Analysis of the CDKN2A Gene in FAMMM Syndrome Families Reveals Early Age of Onset for Additional Syndromic Cancers.

Familial atypical multiple mole melanoma (FAMMM) syndrome is a hereditary cancer syndrome that results from mutations in several genes, including the CDKN2A gene. In addition to melanoma, certain other malignancies such as pancreatic cancer are known to occur more frequently in family members who carry the mutation. However, as these families have been followed over time, additional cancers have been observed in both carriers and noncarriers. We sought to determine whether these additional cancers occur at higher frequencies in carriers than noncarriers. We performed survival analyses using 10 FAMMM syndrome families (N = 1,085 individuals) as well as a mixed effects Cox regression, with age at last visit to the clinic or age at cancer diagnosis as our time variable. This analysis was done separately for the known FAMMM-related cancers and "other" cancer groups. The survival curves showed a significant age effect with carriers having a younger age at cancer onset than noncarriers for FAMMM-related cancers (as expected) as well as for newly associated cancers. The Cox regression reflected what was seen in the survival curves, with all models being highly significant (P = 7.15E-20 and P = 5.00E-13 for the FAMMM-related and other cancers, respectively). These analyses support the hypothesis that CDKN2A mutation carriers in FAMMM syndrome families have increased risk for early onset of several cancer types beyond the known cancers. Therefore, these individuals should be screened for additional cancers, and mutation screening should be extended to more than first-degree relatives of an index carrier patient. SIGNIFICANCE: This study shows that carriers of mutations in the CDKN2A gene in FAMMM syndrome are at increased risk for early onset of several cancer types beyond the known cancers.

Dysplastic vs. Common Naevus-associated vs. De novo Melanomas: An Observational Retrospective Study of 1,021 Patients.

The aim of this case-case study was to determine the differences between dysplastic and common naevus-associated melanomas (NAM) and de novo melanomas. A total of 1,021 prospectively collected patients with invasive cutaneous melanoma from an oncology referral centre were included in the study. Of these, 75.51% had de novo melanomas, 12.93% dysplastic NAM, and 11.56% common NAM. Dysplastic NAM, compared with de novo melanomas, were associated with intermittently photo-exposed sites, atypical melanocytic naevi, decreased tumour thickness, and presence of MC1R non-synonymous variants. Common NAM were more frequent on the trunk and of superficial spreading type. Comparison of dysplastic with common NAM showed significant difference only with regard to mitoses. Both subtypes of NAM shared less aggressive traits than de novo melanomas, albeit with no significant differences in survival after multivariate adjustment. In conclusion, NAM present with less aggressive traits, mostly due to a greater awareness among patients of changing moles than due to their intrinsic biological characteristics.

Familial atypical multiple mole melanoma (FAMMM) syndrome: history, genetics, and heterogeneity.

Approximately 5-10 % of cutaneous melanoma occurs in kindreds with a hereditary predisposition. Mutations in the CDKN2A gene are found to occur in approximately 20-40 % of these kindreds. The first historical mention of what is now called the familial atypical multiple mole melanoma syndrome appears to be from 1820, with more reports throughout the 1950s, 1960s, and later years. In 1991, Lynch and Fusaro described an association between familial multiple mole melanoma and pancreatic cancer and work continues to elucidate the syndrome's genotypic and phenotypic heterogeneity. Individuals at risk for familial melanoma need periodic screenings. Unfortunately, adequate screening for pancreatic cancer does not currently exist, but pancreatic cancer's prominence in the hereditary setting will hopefully act as a stimulus for development of novel screening measures.

Immunosuppression is an independent prognostic factor associated with aggressive tumor behavior in cutaneous melanoma.

BACKGROUND: A number of factors other than those identified by the American Joint Committee on Cancer (AJCC) may have prognostic significance in the evaluation of melanoma. OBJECTIVE: We sought to evaluate commonly recorded clinical features potentially associated with aggressive melanoma. METHODS: We conducted a retrospective case-control study. We included patients given a diagnosis of cutaneous melanoma with at least 5 years of follow-up or documented metastases. Patients were divided into nonaggressive and aggressive groups. Univariate and multivariate statistical analyses were performed to evaluate the association of multiple clinical and histologic parameters and metastases. RESULTS: We included 141 patients. Significant prognostic factors in univariate analysis associated with nonaggressive disease included history of dysplastic nevus syndrome and ABCDE criteria. Significant factors in univariate analysis associated with aggressive disease included age and immunosuppression. Only age and immunosuppression remained significant in multivariate analysis when controlled across statistically significant histologic variables from AJCC. LIMITATIONS: The study is retrospective and has a small sample size. CONCLUSION: Older patients and those with a history of immunosuppression may be at higher risk for aggressive disease and should be closely monitored after an initial diagnosis of melanoma.

C-kit expression of melanocytic neoplasm and association with clinicopathological parameters and anatomic locations in Chinese people.

Distinct genetic aberrations between melanomas in different anatomical locations have been confirmed in recent years. However, the associations between immunohistochemical expression, tumor sites, and clinical parameters are not clear. We examined the correlation of protein expression and gene mutation of c-kit with clinicopathological parameters and lesion locations in patients with malignant melanoma (MM). We collected 170 melanocytic lesions, including 106 cutaneous MM from acral melanoma (AM) and nonacral melanoma (NAM) sites, 24 dysplastic nevi, and 40 common melanocytic nevi. Tissue microarray was constructed, and immunohistochemical expression for c-kit was assessed with correlation with clinical parameters. Mutation in exons 11, 13, 17, and 18 of KIT gene in genomic DNA by polymerase chain reaction sequencing was also analyzed. Immunostaining scores for c-kit were found to be statistically higher in Dysplastic Nevi than in common melanocytic nevi and MM. In addition, cytoplasmic c-kit staining was significantly correlated with poor survival in patients with AM but not in those with NAM. Twenty-nine cases of MM (including 9 NAM and 20 AM) are analyzed for mutation in exons 11, 13, 17, and 18 of KIT gene in genomic DNA by polymerase chain reaction sequencing, and no genetic mutation is found. Our findings confirm that KIT mutations, in contrast to previous white cohorts, are not common in both AM and NAM of the Chinese and do not necessarily correlate with c-kit expression. The significantly different association between the expression of c-kit immunoreactivities and the mortality risks of melanomas on acral versus nonacral sites might change site-specific targeted therapeutic concepts in melanoma in the future.

Role of Tip60 in human melanoma cell migration, metastasis, and patient survival.

The tumor suppressor Tip60 regulates gene transcription, DNA damage response, apoptosis, and cancer development, but its role in melanoma is unknown. In this study, we investigated the expression pattern of Tip60 in melanoma and assessed its prognostic value. Using tissue microarrays consisting of 448 cases of melanomas (201 for the training set and 247 for the validation set) and 105 cases of nevi, we found that Tip60 expression was significantly reduced in metastatic melanoma compared to common nevi (P=0.045), dysplastic nevi (P=0.047), and primary melanoma (P=0.001). Kaplan-Meier survival curve and univariate Cox regression analyses showed that reduced Tip60 expression was associated with a poorer 5-year disease-specific survival in primary melanoma (P=0.016) and metastatic melanoma patients (P=0.027). Multivariate Cox regression analyses indicated that Tip60 expression was an independent prognostic marker for primary (P=0.024) and metastatic melanomas (P=0.035). In vitro wound healing assay showed that enforced Tip60 expression inhibited but Tip60 knockdown enhanced melanoma cell migration, suggesting that Tip60 might regulate melanoma metastasis. Finally, we showed that overexpression of Tip60 in melanoma cells resulted in significantly increased chemosensitivity. Our data indicate that Tip60 may serve as a potential biomarker for melanoma patient outcome as well as a potential therapeutic target.

Myeloid leukemia-1 expression in benign and malignant melanocytic lesions.

Myeloid leukemia-1 (Mcl-1) is an anti-apoptotic protein implicated in tumor progression. Its expression was found to be elevated in many types of human cancers and is correlated with tumor progression. The expression of Mcl-1 in melanoma is not fully understood. We investigated the expression of Mcl-1 in normal nevi, dysplastic nevi, primary melanoma and melanoma metastases by tissue microarray and immunohistochemistry. We found that Mcl-1 expression was significantly increased in dysplastic nevi, primary melanoma and melanoma metastases when compared to normal nevi, though the expression of Mcl-1 was decreased in metastatic melanoma when compared to dysplastic nevi. We did not find any correlation between Mcl-1 expression and melanoma patient survival. Our data suggest that Mcl-1 may play a critical role in the initiation of melanoma development.

Improving screening for melanoma by measuring similarity to pre-classified images.

A new method that can dramatically improve the sensitivity and especially the specificity of skin naevi screening for melanoma by physicians is introduced. The method is based on measuring the similarity to previously classified naevi images. As more naevi are being classified, the power of the method is enhanced. Thus physicians can benefit from experience accumulated by others and the screening can be performed effectively by physicians with less experience.

Excess cancer mortality in six Dutch pedigrees with the familial atypical multiple mole-melanoma syndrome from 1830 to 1994.

An increased incidence of systemic cancers has been described in some reports of familial atypical multiple mole-melanoma kindreds. If the gene defect underlying the familial atypical multiple mole-melanoma syndrome is not only important for the development of melanoma of the skin, the impact of the defect on life expectancy may be much higher than previously thought. We investigated all-cause mortality from 1830 to the present and causes of death from 1941 to 1994 in proven, obligate, and potential CDKN2 mutation carriers to obtain an estimate of the impact of a hereditary defect of the CDKN2 gene on mortality. From 1830 to 1994 there were 65 deaths, although only 42 deaths were expected [standardized mortality ratio (SMR) 1.6, 95% confidence interval (CI) 1.2-2.0] and the SMR doubled with calendar time. Excess mortality was shown in most of the families, but was confined to ages 35-70 y (SMR 2.1, 95%CI 1.5-2.9). Excess mortality could be fully attributed to cancer mortality, especially to pancreatic carcinoma and melanoma of the skin. There appeared to be some heterogeneity among the families, especially due to the specific cancer pattern within a family. The impact of the defect of the CDKN2 gene is rising over calendar time, mainly because the mortality in the general population has been falling. Excess mortality was not only due to melanoma, but also to pancreatic carcinoma. Therefore, follow-up programs of affected family members should not be confined to a regular check of the atypical nevi.