High-risk Melanoma Susceptibility Genes and Pancreatic Cancer, Neural System Tumors, and Uveal Melanoma across GenoMEL

Abstract

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available. (Cancer Res 2006; 66(20): 9818-28)

Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling

“…Our study found that the pattern and location of mutations in CDKN2A does not appear to differ significantly from that seen in melanoma kindreds, 25,26 although the frequency of mutations detected in pancreatic cancer probands (0.6%) is less than that seen in a population-based series of melanoma patients (1.8%). This is also substantially lower than the 4% frequency reported in 120 unselected Italian pancreatic cancer patients, although a founder mutation at G101W may have elevated this frequency.…”

“…25 The D153spl mutation in the last nucleotide of exon 2 has also been previously reported, 25 and affects splicing in both p16 and p14. 30 Interestingly, one of the two identified carriers had a personal and family history of melanoma, while the other had only pancreatic cancer.…”

“…13 The GenoMEL report of CDKN2A screening in 466 melanoma families reported a higher frequency of mutations affecting both p16 and p14ARF (49%), rather than p16 alone (26%) in families with members affected with pancreatic cancer. 25 However, one smaller study of 23 families with familial pancreatic cancer revealed two truncating mutations (both in families also affected by melanoma) affecting p16 but none in p14ARF. 3 With regard to the type of mutation in CDKN2A, one previous report suggests that splicing mutations were more common in melanoma families affected with pancreatic cancer than in those without (17 vs 5% of mutations), 29 however, the underlying reason for an individual developing pancreatic cancer rather than melanoma is not yet fully understood.…”

The use of hierarchical models for estimating relative risks of individual genetic variants: An application to a study of melanoma

“…The second higher-level covariate included in the analysis is a binary variable which indicates for each variant whether or not the variant has been observed in families with three or more melanoma patients based on data reported by the International Melanoma Genetics Consortium (GenoMEL) [ 14 ]. The GenoMEL registry comprises major familial melanoma research groups from North America, Europe, and Australia.…”

Nevo displásico (nevo atípico)

“…It is possible to detect germline mutations in affected patients at a frequency ranging from 20% to 40%, depending on the number of affected patients in the family, the average age at diagnosis, the occurrence of pancreatic carcinoma, tumors of the central nervous system and multiple primary melanoma. 34 The CDKN2A gene is considered a tumor suppressor gene, acting in the two checkpoints of the cell cycle through its primary transcripts, p16 and p14. p16 acts in the G1 restriction point and is encoded by exons 1a, 2 and 3, and its expression is regulated by an independent promoter.…”