Utility of a Noninvasive 2-Gene Molecular Assay for Cutaneous Melanoma and Effect on the Decision to Biopsy.

Importance: Expression of long intergenic non-protein coding RNA 518 (LINC00518) and preferentially expressed antigen in melanoma (PRAME) genes, obtained via noninvasive adhesive patch biopsy, is a sensitive and specific method for detection of cutaneous melanoma. However, the utility of this test in biopsy decisions made by dermatologists has not been evaluated. Objective: To determine the utility of the pigmented lesion assay (PLA) for LINC00518/PRAME expression in decisions to biopsy a series of pigmented skin lesions. Design, Setting, and Participants: In this secure web-based, multiple-reader-multiple-case study, 45 board-certified dermatologists each evaluated 60 clinical and dermoscopic images of clinically atypical pigmented lesions, first without and then with PLA gene expression information and were asked whether the lesions should be biopsied. Data were collected from March 24, 2014, through November 13, 2015. Interventions: Participants were given a report for each lesion, which included the results of an assay for expression of LINC00518/PRAME and a PLA score with data on the predictive values of the information provided. Main Outcomes and Measures: Biopsy sensitivity and specificity with vs without PLA data. Results: Forty-five dermatologists (29 male and 16 female) performed the evaluation. After incorporating the PLA into their decision as to whether to biopsy a pigmented lesion suggestive of melanoma, dermatologists improved their mean biopsy sensitivity from 95.0% to 98.6% (P = .01); specificity increased from 32.1% to 56.9% (P < .001) with PLA data. Conclusions and Relevance: The noninvasive PLA enables dermatologists to significantly improve biopsy specificity while maintaining or improving sensitivity. This result may increase the number of early melanomas biopsied and reduce the number of benign lesions biopsied, thereby improving patient outcomes and reducing health care costs.

Development of a novel noninvasive adhesive patch test for the evaluation of pigmented lesions of the skin.

BACKGROUND: The accurate clinical assessment of melanocytic neoplasms is a challenge for clinicians. Currently, obtaining a biopsy specimen and conducting a histologic examination is the standard of care. The incidence of melanoma in white populations is high, resulting in a large number of biopsy specimens. OBJECTIVE: The objective of this study is to develop a noninvasive genomic method using mRNA to classify pigmented skin lesions as either benign or malignant. METHODS: An adhesive patch method was used to obtain cells from the surface of melanocytic lesions. mRNA was extracted and a genomic signature was formulated in a training set of benign and malignant melanocytic neoplasms and subsequently tested in a validation set. RESULTS: A 2-gene signature assessing the expression levels of CMIP and LINC00518 was able to differentiate melanomas from nevi in an independent validation set of 42 melanomas and 22 nevi with a sensitivity of 97.6% and specificity of 72.7%. LIMITATIONS: Larger and more diverse sets of melanomas and nevi are needed for additional validation of the molecular expression profiling in various subsets of melanocytic neoplasms. CONCLUSION: Our data suggest that mRNA molecular signatures can serve as a highly useful noninvasive method of differentiating melanoma from nevi and decrease the number of unnecessary biopsies.

Obsessive-compulsive symptom dimensions in affected sibling pairs diagnosed with Gilles de la Tourette syndrome.

Obsessive-compulsive disorder (OCD) is an etiologically heterogeneous disorder. Recent factor analyses have consistently identified several symptom dimensions, two of which are associated with increased familial risk for OCD; aggressive, sexual, and religious obsessions and checking compulsions (FACTOR 1) and symmetry and ordering obsessions and compulsions (FACTOR 2). Both of these symptom dimensions are also frequently seen in association with Gilles de la Tourette syndrome (GTS). The purpose of this study was to determine whether these obsessive-compulsive (OC) symptom dimensions are correlated within families (between sibs and between parent-child pairs). Using data collected by the Tourette Syndrome Association International Consortium for Genetics Affected Sibling Pair Study, the authors selected all available GTS sib pairs and their parents for which these OC symptom dimensions (factor scores) could be generated. This group included 128 full sibs and their mothers (54) and fathers (54). Four OC symptom dimension scores were computed for each family member using an algorithm derived from item endorsements from the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) symptom checklist. In addition to a series of univariate analyses, complex segregation analyses were also completed using these quantitative OC symptom dimension scores. FACTOR 1 and FACTOR 2 scores were significantly correlated in sib pairs concordant for GTS. The mother-child correlations, but not father-child correlations, were also significant for these two factors. Segregation analyses were consistent with dominant major gene effects for both FACTOR 1 and FACTOR 2. We conclude that familial factors contribute significantly to OC symptom dimension phenotypes in GTS families. This familial contribution could be genetic or environmental.

A factor analysis of tic symptoms in Gilles de la Tourette's syndrome.

OBJECTIVE: Gilles de la Tourette's syndrome is a well-characterized disorder with clear DSM-IV criteria. However, the great deal of clinical variability across patients may represent an underlying etiologic complexity. Issues of phenotypic heterogeneity are particularly critical to current efforts at mapping genes involved in this syndrome. METHOD: Lifetime tic symptom data were obtained from direct structured interviews of 85 Tourette's disorder probands. Information on 29 tic symptoms was elicited. The probands' tic symptoms were grouped by using agglomerative hierarchical clustering, with no a priori assumptions concerning the relatedness of symptoms. Scores for the probands' symptom clusters were used as variables in a principal-component factor analysis. The relationships of the resulting factor scores to comorbidity in probands and recurrence risks in relatives were examined. In addition, intraclass correlations were calculated for within-family factor scores of 36 families. RESULTS: Four significant factors were identified: 1) aggressive phenomena (e.g., kicking, temper fits, argumentativeness), 2) purely motor and phonic tic symptoms, 3) compulsive phenomena (e.g., touching of others or objects, repetitive speech, throat clearing), and 4) tapping and absence of grunting. Analysis of the symptom loadings, comorbidity, recurrence risks, and within-family correlations indicate that these factors represent a valid structure with clinical and biological relevance. CONCLUSIONS: In this symptom-based factor analysis of Tourette's disorder, four factors accounted for 61% of the phenotypic symptom variance in Tourette's disorder probands and their first-degree relatives. Three of these factors may indicate the presence of heritable components of the Tourette's disorder phenotype.

Association between the COMT locus and obsessive-compulsive disorder in females but not males.

A polymorphism in the coding region of catechol-O-methyltransferase gene (COMT) was previously reported to be associated with obsessive-compulsive disorder (OCD), particularly in male probands. We attempted to replicate the previous finding using a family-based genetic design in haplotype relative risk (HRR) and transmission disequilibrium (TDT) analyses. Fifty-six OCD probands and their parents were genotyped for the COMT locus using established methods. Analysis of allele and genotype frequencies between the proband genotypes and the control (parental nontransmitted) genotypes failed to replicate the previous finding of gender divergence, gave no evidence of overall association, nor was linkage detected by TDT. However, further analysis of the COMT allele frequencies by proband gender gave evidence of a mildly significant association with the low-activity COMT allele in female probands (P=0.049), but not in male probands. These findings indicate that COMT may be etiologically relevant to OCD in a gender-specific manner opposite to that shown in previous studies.