Role of rare germline copy number variation in melanoma-prone patients.

AIM: This work evaluates a possible causative role for germline copy number variants (CNVs) in melanoma predisposition. PATIENTS & METHODS: A total of 41 melanoma-prone Brazilian patients were investigated for CNVs using 850K single nucleotide polymorphism arrays. RESULTS: Ten rare CNVs were identified in nine patients, comprising 54 known genes, mostly related to cancer. In silico analyses revealed gene enrichment for cellular development and growth, and proliferation, highlighting five genes directly associated with the melanoma phenotype (ANGPT1, IDH1, PDE5A, HIST1H1B and GCNT2). CONCLUSION: Patients harboring rare CNVs exhibited a decreased age of disease onset, in addition to an overall higher skin cancer predisposition. Our findings suggest that rare CNVs contribute to melanoma susceptibility, and should be taken into account when investigating cancer risk factors.

Genome-wide DNA methylation profile of leukocytes from melanoma patients with and without CDKN2A mutations.

Melanoma is a highly aggressive cancer, accounting for up to 75% of skin cancer deaths. A small proportion of melanoma cases can be ascribed to the presence of highly penetrant germline mutations, and approximately 40% of hereditary melanoma cases are caused by CDKN2A mutations. The current study sought to investigate whether the presence of germline CDKN2A mutations or the occurrence of cutaneous melanoma would result in constitutive genome-wide DNA methylation changes. The leukocyte methylomes of two groups of melanoma patients (those with germline CDKN2A mutations and those without CDKN2A mutations) were analyzed together with the profile of a control group of individuals. A pattern of DNA hypomethylation was detected in the CDKN2A-negative patients relative to both CDKN2A-mutated patients and controls. Additionally, we delineated a panel of 90 CpG sites that were differentially methylated in CDKN2A-mutated patients relative to controls. Although we identified a possible constitutive epigenetic signature in CDKN2A-mutated patients, the occurrence of reported SNPs at the detected CpG sites complicated the data interpretation. Thus, further studies are required to elucidate the impact of these findings on melanoma predisposition and their possible effect on the penetrance of CDKN2A mutations.

Germline CDKN2A mutations in Brazilian patients of hereditary cutaneous melanoma.

Approximately 10 % of all cutaneous melanoma cases occur in a familial context. The major susceptibility gene for familial melanoma is CDKN2A. In Latin America, genetic studies investigating melanoma predisposition are scarce. The aim of this work was to investigate germline CDKN2A point mutations and genomic rearrangements in a cohort of 59 Brazilian melanoma-prone patients. Screening of CDKN2A alterations was performed by sequencing and multiplex ligation probe amplification. Germline CDKN2A mutations affecting p16(INK4a) were detected in 8 unrelated probands (13.6 %), including 7 familial cases and one patient with multiple melanomas; 4 out of 8 mutation carriers met the criteria for familial melanoma and had multiple primary lesions. Although this study adds to the literature on melanoma susceptibility in Latin America, it is limited by the small size of the cohort. Our findings suggest that stringent inclusion criteria led to a substantially increased rate of CDKN2A mutation detection. This consideration should be taken into account when referring patients for genetic screening in a setting of limited budget, such as in developing countries.

Association of melanoma with intraepithelial neoplasia of the pancreas in three patients.

Melanoma and pancreatic cancer are two low frequency types of cancer. In this study, three patients who developed both melanoma and intraepithelial neoplasia of the pancreas were tested for CDKN2A mutations and deletions, and investigated for rare germline copy number variations (CNVs). The three patients were negative for CDKN2A point mutations and intragenic deletions. One of these patients carried two large (>300 kb) germline CNVs, both genomic duplications affecting coding sequences that are not copy number variable in the population. A second patient exhibited loss of the entire Y chromosome, an event probably coincidental related to his advanced age (79 years-old). Our data pinpoint that rare germline CNVs harboring genes can contribute to the cancer predisposition of melanoma and intraepithelial neoplasia of the pancreas.

Proteins involved in pRb and p53 pathways are differentially expressed in thin and thick superficial spreading melanomas.

Cutaneous melanoma is one of the leading causes of cancer-related death. Malignant transformation of epidermal melanocytes is a multifactorial process involving cell cycle and death control pathways. The purpose of this study was to analyze the immunohistochemical expression of cell-cycle-related and apoptosis-related proteins in cutaneous superficial spreading melanomas using the tissue microarray technique to further understand tumor development. A total of 20 samples of in-situ melanomas and 44 melanomas 1.0 mm) and metastases lost p16 expression in 100% of the cases and in-situ and thin melanomas (

Alpha-v-beta3 integrin expression in melanocytic nevi and cutaneous melanoma.

BACKGROUND: Alpha-v-beta3 integrin (alphavbeta3) is a vitronectin ligand and plays an important role in melanoma progression. OBJECTIVES: The purpose of the study was to evaluate the expression of alphavbeta3 in superficial spreading cutaneous melanoma, in both conventional and tissue microarray (TMA) paraffin-embedded-tissue specimens, and correlate with histopathological variables and patient survival. MATERIAL AND METHODS: A total of 159 tissue samples from compound nevi (n = 19), in situ melanoma (n = 5), thin melanoma (n = 34), thick melanoma (n = 72) and metastatic melanoma (n = 29) were studied. RESULTS: Compound nevus epithelioid cells had a mild expression of alphavbeta3. In situ melanoma cells had the highest expression among all specimens, when compared to nevi (p = 0.0000) and to invasive melanoma (p = 0.0003). Expression of alphavbeta3 did not differ according to depth of invasion or did it increase in metastatic cells. CONCLUSION: Our results suggested that alphavbeta3 integrin might have no impact on melanoma behavior. However, high levels of alphavbeta3-integrin expression for in situ melanoma may be related to pre-invasive phenotype with marked potential to invade.

Cutaneous melanoma in childhood and adolescence: retrospective study of 32 patients.

This study was performed to analyse the behaviour, risk factors, prognosis and evolution of cutaneous melanoma in childhood and adolescence treated in a single institution. A retrospective study was performed between 1980 and 2000 of patients aged 18 years or younger followed at the Hospital do Cancer de Sao Paulo, Brazil. Data included demographic status, risk factors, clinical and histopathological characteristics of the primary and metastatic lesions, stage and follow-up. Seventeen female (53.1%) and 15 male (46.9%) patients were studied. Twelve patients (37.5%) were aged 12 years or younger. The trunk was the most common location (14 patients; 43.8%). Five patients (15.6%) had giant congenital melanocytic naevus, three (9.4%) had xeroderma pigmentosum and one (3%) had dysplastic melanocytic naevus. Nodular melanoma was the most frequent histological type and 43.8% had a thickness of more than 4 mm. Five of the 32 patients (15.6%) were lost to follow-up and 15 (46.9%) were alive at the last year's follow-up, 11 (34.4%) without disease and four (12.5%) with active disease. The 5-year overall survival was 64.34%. An overall survival of 11.71% was found in patients with visceral metastasis with or without cutaneous and/or lymph node involvement, whereas the corresponding value was 90.48% (P value=0.0002) in patients with only cutaneous and/or lymph node metastasis. Cutaneous melanomas are uncommon in the young and are seldom diagnosed in the early stages, perhaps due to a reluctance to accept this diagnosis in this age group. Prevention and early stage diagnosis depend upon the recognition that this disease is present in the young.