Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 6 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2006. / Härtill 5 uppsatser.

Spitz nevus was first described by Sophie Spitz in 1948 as juvenile melanoma. The lesion is a benign melanocytic tumor, which consists of epiteloid- and spindelshaped cells. Histological is spitz nevus difficult to distinguish from malign melanomas and spitzoid melanomas. Loss of symmetry, loss of maturation in the deep component, nuclear polymorphism and hyper chromatic nucleus are features which can be found in melanomas. Some of these features are often seen in spitz nevus. The purpose of this study was to investigate what help we have from immunohistochemical markers Anti- human HMB-45 (human melanosoma black 45), Anti- human CD99 and Anti- human Ki- 67 antigen to distinguish spitz nevus from spitzoid melanomas and malign melanomas. The study included 21 cases with formalin fixed paraffin embedded tissue. These cases where previous diagnosed as spitz nevus, spitzoid melanomas and malign melanomas. Immunohistochemical staining includes several methods where antibodies are used to detect antigen in tissues. Different visualization systems are used to visualize an antibody- antigen reaction. The most common visualization systems are enzymes. The study was made according to EnVision method (Dako, Denmark), which is an indirect method with secondary antibodies and HRP (horseradish peroxidase) bound to a dextranchain. Paraffin embedded, formalin fixed tissue requires an antigen retrieval before immunohistochemical staining. HIER (heat induced epitope retrieval) is most common use in this purpose. The results were assessed microscopic, where browning endproduct was seen after immunohistochemical staining.  Immunohistochemical staining gave clear positive controls. Anti- human HMB- 45 was present in all immature melanocytic cells. Strong, diffuse staining in superficial component was seen in all cases with Anti- human HMB- 45. Anti- human Ki- 67 was an unpredictable antibody, because lymphocytes had high proliferation and where hard to distinguish from melanocytes. Anti- human CD99 gave a brown stained plasma membrane. There was no difference in staining between spitz nevus and spitzoid melanoma/ malign melanoma with Anti- human CD99. This pilot study shows that staining with immunohistochemical markers is not a helpful tool to distinguish spitz nevus from spitzoid melanomas and malign melanomas.

El nevus displásico (ND), factor de riesgo de melanoma maligno (MM), ha sido fuente de controversia en diferentes sentidos desde su descripción, desde el nombre asignado, los criterios clínicos e histológicos que la caracterizan hasta la gradación de los mismos en tres grados de atipia: leve, moderado y severo. Se ha evaluado en primer lugar si el grado de atipia de los ND tiene alguna relación con el riesgo de padecer melanoma mediante un estudio de datos clínicos y en segundo lugar, buscar un marcador que permita realizar una clasificación del grado de atipia de los nevus displásicos basada en criterios objetivos mediante el estudio de la expresión del marcador de proliferación Ki-67 y el marcador de migración ChAT (Acetil-colina transferasa).En la primera parte del estudio se revisaron los informes de 20.275 nevus recibidos entre 1989 y 1996, constatándose que 6.275 eran ND que pertenecían a 4.481 pacientes. Los pacientes fueron clasificados con respecto a su lesión con mayor grado de atipia y se revisó sus datos clínicos con respecto a la historia de melanoma. Se calculó la Odds Ratio (OR) como medida de asociación entre los grados de atipia de los ND e historia de melanoma. En la segunda parte del estudio se realizó estudio inmunohistoquímico con doble marcaje para HMB-45 y Ki-67 en 36 ND con atipia leve, 36 ND con atipia moderada, 36 ND con atipia severa, 18 nevus melanocíticos benignos (NMB) y 18 MM in-situ, evaluándose la proporción de células melanocíticas de la unión dermo-epidérmica positivas para Ki-67. Así mismo se realizó estudio inmunohistoquímico para ChAT en 30 ND con atipia leve, 30 con atipia moderada y 30 con atipia severa.Los resultados pusieron de manifiesto que 2.504 pacientes presentaban ND con atipia leve como nevus con mayor grado de atipia, 1.657 ND con atipia moderada y 320 ND con atipia severa. La revisión de sus datos clínicos puso de manifiesto que 142 pacientes del grupo de atipia leve, 133 pacientes del grupo con atipia moderada y 63 pacientes del grupo con atipia severa tenían historia de melanoma (c2= 59,89; p<0,001). El estudio de la asociación del grado de atipia con historia de melanoma dio como resultado una OR de 4,08 (2.91-5,7) para los ND con atipia severa versus ND con atipia leve, 2,81 (2-3,95) para los ND con atipia severa vs ND con atipia moderada y 1,45 (1,13-1,87) para ND con atipia moderada vs leve. El estudio inmunohistoquímico con doble marcaje con HMB-45 y Ki-67 mostraron diferencias significativas entre ND vs NMB vs MM (p<0,0001) y entre ND con atipia severa vs ND con atipia leve y moderada (p<0,0003). No se observaron diferencias significativas en el estudio mediante ChAT.En conclusión, la gradación de la atipia citológica de los ND se correlaciona con el riesgo de presentar historia de melanoma y el estudio del índice de proliferación Ki-67 puede ser de ayuda para diferenciar entre NMB, ND y MM, así como para distinguir entre ND con alto y bajo grado de atipia (leve y moderada). / Classification of the different aspects of dysplastic nevus (DN), a risk factor of malignant melanoma (MM), has been source of controversy from its decription, its assigned name and clinical and histological criteria, by which it is chacarcterized, to the ranking of the same into three grades of atypia: mild, moderate, and severe. In the first place, through a study of clinical data, it has been assessed if the grade of DN atypia has some relationship to the risk of suffering from MM; and, in the second place, through studies of the proliferation marker Ki-67 and the ChAT migration marker (acetyl choline transferase), a marker has been searched for, which will allow the classification of the grade of atypia for DN, based on objective criteria. In the first part of the study, reports on 20,275 nevi received between 1989 and 1996 were examined, verifiying that 6,275 of them were DN belonging to 4,481 patients. The patients were classified with respect to their lesions, having the greatest grade of atypia, and their clinical data was also examined, with respect to their history of melanoma. The Odds Ratio (OR) was calculated as a measure of association between the grades of DN aypia and the history of melanoma. In the second part of the study, an immunohistochemical study was conducted, with double staining for HMB-45 and Ki-67 on 36 DN with mild atypia, 36 DN with moderate atypia, 36 DN with severe atypia,18 BMN and 18 MM in-situ, evaluating the proportion of melanocytic cells in the dermo-epidermic junction, showing positive for Ki-67. In this way, an immunohistochemical study was also carried out for ChAT in 30 DN with mild atypia, 30 with moderate atypia and 30 with severe atypia.Results made clear that 2,504 patients presented DN with mild atypia as the highest presenting grade of atypia, 1,657 DN presented with moderate atypia, and 320 presented DN with severe grade of atypia. The review of the clinical data made clear that there were 142 patients in the group having mild atypia, 133 having moderate atypia, and 63 with sever atypia, who all had personal histories of MM (c2= 59,89; p<0,001). The study of the association of the grade of atypia with the history of MM gave as its result an OR of 4.08 (2.91-5.7) for the DN with severe atypia: DN with mild atypia; 2.81 (2-3.95) for the DN with severe atypia: DN with moderate atypia; and 1.45 (1.13-1.87) for DN with moderate atypia : DN with mild atypia. The immunohistochemical study with double staining for HMB-45 and Ki-67 showed significant differences between DN:BMN:MM (p<0.0001) and between DN with severe atypia : DN with mild and moderate atypia (p<0.0003). No significant differences were observed in the study using ChAT. In conclusion, the ranking of the cytological atypia of DN is correlated to the risk of presenting a history of melanoma, and the study of the proliferation rate of Ki-67 can help in the differentiation between BMN, DN, and MM, such as between DN with severe and mild+moderate atypia.

BASE TEÓRICA: O Nevo recorrente (NR) é uma lesão melanocítica que surge na cicatriz de tratamentos cirúrgicos de um nevo melanocítico benigno prévio, apresentando uma alta prevalência na prática dermatológica diária. A recorrência ocorre principalmente após exéreses por shaving, método cirúrgico muito usado na prática clínica devido ao seu bom resultado estético e simplicidade técnica. Estas lesões podem ser um desafio para o dermatologista devido ao fato de algumas vezes simularem tanto clínica quanto histologicamente o melanoma. OBJETIVOS: Avaliar as características dermatoscópicas da lesão primária, potencialmente relacionadas com a sua recorrência após exérese por shaving. Avaliar também as características clínicas, histológicas e a dermatoscopia do reverso da peça cirúrgica preditoras de recorrência. MÉTODOS: Foi realizada a avaliação clínica, histológica e dermatoscópica de 224 nevos melanocíticos benignos de 61 pacientes antes da sua remoção por shaving. A remoção foi realizada de maneira padronizada e o reverso da peça cirúrgica avaliado também dermatoscopicamente após o procedimento. Após seis meses, os pacientes foram reavaliados quanto à presença de recorrência local. RESULTADOS: Recorrência de nevo foi observada em 59 (30,3%) lesões. No modelo de regressão univariável a presença de nevo recorrente mostrou associação inversa com a idade, sendo que em cada ano de aumento na mesma, há uma redução de 3% na prevalência das recorrências (p<0,001). Houve também associação com o fototipo, sendo os mais altos mais prevalentes (p=0,043). O tipo histológico da lesão primária mais associado com a recorrência foi o composto (p=0,005). Quanto às características dermatoscópicas, a presença de pigmento dermatoscópico no reverso da lesão (p<0,001), a presença de coloração marrom-escura (p=0,025), presença de pontos (p=0,007), presença de pêlo terminal (p=0,040) e presença de hiperpigmentação anular (p<0,001) se correlacionaram com os nevos recorrentes. A presença de um maior número de cores à dermatoscopia, também aumenta a prevalência da recorrência (p=0,002). Por outro lado, a presença de vasos (p=0,008) e presença de vasos lineares (p=0,014) se correlacionaram com a ausência de recorrência. Na análise multivariável a presença de hiperpigmentação anular [RP=3,659 (IC: 2,544 – 5,264) p<0,001] e a idade [PR=0,971 (CI: 0,958 – 0,984) p<0,001] destacam-se como os preditores mais significativos para recorrência. CONCLUSÃO Em cada ano de aumento da idade, a prevalência dos NRs é reduzida em 3%. Descrevemos um novo padrão de pigmentação, onde o pigmento é visto distribuído de forma anular, muitas vezes circundando as estruturas anexiais, que se relaciona a uma maior prevalência de recorrência. As lesões que apresentam este padrão, têm uma prevalência de recorrência 3,66 vezes maior, corrigida para a idade. / BACKGROUND: Recurrent Nevus (RN) is a melanocytic lesion that arises in a scar after removal of a previous benign melanocytic nevus. Shaving excisions, that are commonly used due to its optimal cosmetic outcomes and technical simplicity, are mostly related with recurrent nevi. Recurrences might be a challenge for the dermatologist due its clinical and histological aspects that might simulate melanomas. OBJECTIVES: This study aimed to evaluate the dermoscopic features observed in primary lesion of recurrent nevi after shaving excision. Additionally, we analyzed clinical and histological features and surgical specimen reverse of these lesions. METHODS: Clinical, histological and dermoscopic evaluation of 224 benign melanocytic nevi from 61 patients, prior to their removal by shaving, was performed. The removal was performed by standard method. Additionally we performed ex-vivo dermoscopy on the reverse of the surgical specimen after the procedure. After six months, patients were reassessed for the presence of local recurrence. RESULTS: Nevus recurrence was observed in 59 (30.3%) lesions. In the univariate regression model the presence of recurrent nevus was inversely associated with age, and in each year of increase in the same, there is a 3% reduction in the prevalence of recurrence (p <0.001). Was also found an association with skin type. Higher skin types are more associated with recurrent nevus (p = 0.043). Regarding histologyc type of the primary lesion, the compound nevus presents de higher prevalence of recurrence (p=0.005). Regarding dermoscopic characteristics, the presence of pigment in the reverse of surgical specimen (p <0.001), the presence of dark brown color (p = 0.025), presence of dots (p = 0.007), the presence of terminal hair (p = 0.040) and the presence of annular hyperpigmentation (p <0.001) correlated with recurrent nevi. The presence of a larger number of colors in dermatoscopy also increases the prevalence of recurrence (p = 0.002). On the other hand, the presence of blood vessels (p = 0.008) and the presence of linear vessels (p = 0.014) correlated with the absence of recurrence. In multivariable analysis, the presence of annular hyperpigmentation [PR=3.659 (CI: 2.544 – 5.264) p<0.001] and age [PR=0.971 (CI: 0.958 – 0.984) p<0.001] remained significant. CONCLUSION: The prevalence of RN is reduced by 3% after each year of increasing age. We describe annular hyperpigmentation, especially around adnexial structures as a novel dermoscopic structure as a predictor of nevi recurrency. The lesions with annular hyperpigmentation have a 3.66 times higher prevalence of RN.

BASE TEÓRICA: O Nevo recorrente (NR) é uma lesão melanocítica que surge na cicatriz de tratamentos cirúrgicos de um nevo melanocítico benigno prévio, apresentando uma alta prevalência na prática dermatológica diária. A recorrência ocorre principalmente após exéreses por shaving, método cirúrgico muito usado na prática clínica devido ao seu bom resultado estético e simplicidade técnica. Estas lesões podem ser um desafio para o dermatologista devido ao fato de algumas vezes simularem tanto clínica quanto histologicamente o melanoma. OBJETIVOS: Avaliar as características dermatoscópicas da lesão primária, potencialmente relacionadas com a sua recorrência após exérese por shaving. Avaliar também as características clínicas, histológicas e a dermatoscopia do reverso da peça cirúrgica preditoras de recorrência. MÉTODOS: Foi realizada a avaliação clínica, histológica e dermatoscópica de 224 nevos melanocíticos benignos de 61 pacientes antes da sua remoção por shaving. A remoção foi realizada de maneira padronizada e o reverso da peça cirúrgica avaliado também dermatoscopicamente após o procedimento. Após seis meses, os pacientes foram reavaliados quanto à presença de recorrência local. RESULTADOS: Recorrência de nevo foi observada em 59 (30,3%) lesões. No modelo de regressão univariável a presença de nevo recorrente mostrou associação inversa com a idade, sendo que em cada ano de aumento na mesma, há uma redução de 3% na prevalência das recorrências (p<0,001). Houve também associação com o fototipo, sendo os mais altos mais prevalentes (p=0,043). O tipo histológico da lesão primária mais associado com a recorrência foi o composto (p=0,005). Quanto às características dermatoscópicas, a presença de pigmento dermatoscópico no reverso da lesão (p<0,001), a presença de coloração marrom-escura (p=0,025), presença de pontos (p=0,007), presença de pêlo terminal (p=0,040) e presença de hiperpigmentação anular (p<0,001) se correlacionaram com os nevos recorrentes. A presença de um maior número de cores à dermatoscopia, também aumenta a prevalência da recorrência (p=0,002). Por outro lado, a presença de vasos (p=0,008) e presença de vasos lineares (p=0,014) se correlacionaram com a ausência de recorrência. Na análise multivariável a presença de hiperpigmentação anular [RP=3,659 (IC: 2,544 – 5,264) p<0,001] e a idade [PR=0,971 (CI: 0,958 – 0,984) p<0,001] destacam-se como os preditores mais significativos para recorrência. CONCLUSÃO Em cada ano de aumento da idade, a prevalência dos NRs é reduzida em 3%. Descrevemos um novo padrão de pigmentação, onde o pigmento é visto distribuído de forma anular, muitas vezes circundando as estruturas anexiais, que se relaciona a uma maior prevalência de recorrência. As lesões que apresentam este padrão, têm uma prevalência de recorrência 3,66 vezes maior, corrigida para a idade. / BACKGROUND: Recurrent Nevus (RN) is a melanocytic lesion that arises in a scar after removal of a previous benign melanocytic nevus. Shaving excisions, that are commonly used due to its optimal cosmetic outcomes and technical simplicity, are mostly related with recurrent nevi. Recurrences might be a challenge for the dermatologist due its clinical and histological aspects that might simulate melanomas. OBJECTIVES: This study aimed to evaluate the dermoscopic features observed in primary lesion of recurrent nevi after shaving excision. Additionally, we analyzed clinical and histological features and surgical specimen reverse of these lesions. METHODS: Clinical, histological and dermoscopic evaluation of 224 benign melanocytic nevi from 61 patients, prior to their removal by shaving, was performed. The removal was performed by standard method. Additionally we performed ex-vivo dermoscopy on the reverse of the surgical specimen after the procedure. After six months, patients were reassessed for the presence of local recurrence. RESULTS: Nevus recurrence was observed in 59 (30.3%) lesions. In the univariate regression model the presence of recurrent nevus was inversely associated with age, and in each year of increase in the same, there is a 3% reduction in the prevalence of recurrence (p <0.001). Was also found an association with skin type. Higher skin types are more associated with recurrent nevus (p = 0.043). Regarding histologyc type of the primary lesion, the compound nevus presents de higher prevalence of recurrence (p=0.005). Regarding dermoscopic characteristics, the presence of pigment in the reverse of surgical specimen (p <0.001), the presence of dark brown color (p = 0.025), presence of dots (p = 0.007), the presence of terminal hair (p = 0.040) and the presence of annular hyperpigmentation (p <0.001) correlated with recurrent nevi. The presence of a larger number of colors in dermatoscopy also increases the prevalence of recurrence (p = 0.002). On the other hand, the presence of blood vessels (p = 0.008) and the presence of linear vessels (p = 0.014) correlated with the absence of recurrence. In multivariable analysis, the presence of annular hyperpigmentation [PR=3.659 (CI: 2.544 – 5.264) p<0.001] and age [PR=0.971 (CI: 0.958 – 0.984) p<0.001] remained significant. CONCLUSION: The prevalence of RN is reduced by 3% after each year of increasing age. We describe annular hyperpigmentation, especially around adnexial structures as a novel dermoscopic structure as a predictor of nevi recurrency. The lesions with annular hyperpigmentation have a 3.66 times higher prevalence of RN.

BASE TEÓRICA: O Nevo recorrente (NR) é uma lesão melanocítica que surge na cicatriz de tratamentos cirúrgicos de um nevo melanocítico benigno prévio, apresentando uma alta prevalência na prática dermatológica diária. A recorrência ocorre principalmente após exéreses por shaving, método cirúrgico muito usado na prática clínica devido ao seu bom resultado estético e simplicidade técnica. Estas lesões podem ser um desafio para o dermatologista devido ao fato de algumas vezes simularem tanto clínica quanto histologicamente o melanoma. OBJETIVOS: Avaliar as características dermatoscópicas da lesão primária, potencialmente relacionadas com a sua recorrência após exérese por shaving. Avaliar também as características clínicas, histológicas e a dermatoscopia do reverso da peça cirúrgica preditoras de recorrência. MÉTODOS: Foi realizada a avaliação clínica, histológica e dermatoscópica de 224 nevos melanocíticos benignos de 61 pacientes antes da sua remoção por shaving. A remoção foi realizada de maneira padronizada e o reverso da peça cirúrgica avaliado também dermatoscopicamente após o procedimento. Após seis meses, os pacientes foram reavaliados quanto à presença de recorrência local. RESULTADOS: Recorrência de nevo foi observada em 59 (30,3%) lesões. No modelo de regressão univariável a presença de nevo recorrente mostrou associação inversa com a idade, sendo que em cada ano de aumento na mesma, há uma redução de 3% na prevalência das recorrências (p<0,001). Houve também associação com o fototipo, sendo os mais altos mais prevalentes (p=0,043). O tipo histológico da lesão primária mais associado com a recorrência foi o composto (p=0,005). Quanto às características dermatoscópicas, a presença de pigmento dermatoscópico no reverso da lesão (p<0,001), a presença de coloração marrom-escura (p=0,025), presença de pontos (p=0,007), presença de pêlo terminal (p=0,040) e presença de hiperpigmentação anular (p<0,001) se correlacionaram com os nevos recorrentes. A presença de um maior número de cores à dermatoscopia, também aumenta a prevalência da recorrência (p=0,002). Por outro lado, a presença de vasos (p=0,008) e presença de vasos lineares (p=0,014) se correlacionaram com a ausência de recorrência. Na análise multivariável a presença de hiperpigmentação anular [RP=3,659 (IC: 2,544 – 5,264) p<0,001] e a idade [PR=0,971 (CI: 0,958 – 0,984) p<0,001] destacam-se como os preditores mais significativos para recorrência. CONCLUSÃO Em cada ano de aumento da idade, a prevalência dos NRs é reduzida em 3%. Descrevemos um novo padrão de pigmentação, onde o pigmento é visto distribuído de forma anular, muitas vezes circundando as estruturas anexiais, que se relaciona a uma maior prevalência de recorrência. As lesões que apresentam este padrão, têm uma prevalência de recorrência 3,66 vezes maior, corrigida para a idade. / BACKGROUND: Recurrent Nevus (RN) is a melanocytic lesion that arises in a scar after removal of a previous benign melanocytic nevus. Shaving excisions, that are commonly used due to its optimal cosmetic outcomes and technical simplicity, are mostly related with recurrent nevi. Recurrences might be a challenge for the dermatologist due its clinical and histological aspects that might simulate melanomas. OBJECTIVES: This study aimed to evaluate the dermoscopic features observed in primary lesion of recurrent nevi after shaving excision. Additionally, we analyzed clinical and histological features and surgical specimen reverse of these lesions. METHODS: Clinical, histological and dermoscopic evaluation of 224 benign melanocytic nevi from 61 patients, prior to their removal by shaving, was performed. The removal was performed by standard method. Additionally we performed ex-vivo dermoscopy on the reverse of the surgical specimen after the procedure. After six months, patients were reassessed for the presence of local recurrence. RESULTS: Nevus recurrence was observed in 59 (30.3%) lesions. In the univariate regression model the presence of recurrent nevus was inversely associated with age, and in each year of increase in the same, there is a 3% reduction in the prevalence of recurrence (p <0.001). Was also found an association with skin type. Higher skin types are more associated with recurrent nevus (p = 0.043). Regarding histologyc type of the primary lesion, the compound nevus presents de higher prevalence of recurrence (p=0.005). Regarding dermoscopic characteristics, the presence of pigment in the reverse of surgical specimen (p <0.001), the presence of dark brown color (p = 0.025), presence of dots (p = 0.007), the presence of terminal hair (p = 0.040) and the presence of annular hyperpigmentation (p <0.001) correlated with recurrent nevi. The presence of a larger number of colors in dermatoscopy also increases the prevalence of recurrence (p = 0.002). On the other hand, the presence of blood vessels (p = 0.008) and the presence of linear vessels (p = 0.014) correlated with the absence of recurrence. In multivariable analysis, the presence of annular hyperpigmentation [PR=3.659 (CI: 2.544 – 5.264) p<0.001] and age [PR=0.971 (CI: 0.958 – 0.984) p<0.001] remained significant. CONCLUSION: The prevalence of RN is reduced by 3% after each year of increasing age. We describe annular hyperpigmentation, especially around adnexial structures as a novel dermoscopic structure as a predictor of nevi recurrency. The lesions with annular hyperpigmentation have a 3.66 times higher prevalence of RN.

Australia has the highest incidence of melanoma in the world. Melanocytic nevi and mutations in the CDKN2A gene are the main risk factors for the development of cutaneous melanocytic melanoma, and particularly in those of European descent. My study uses genetic epidemiological methods to investigate causes of variation in the number of melanocytic nevi and pigmentary traits such as freckles, eye colour, hair colour and skin colour collected on a sample of adolescent twins and siblings from the Brisbane Twin Nevus Study (1992-2006). Information was available for 2524 individuals from 973 families (from the first visit when the twins were aged 12 years), and from a repeat visit (two years later) for 1598 individuals from 791 families. Using the twin study design extended to siblings and parents, variance components analyses showed that the proportion of phenotypic variance explained by genetic factors ranged from 43 to 99 percent for the traits studied. The atypical nevus count and freckles showed sex differences in the magnitude of genetic and environmental effects. Genetic correlations among counts of three types of nevus (flat, raised and clinically atypical) ranged from 0.46 to 0.63. Nevus count was genetically correlated with skin colour (r=0.23). I analysed genome-wide linkage data using a total of 1190 microsatellite (STR) markers from three scans for 644 families with 1646 twins and siblings, plus genotypes for 1033 parents. These were combined with an additional 169 families with genome-wide association 100K SNP (single nucleotide polymorphism) data, where I selected a linkage analysis panel of 13,000 SNPs making a total of 3365 individuals from 811 families (each individual had more than 200 markers typed). Suggestive linkages for flat nevus count (FNC) were identified on chromosomes 2p25 and 9p21 with lod scores of 3.19 and 2.62 respectively. For raised nevus count (RNC), a suggestive QTL with a lod score of 2.20 was found on chromosome 2q37.2, and for atypical nevus count (ANC) a lod score of 2.71 was found on chromosome 7p14.1. There was suggestive evidence of linkage for freckling on chromosomes 2 and 9. Eye colour was strongly linked (lod=17.86) to chromosome 15, at the OCA2 locus. I have also carried out genetic association analyses using the 100K SNP data in 169 families, and additional fine mapping using SNPs (as well as STR markers) in the complete data set. A sample size of 169 families (461 twins) for genome-wide association data means that statistical power is low. From the 100K SNP data, the best association for total nevus count (TNC) was with SNP rs2420070, p=6.0×10-6 on chromosome 10, and included another two nearby SNPs; rs7086663, p=2.0×10-4 and rs7090904, p=1.5×10-4. These 3 SNPs also showed possible association with FNC; rs2420070, p=3.9×10-6, rs2420070, p=1.3×10-4 and rs2420070, p=8.9×10-5. For raised nevus count the top three associated SNPs were rs1885238, p=1.8×10-5 on chromosome 9; rs10503048, p=3.7×10-5 on chromosome 18 and rs4769189, p=4.0×10-5 on chromosome 13. SNP rs1412341 which is located near CDKN2A on chromosome 9, was also associated with p=2.8×10-4. There were a total 18 SNPs which showed evidence of association with atypical nevus count, the strongest signal being with rs951099 (p=3.7×10-5) on chromosome 9. In a fine-mapping dataset, I studied the association of CDKN2A SNP rs2218220 with TNC, FNC, RNC and ANC. The best SNP, rs2218220, gave p values of 2.8×10-10, 7.7×10-8, 2.7×10-12 and 9.1×10-8, respectively. A SNP, rs1800407 (R419Q) located in the OCA2 gene (chromosome 15q11.2-15q12) showed evidence of association with eye colour and particularly with blue and green eye colours, (p=1.7×10-12 and p=6.0×10-7). SNP rs12913832 from the Hect Domain and RCC1-like Domain 2 gene (HERC2) on chromosome 15q13.1, was also strongly associated with eye colour p=3.6×10-155. This SNP was associated with blue (p= 7.9×10-150) and brown (p=5.3×10-158), but not green eye colour. In addition I confirmed the association of the MC1R SNP rs1805007 and freckling (p=4.8×10-12). This SNP was also associated with FNC (p=3.5×10-8), a finding not previously described in the literature. I also carried out multi-allelic association analysis using STR markers with these traits and uncovered suggestive findings for several regions. Finally, I conducted a multivariate association analysis searching for SNPs with pleiotropic effects. The most interesting results for all types of nevi were with rs801840, p=3.5×10-5, and rs10487075, p=4.9×10-5, both on chromosome 7q21.13. Another four SNPs on chromosome 8p23.1 also showed associations, rs7009724, p=1.4×10-4, rs10503389, p=1.9×10-4, rs7832398, p=6.2×10-4 and rs7005133, p=6.9×10-4 (close to a candidate gene, MFHAS1, implicated in sarcoma risk). In conclusion I have characterised a number of definite and possible genetic factors influencing important risk factors for melanoma.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Made available in DSpace on 2015-12-06T23:04:48Z (GMT). No. of bitstreams: 0 Previous issue date: 2003 / Objetivo: Avaliar, por meio de estudo epidemiologico, a frequencia e a distribuicao corporea dos nevos melanociticos adquiridos (NMA) e observar a influencia das variaveis ambientais e constitucionais nos fenotipos heterogeneos, em uma regiao geografica de intensa exposicao solar. Metodos: Foi realizado estudo transversal das frequencias absoluta e relativa dos NMA de todos os tamanhos, com a inclusao de todas as regioes anatomicas padronizadas pelo protocolo internacional (IARCI OMS, 1990), em 1.279 criancas e adolescentes, com idades de 2 a 18 anos, de creches e escolas publicas na cidade de Votuporanga (20°S), São Paulo, Brasil. Resultados: Setenta e cinco por cento dos individuos apresentaram ate 13 nevos, 50 por cento ate seis nevos e 5 por cento mais de 30 nevos. A contagem de NMA de todos os tamanhos foi mais alta nas regioes toracica e abdominal superior, ombros, face e dorso. Os membros superiores apresentaram mais NMA do que os membros inferiores e houve baixa contagem de NMA nas maos e nos pes. O sexo feminino apresentou quantidade de NMA estatisticamente semelhante ao sexo masculino. As mulheres apresentaram maior contagem de NMA nas faces externas dos membros superiores, face interna do membro superior direito, faces anteriores e posteriores dos membros inferiores, e gluteos. Os homens apresentaram maior contagem de NMA na regiao posterior do pescoco. Observou-se aumento progressivo da contagem de NMA com a idade, com picos aos 13 e aos 16 anos. As regioes de exposicao solar apresentaram maior numero de NMA de maiores diametros (ombros, torax, abdome superior, face e dorso). Os tamanhos dos NMA apresentaram correlacao com a idade, exceto para os gluteos, faces internas dos membros superiores e face posterior da perna direita. Houve forte correlacao entre o numero de NMA e o complexo de pele tipo 3. Exposicao solar, cor dos cabelos e dos olhos, efelides e queimadura solar, tambem apresentaram associacao com alta contagem dos NMA. Conclusoes: Os NMA estao distribuidos por toda a superficie corporal, e em maior numero e tamanho nas regioes de exposicao solar. O aparecimento precoce dos NMA, a distribuicao corporea e a contagem baixa de NMA na populacao heterogenea sustentam a hipotese de que a miscigenacao racial e as regioes anatomicas especificas apresentam diferencas no potencial de proliferacao dos nevos / BV UNIFESP: Teses e dissertações