melanoma was associated with number of large nevi in DZ twins (adjusted OR = 26.6 (4.2-170.8) for three or more large moles), this was not the case for MZ twins (adjusted OR = 1.4 (0.6-3.2) for three or more large moles). Elevated risks of developing melanoma with site-specific sun exposures resulting in sunburn also appeared to be confined to DZ twins. Despite the number of identical twins reporting a difference in mole prevalence, we observed only a modest and inconsistent increase in melanoma risk attributable to that factor, whereas the increase within fraternal twin pairs was larger by an order of magnitude. If confirmed, this indicates that the significance of mole prevalence as a risk factor for melanoma is largely as a genetic, rather than an environmental, factor. We noticed an increased risk of developing melanoma among DZ twins who drank moderate amounts of beer, but we believe this result may be due to the sun-exposure activities of those people most likely to drink moderate amounts of beer.

Role of Sun Exposure on Nevus

These studies were designed to assess the influence of sun exposure on nevi in white people. To eliminate the confounding effect of age, sex, and phenotype, two parallel studies were conducted on people of the same age (17 to 24 years; median, 20 years old), sex (male), and phenotype: one in people with "red" phenotype (red or red-blond hair, white complexion on the inner part of the arm, and inability to tan) and one in people with "dark" phenotype (brown or black hair, dark complexion on the inner part of the arm, absence of freckles, and easy tanning without burning). In both groups, comparison of nevus counts on the inner and outer side of the upper extremities and comparison of mean density of nevi (number per square meter) in always-exposed and never-exposed skin show that the number of nevi is higher in sun-exposed areas. The density of large and atypical nevi was maximal on intermittently sun-exposed skin while the density of small nevi was maximal on always-exposed skin. The number of large nevi on intermittently exposed skin correlated with cumulative intensive exposure during beach recreation in the red phenotype group. The number of large nevi was significantly higher in red phenotypes who repeatedly experienced severe sunburns in their first 20 years of life. The number of nevi at the end of the second decade is influenced by cumulative sun exposure from birth. "Traumatizing" sun exposure, which is more frequent in the red phenotype than in the dark phenotype, has an influence on the number of large nevi and is therefore likely to make small nevi grow.

Count of benign melanocytic nevi as a major indicator of risk for nonfamilial nodular and superficial spreading melanoma

A study of 207 consecutive white patients older than 18 years of age with nonfamilial nodular and superficial spreading melanoma and 295 controls was conducted in southeast France. Controls were recruited in a public health center. They were matched for sex and age to the overall population older than 18 years of age according to the last census. Melanocytic nevi were counted over the entire body, and data on sun exposure and skin type were collected. A multiple logistic model was used to determine the variables best predicting the risk of melanoma. In order of entry into the model, these variables were number of nevi from 5 to less than 10 mm (N5/10), outdoor leisure per year, frequency of sunburn in the last years, depth of suntan, number of nevi less than 5 mm in diameter (N1/5), age, social level, and hair color. Nevi counts were shown to be indispensable to the construction of a good predictive model for nonfamilial melanoma. After adjustment, estimated relative risks for nonfamilial melanoma rose with increasing number of N1/5, N5/10, and clinically atypical nevi (CAN) on the whole body. Compared with baseline groups the presence of more than 120 N1/5 was associated with a RR of 19.6, the presence of at least five N5/10 with a RR of 10, and the presence of more than one CAN with a RR of 2.77. The number of nevi on the buttocks seemed to be a strong risk factor of melanoma and may provide a simple technique for mass screening. The association between CAN and nonfamilial melanoma could be explained largely by the association between this tumor and the number of large nevi (greater than or equal to 5 mm). It is suggested that when using number of nevi as risk markers, their size might be more important than the other features of clinical atypia. Phenotypic traits and sun exposure, on the one hand, and number of nevi, on the other, seem to be independent risk factors. On the basis of nevus count alone, high-risk subgroups can be identified, which represent only a small part of the overall population older than 18 years of age and from which a large proportion nonfamilial melanoma would theoretically derive.

Surgical Excision of Nevi-Reply

<h3>To the Editor:—</h3> First of all, the removal of nevi at anatomic pressure points is consistent with the recommendations probably made by almost all doctors who see a large number of nevi. Secondly, there is a considerable difference between the relationship of the pigment to the pathogenesis of melanoma, and recommended prophylactic treatment of black moles in children. Lastly, I believe we have one example of a hairy mole in 1,500 odd cases of melanoma in adults. Hence it is most unusual.