Early Adolescent Trajectories of Impulsiveness and Sensation Seeking in Children of Fathers with Histories of Alcohol and Other Substance Use Disorders.

BACKGROUND: Problem substance use often begins in adolescence. This vulnerability likely stems, at least partially, from relatively rapid increases in sensation seeking occurring in early to mid-adolescence and more gradual improvements in impulse control occurring through later adolescence. Better understanding how these processes develop in high-risk youth may lead to enhanced substance use disorder treatment and prevention strategies. METHODS: We characterized trajectories of self-reported impulsivity and sensation seeking in 305 FH+ youths who at minimum had a father with a history of alcohol or other drug use disorders and 81 youths with no family histories of substance use disorders (FH-). Assessments started at ages 10 to 12 and continued at 6-month intervals for up to 42 months. In addition, a subset of 58 FH+ youths who began alcohol or other drug use before age 15 (FH+ Users) were compared to 58 FH+ propensity-matched adolescents who did not initiate substance use before age 15 (FH+ Non-Users). RESULTS: Compared to FH- youths at preadolescence, FH+ youths reported higher general impulsivity and higher impulsivity related to poor planning and attention. Over time, there were no differential effects of FH status on changes in impulsivity or sensation seeking across adolescence. FH+ Users had smaller decreases in general impulsivity and impulsivity related to restlessness and fidgeting across adolescence than FH+ Non-Users. FH+ Users also had greater increases in sensation seeking across adolescence than FH+ Non-Users. CONCLUSIONS: Increased impulsivity in FH+ youths may make them less able to regulate sensation seeking drives that peak in adolescence, which may contribute to their high risk for developing substance use disorders. Additionally, FH+ adolescents who initiate early use may be at increased risk in part due to increased impulsivity coupled with greater increases in sensation seeking.

Family Functioning as a Mediator of Relations between Family History of Substance Use Disorder and Impulsivity.

Impulsivity is strongly related to the development of adolescent substance use. Therefore, understanding factors that influence impulsive characteristics is important for the development of prevention and intervention programs. Intervention and prevention programs focused on factors that influence impulsive characteristics are especially important for those at particularly high risk for the expression of impulsivity - those with a family history of substance use disorder. A factor of particular interest is family functioning. AIM: To examine family functioning as a mediator of relations between having a family history of substance use disorder and impulsivity. METHODS: Participants included a majority Hispanic sample of pre-adolescent boys and girls (mean age 10.99, SD = .84) recruited from the community who did (FH+) and did not (FH-) have a family history of substance use disorder. FH status and the quality of family functioning were compared at the initial visit with impulsiveness assessed a year later. RESULTS: Results showed FH+ children had worse family functioning; worse family functioning was related to higher levels of impulsivity, and higher levels of impulsivity among FH+ children were due to the influence of family functioning on levels of impulsivity. In other words, family functioning mediated relations between having a family history of substance use disorder and impulsivity. CONCLUSION: These results indicate that higher levels of impulsivity in FH+ children are due in part to worse family functioning.

Pubertal Maturation Compression and Behavioral Impulsivity among Boys at Increased Risk for Substance Use.

OBJECTIVES: While early onset of puberty among girls has been related to substance use involvement and other adverse outcomes, less research has examined pubertal development and outcomes in boys. Further, research on puberty has not been conducted in the context of other risk factors for substance use involvement such as impulsivity. To address these gaps, this study characterized boys' pubertal development from preadolescence to mid-adolescence and related it to substance use risk and behavioral impulsivity. METHODS: A sample of 153 boys completed the Pubertal Development Scale to assess perception of their pubertal development relative to same age peers from ages 10 to 16 years, at 6-month intervals. Group-based trajectory modeling identified three distinct patterns of pubertal development: boys with more slowly developing boys with either earlier (n = 54) or later (n = 43) pubertal timing, and boys with faster tempo of pubertal development (n = 56). The groups were compared on demographic and substance use risk characteristics, as well as behavioral measures of impulsivity. RESULTS: Boys who had the accelerated progression through puberty had the highest proportion of family histories of substance use disorder and perform more impulsively on reward choice measures. CONCLUSIONS: Outcomes are consistent within the Maturation Compression Hypothesis and social neuroscience models of adolescent developmental risk.

Clinical and Social/Environmental Characteristics in a Community Sample of Children With and Without Family Histories of Substance Use Disorder in the San Antonio Area: A Descriptive Study.

This is a descriptive study of the recruitment and clinical/environmental characteristics of a child cohort (ages 10-12) established to test transmission of impulsivity in children with (FH+; n = 305) and without (FH-; n = 81) family history of substance use disorder. Among this cohort FH+ children had more emotional and behavioral symptoms, worse family relationships, and more deviant peers compared to FH- children. This cohort of children was established prior to the initiation of regular substance use and significant clinical problems, which will allow the opportunity to examine reciprocal relations between development of impulse control and substance use development.

Using contingency management procedures to reduce at-risk drinking in heavy drinkers.

BACKGROUND: Treatments for alcohol use disorders typically have been abstinence based, but harm reduction approaches that encourage drinkers to alter their drinking behavior to reduce the probability of alcohol-related consequences, have gained in popularity. This study used a contingency management procedure to determine its effectiveness in reducing alcohol consumption among heavy drinkers. METHODS: Eighty-two nontreatment-seeking heavy drinkers (ages 21 to 54, M = 30.20) who did not meet diagnostic criteria for alcohol dependence participated in the study. The study had 3 phases: (i) an Observation phase (4 weeks) where participants drank normally; (ii) a Contingency Management phase (12 weeks) where participants were paid $50 weekly for not exceeding low levels of alcohol consumption as measured by transdermal alcohol concentrations, <0.03 g/dl; and (iii) a Follow-up phase (12 weeks) where participants (n = 66) returned monthly for 3 months to self-report drinking after the contingencies were removed. Transdermal alcohol monitors were used to verify meeting contingency requirements; all other analyses were conducted on self-reported alcohol use. RESULTS: On average 42.3% of participants met the contingency criteria and were paid an average of $222 during the Contingency Management phase, with an average $1,998 in total compensation throughout the study. Compared to the Observation phase, the percent of any self-reported drinking days significantly decreased from 59.9 to 40.0% in the Contingency Management and 32.0% in the Follow-up phases. The percent of self-reported heavy drinking days reported also significantly decreased from 42.4% in the Observation phase to 19.7% in the Contingency Management phase, which was accompanied by a significant increase in percent days of self-reported no (from 40.1 to 60.0%) and low-level drinking (from 9.9 to 15.4%). Self-reported reductions in drinking either persisted, or became more pronounced, during the Follow-up phase. CONCLUSIONS: Contingency management was associated with a reduction in self-reported episodes of heavy drinking among nontreatment-seeking heavy drinkers. These effects persisted even after incentives were removed, indicating the potential utility of contingency management as a therapeutic intervention to reduce harmful patterns of drinking.

Behavioral Impulsivity and Risk-Taking Trajectories Across Early Adolescence in Youths With and Without Family Histories of Alcohol and Other Drug Use Disorders.

BACKGROUND: Youths with family histories of alcohol and other drug use disorders (FH+) are at increased susceptibility for developing substance use disorders relative to those without such histories (FH-). This vulnerability may be related to impaired adolescent development of impulse control and elevated risk-taking. However, no previous studies have prospectively examined impulse control and risk-taking in FH+ youth across adolescence. METHODS: A total of 386 pre-adolescents (305 FH+, 81 FH-; aged 10 to 12) with no histories of regular alcohol or other drug use were compared on behavioral measures of impulsivity including delay discounting, response initiation (Immediate Memory Task), response inhibition impulsivity (GoStop Impulsivity Paradigm), and risk-taking (Balloon Analogue Risk Task-Youth). Youths completed these laboratory tasks every 6 months, allowing for the examination of 10- to 15-year-olds. Hierarchical linear modeling was used to characterize the development of impulse control and risk-taking as shown in performance of these tasks throughout adolescence. RESULTS: We found that (i) FH+ youths had increased levels of delay discounting and response inhibition impulsivity at study entry; (ii) regardless of FH status, all youths had relatively stable delay discounting across time, improvements in response inhibition and response initiation impulsivity, and increased risk-taking; and (iii) although FH+ youths had increased response inhibition impulsivity at pre-adolescence, these differences were negligible by mid-adolescence. CONCLUSIONS: Heightened delay discounting in FH+ pre-adolescents coupled with normal adolescent increases in risk-taking may contribute to their increased susceptibility toward problem substance use in adolescence.

Assessing the Validity of Participant-Derived Compared to Staff-Derived Values to Compute a Binge Score.

AIMS: This study examined the validity of two methods of classifying binge drinkers. METHODS: Adult drinkers (n = 166) completed the Alcohol Use Questionnaire (AUQ) and a Timeline Followback (TLFB) interview to characterize drinking during the past 28 days. Using Townshend and Duka's (2005) recommendations, answers on three AUQ items (average drinks per hour, number of times drunk within the prior 6 months and percentage of times drunk when drinking) were used to derive a binge score that was then used to classify drinkers as Binge, Non-Binge and Unclassifiable. Two methods for calculating binge scores were compared: (a) Participant-derived, using participants' answers on the 3 AUQ items; and (b) Staff-derived, staff used TLFB interview information to answer the 3 AUQ items. Additionally, Participant- and Staff-derived classifications were used to predict future drinking behaviors assessed by a second TLFB interview. RESULTS: Participant- and Staff-derived binge scores had a low concordance rate. Staff-derived classifications were better than Participant-derived classifications at predicting future binge drinking behavior and identifying group differences in drinking behavior reported during the second TLFB interview (average drinks per hour, number of times drunk within the prior 6 months, and percentage of times drunk when drinking). CONCLUSIONS: Classifying drinkers using staff-guided TLFB interview methods instead of self-reported participant generalizations of typical drinking habits better relates to real-world drinking. Classification schemes that rely on dichotomous categorization of drinkers (Binge vs. Non-Binge) may be missing individuals who engage in harmful patterns of drinking. A continuous scale or index characterizing problematic drinking may be more useful.

The Potential Clinical Utility of Transdermal Alcohol Monitoring Data to Estimate the Number of Alcoholic Drinks Consumed.

OBJECTIVES: Transdermal alcohol monitoring is used extensively in forensic settings to identify whether individuals have violated court-ordered mandates to abstain from drinking. Despite widespread use in that setting, comparatively few studies have explored the clinical utility of transdermal alcohol monitoring. Furthermore, of the few studies conducted, most have relied on the forensically established conservative criteria to identify whether or not a drinking episode has occurred. Here, we explore how transdermal alcohol monitoring data can be used to estimate more clinically meaningful parameters relevant to clinical treatment programs. METHODS: We developed a procedure to use transdermal data to objectively estimate the number of standardized drinks an individual has consumed. Participants included 46 men and women who consumed 1 to 5 beers within 2 hours in the laboratory on separate days while wearing devices to monitor transdermal alcohol concentrations (TAC). RESULTS: A mathematical model was derived to estimate the number of standardized alcohol drinks consumed, which included a number of variables (time-to-peak TAC, area under the TAC curve, and sex). The model was then validated by applying it to data from a separate study. Our results indicate that transdermal alcohol devices can be used to estimate the number of standard drinks consumed. CONCLUSIONS: Objective methods characterizing both the level of intoxication achieved and the number of drinks consumed, such as transdermal alcohol monitoring, could be useful in both research and treatment settings.

Increased Pre- and Early-Adolescent Stress in Youth with a Family History of Substance Use Disorder and Early Substance Use Initiation.

Individuals with a family history of substance use disorders (Family History Positive) are more likely to have early-onset substance use (i.e., prior to age 15), which may contribute to their higher rates of substance use disorders. One factor that may differentiate Family History Positive youth who engage in early-onset substance use from other Family History Positive youth is exposure to stressors. The aim of this study was to quantify how exposure to stressors from age 11-15 varies as a function of family history of substance use disorders and early-onset substance use. Self-reported stressors were prospectively compared in a sample of predominately (78.9%) Hispanic youth that included 68 Family History Positive youth (50% female) who initiated substance use by age 15 and demographically matched non-users with (n = 136; 52.9% female) and without (n = 75; 54.7% female) family histories of substance use disorders. Stressors were assessed at 6-month intervals for up to 4 years. Both the severity of stressors and the degree to which stressors were caused by an individual's own behavior were evaluated. All three groups differed from one another in overall exposure to stressors and rates of increase in stressors over time, with Family History Positive youth who engaged in early-onset substance use reporting the greatest exposure to stressors. Group differences were more pronounced for stressors caused by the participants' behavior. Family History Positive users had higher cumulative severity of stressors of this type, both overall and across time. These results indicate greater exposure to stressors among Family History Positive youth with early-onset substance use, and suggest that higher rates of behavior-dependent stressors may be particularly related to early-onset use.

Single nucleotide polymorphism array analysis of uveal melanomas reveals that amplification of CNKSR3 is correlated with improved patient survival.

Metastatic death from uveal melanoma occurs almost exclusively with tumors showing monosomy of chromosome 3. However, approximately 5% of patients with a disomy 3 uveal melanoma develop metastases, and a further 5% of monosomy 3 uveal melanoma patients exhibit disease-free survival for >5 years. In the present study, whole-genome microarrays were used to interrogate four clinically well-defined subgroups of uveal melanoma: i) disomy 3 uveal melanoma with long-term survival; ii) metastasizing monosomy 3 uveal melanoma; iii) metastasizing disomy 3 uveal melanoma; and iv) monosomy 3 uveal melanoma with long-term survival. Cox regression and Kaplan-Meier survival analysis identified that amplification of the CNKSR3 gene (log-rank, P = 0.022) with an associated increase in its protein expression (log-rank, P = 0.011) correlated with longer patient survival. Although little is known about CNKSR3, the correlation of protein expression with increased survival suggests a biological function in uveal melanoma, possibly working to limit metastatic progression of monosomy 3 uveal melanoma cells.

Do variable rates of alcohol drinking alter the ability to use transdermal alcohol monitors to estimate peak breath alcohol and total number of drinks?

BACKGROUND: Transdermal alcohol monitoring is a noninvasive method that continuously gathers transdermal alcohol concentrations (TAC) in real time; thus, its use is becoming increasingly more common in alcohol research. In previous studies, we developed models that use TAC data to estimate peak breath alcohol concentration (BrAC) and standard units consumed when the rate of consumption was tightly controlled. METHODS: Twenty-two healthy participants aged 21 to 52 who reported consuming alcohol on 1 to 4 days per week were recruited from the community. The final study sample included 11 men and 8 women. Both TAC and BrAC were monitored while each participant drank 1, 2, 3, 4, and 5 beers in the laboratory on 5 separate days. In contrast to previous studies, a self-paced alcohol administration procedure was used. RESULTS: While there was considerable variation in the times it took to consume each beer, key TAC parameters were not affected by pace of drinking. TAC data were then used in combination with the previously derived equations and estimated peak BrAC and standard units of alcohol consumed. CONCLUSIONS: Transdermal alcohol monitoring can be used to reliably estimate peak BrAC and standard number of units consumed regardless of the rate of consumption, further demonstrating its usefulness in clinical research.

Combined p53 and MDM2 biomarker analysis shows a unique pattern of expression associated with poor prognosis in patients with renal cell carcinoma undergoing radical nephrectomy.

OBJECTIVE: To resolve much debated issues surrounding p53 function, expression and mutation in renal cell carcinoma (RCC), we performed the first study to simultaneously determine p53/MDM2 expression, TP53 mutational status (in p53-positive patients) and outcome in RCC. PATIENTS AND METHODS: In total, 90 specimens obtained from patients with RCC, who were treated by radical nephrectomy, were analyzed by immunohistochemistry for p53 and MDM2 on a tissue microarray, and p53 was functionally and genetically analyzed in p53 positive samples. Outcome analysis was by the Kaplan-Meier method and univariate analysis was used to identify variables for subsequent multivariate analysis of correlations between clinical parameters and biomarker expression. RESULTS: Up-regulation of p53 in RCC is strongly linked with MDM2 up-regulation (P < 0.001). Increased coexpression of p53 and MDM2 identifies those patients with a significantly reduced disease-specific survival by univariate (P= 0.036) and Cox multiple regression analysis (P= 0.027; relative risk, 3.20). Functional (i.e. functional analysis of separated alleles in yeast) and genetic analysis of tumours with increased p53 expression shows that most patients (86%) retain wild-type p53. CONCLUSIONS: Coexpression of p53/MDM2 identifies a subset of patients with poor prognosis, despite all of them having organ-confined disease. Up-regulated p53 is typically wild-type and thus provides a mechanistic explanation for the association between p53 and MDM2 expression: up-regulated wild-type p53 likely promotes the observed MDM2 coexpression. The results obtained in the present study suggest that the p53 pathway is altered in a tissue/disease-specific manner and that therapeutic strategies targeting this pathway should be investigated to determine whether the tumour suppressive function of p53 can be rescued in RCC.

GDF-15: a novel serum marker for metastases in uveal melanoma patients.

BACKGROUND: About 50% of patients with uveal melanoma (UM) develop metastases during the course of their disease. We analyzed serum levels of Growth Differentiation Factor-15 (GDF-15), with the aim of identifying patients with early metastases. METHODS: GDF-15 concentration was measured using an enzyme-linked immunosorbent assay (ELISA) in serum samples from 188 UM patients (170 patients without metastases; 18 patients with clinically detectable metastases) and 18 healthy control individuals. Data were analyzed with respect to differences between patients with and without clinically detectable UM metastases. GDF-15 serum levels were further analyzed with regard to significant patient and tumor characteristics as revealed by histology and multiplex ligation-dependent probe amplification (MLPA) to determine chromosome 3 copy number. GDF-15 expression in UM was investigated by immunohistochemistry. RESULTS: Patients with clinically detectable metastases had significantly higher GDF-15 serum levels compared to those without clinically detectable metastases as well as to healthy individuals (ANOVA; p < 0.001). GDF-15 concentrations in UM patients with overt clinically detectable metastases were significantly higher than those in UM patients with a second malignancy in remission but without clinically detected UM metastases (ANOVA; p < 0.001). No association between serum concentration of GDF-15 and clinical, pathological, and genetic features was observed. GDF-15 protein was only expressed in a minority of UM cells in most tumors. CONCLUSIONS: Our data suggest that GDF-15 can be used as a serum marker for the diagnosis of metastases in UM patients. Further data collection and analysis are necessary to evaluate a possible prognostic role of GDF-15 in predicting early metastases.

Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome.

Relatively little is known about the genetic aberrations of conjunctival melanomas (CoM) and their correlation with clinical and histomorphological features as well as prognosis. The aim of this large collaborative multicenter study was to determine potential key biomarkers for metastatic risk and any druggable targets for high metastatic risk CoM. Using Affymetrix single nucleotide polymorphism genotyping arrays on 59 CoM, we detected frequent amplifications on chromosome (chr) 6p and deletions on 7q, and characterized mutation-specific copy number alterations. Deletions on chr 10q11.21-26.2, a region harboring the tumor suppressor genes, PDCD4, SUFU, NEURL1, PTEN, RASSF4, DMBT1, and C10orf90 and C10orf99, significantly correlated with metastasis (Fisher's exact, p ≤ 0.04), lymphatic invasion (Fisher's exact, p ≤ 0.02), increasing tumor thickness (Mann-Whitney, p ≤ 0.02), and BRAF mutation (Fisher's exact, p ≤ 0.05). This enhanced insight into CoM biology is a step toward identifying patients at risk of metastasis and potential therapeutic targets for systemic disease.

Insights into genetic alterations of liver metastases from uveal melanoma.

The liver is the organ usually affected by metastatic uveal melanoma (MUM). Current treatments are almost always ineffective and mortality remains high. In this study, copy number variations (CNVs) were identified in 12 metastatic and five matched primary UMs (PUMs). Our data revealed a wide spectrum of genetic alterations in MUM. Most common were amplifications of chromosome (chr.) 8q; alterations on chr. 3 included monosomy, isodisomy, and large regions of homozygosity (ROH). Genomic profiles of PUM-MUM pairs varied in their degree of similarity and complexity. However, within the pairs, 135 genes were consistently altered. Protein expression of C-MYC and BAP1 was examined by immunohistochemistry (IHC); a positive association between IHC and CNVs was seen for C-MYC. This comprehensive catalogue of CNVs associated with MUM should facilitate the identification of key alterations that drive tumor growth. This would have the potential to select urgently needed novel, targeted, therapeutic regimens.

Transdermal alcohol concentration data collected during a contingency management program to reduce at-risk drinking.

BACKGROUND: Recently, we demonstrated that transdermal alcohol monitors could be used in a contingency management procedure to reduce problematic drinking; the frequency of self-reported heavy/moderate drinking days decreased and days of no to low drinking increased. These effects persisted for three months after intervention. In the current report, we used the transdermal alcohol concentration (TAC) data collected prior to and during the contingency management procedure to provide a detailed characterization of objectively measured alcohol use. METHODS: Drinkers (n=80) who frequently engaged in risky drinking behaviors were recruited and participated in three study phases: a 4-week Observation phase where participants drank as usual; a 12-week Contingency Management phase where participants received $50 each week when TAC did not exceed 0.03g/dl; and a 3-month Follow-up phase where self-reported alcohol consumption was monitored. Transdermal monitors were worn during the first two phases, where each week they recived $105 for visiting the clinic and wearing the monitor. Outcomes focused on using TAC data to objectively characterize drinking and were used to classify drinking levels as either no, low, moderate, or heavy drinking as a function of weeks and day of week. RESULTS: Compared to the Observation phase, TAC data indicated that episodes of heavy drinking days during the Contingency Management phase were reduced and episodes of no drinking and low to moderate drinking increased. CONCLUSIONS: These results lend further support for linking transdermal alcohol monitoring with contingency management interventions. Collectively, studies to date indicate that interventions like these may be useful for both abstinence and moderation-based programs.

Effects of tryptophan depletion and a simulated alcohol binge on impulsivity.

Researchers have suggested binge drinkers experience disproportionate increases in impulsivity during the initial period of drinking, leading to a loss of control over further drinking, and that serotonergic mechanisms may underlie such effects. We examined the effects of a simulated alcohol binge and tryptophan depletion on 3 types of impulsivity-response initiation (immediate memory task [IMT]), response inhibition (GoStop task), and delay discounting (single key impulsivity paradigm [SKIP])-and tested whether observed effects were related to real-world binging. Adults (N = 179) with diverse drinking histories completed a within-subject crossover design over 4 experimental days. Each day, participants underwent 1 of 4 test conditions: tryptophan depletion/alcohol, tryptophan depletion/placebo, tryptophan-balanced control/alcohol, or tryptophan-balanced control/placebo. The simulated binge involved consuming 0.3 g/kg of alcohol at 5, 6, and 7 hr after consuming the tryptophan-depletion/balanced mixture. Impulsivity was measured before and after each drink. Relative to the placebo beverage condition, when alcohol was consumed, impulsive responding was increased at moderate and high levels of intoxication on the IMT and the GoStop but only at high levels of intoxication on the SKIP. Tryptophan depletion had no effect on impulsivity. Effects of alcohol and tryptophan manipulations on impulsivity were unrelated to patterns of binge drinking outside the laboratory. The effects of alcohol consumption on impulsivity depend on the component of impulsivity and the dose of alcohol consumed. Such effects do not appear to be a result of reduced serotonin synthesis. In addition, real-world binge drinking behaviors were unrelated to behavioral changes observed in the laboratory.

Mutations in g protein encoding genes and chromosomal alterations in primary leptomeningeal melanocytic neoplasms.

Limited data is available on the genetic features of primary leptomeningeal melanocytic neoplasms (LMNs). Similarities with uveal melanoma were recently suggested as both entities harbor oncogenic mutations in GNAQ and GNA11. Whether primary LMNs share additional genetic alterations with uveal melanoma including copy number variations is unknown. Twenty primary LMNs ranging from benign and intermediate-grade melanocytomas to melanomas were tested by direct sequencing for hotspot mutations in the genes GNA11, GNAQ, BRAF, NRAS and HRAS. Furthermore, the lesions were tested for copy number variations of chromosomes frequently present in uveal melanoma (1p, 3, 6 and 8q) by multiplex ligation-dependent probe amplification (MLPA). Genome-wide analyses of copy number alterations of two leptomeningeal melanocytic neoplasms were performed using the OncoScan SNP-array. GNAQ(Q209) mutations were present in eleven LMNs, while two of 20 cases carried a GNA11(Q209) mutation. No BRAF, HRAS or NRAS hotspot mutations were detected. Monosomy 3 and gain of 8q were present in one leptomeningeal melanoma, and one intermediate-grade melanocytoma harbored a gain of chromosome 6. With MLPA, the melanocytomas did not show any further gross chromosomal variations. Our data shows that primary LMNs, like uveal melanoma, harbor oncogenic mutations in GNAQ and GNA11 but lack mutations in BRAF, NRAS and HRAS. This finding may help in the differential diagnosis between a primary LMN and a metastasis from a cutaneous melanoma to the central nervous system. Copy number variations in some aggressive LMNs resemble those present in uveal melanoma but their prognostic significance is unclear.