"Pedigrees included in the second phase analyses (phase 2, table 1) were identified and collected in Australia, the United States, the United Kingdom, France, Sweden, and The Netherlands, by members of the Melanoma Genetics Consortium. More details about the families can be found elsewhere (Bergman et al. 1992; Hussussian et al. 1994; Gruis et al. 1995; Platz et al. 1997; Soufir et al. 1998; Hashemi et al. 1999; Newton Bishop et al. 1999; Bishop et al. 2000; Borg et al. 2000; Goldstein et al. 2000; Harland et al. 2000). The goal of the Melanoma Genetics Consortium , established in 1997, is to investigate factors related to the inheritance of an increased risk of melanoma (Kefford et al. 1999; Bishop et al. 2002). "
[Show abstract][Hide abstract] ABSTRACT: Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores >3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.
The American Journal of Human Genetics 09/2003; 73(2):301-13. DOI:10.1086/377140 · 10.93 Impact Factor
"All of the pedigree data, the method of ascertainment, and the histopathological findings on the six 9p-linked Dutch families with FAMMM syndrome have been published elsewhere (Bergman et al. 1992). From these families , 101 carriers of p16-Leiden were included in the single-strand conformation polymorphism (SSCP; Orita et al. 1989) analysis of MC1R. "
[Show abstract][Hide abstract] ABSTRACT: Germline mutations of the cell-cycle regulator p16 (also called "CDKN2A") in kindreds with melanoma implicate this gene in susceptibility to malignant melanoma. Most families with familial atypical multiple-mole melanoma (FAMMM) who are registered at the Leiden dermatology clinic share the same p16-inactivating deletion (p16-Leiden). Incomplete penetrance and variable clinical expression suggest risk modification by other genetic and/or environmental factors. Variants of the melanocortin-1 receptor (MC1R) gene have been shown to be associated with red hair, fair skin, and melanoma in humans. Carriers of the p16-Leiden deletion in Dutch families with FAMMM show an increased risk of melanoma when they also carry MC1R variant alleles. The R151C variant is overrepresented in patients with melanoma who are from families with the p16-Leiden mutation. Although some of the effect of the R151C variant on melanoma risk may be attributable to its effect on skin type, our analyses indicate that the R151C variant contributes an increased melanoma risk even after statistical correction for its effect on skin type. These findings suggest that the R151C variant may be involved in melanoma tumorigenesis in a dual manner, both as a determinant of fair skin and as a component in an independent additional pathway.
The American Journal of Human Genetics 11/2001; 69(4):774-9. DOI:10.1086/323411 · 10.93 Impact Factor
"Families prone to melanoma often have large numbers of nevi, or nevi of an atypical appearance (dysplastic) or distributed atypically (such as on the buttocks). This phenotype is usually referred to as the atypical mole syndrome (AMS), dysplastic nevus syndrome (Kraemer, 1987), or FAMMM syndrome phenotype (Bergman et al, 1992). Germline mutations associated with high penetrance have been identi®ed in CDKN2A (Holland et al, 1995; Dracopoli and Fountain, 1996; Harland et al, 1997) and CDK4 (Zuo et al, 1996). "
[Show abstract][Hide abstract] ABSTRACT: Risk factors for melanoma include environmental (particularly ultraviolet exposure) and genetic factors. In rare families, susceptibility to melanoma is determined by high penetrance mutations in the genes CDKN2A or CDK4, with more common, less penetrant genes also postulated. A further, potent risk factor for melanoma is the presence of large numbers of melanocytic nevi so that genes controlling nevus phenotype could be such melanoma susceptibility genes. A large Australian study involving twins aged 12 y of predominantly U.K. ancestry showed strong evidence for genetic influence on nevus number and density. We carried out essentially the same study in the U.K. to gain insight into gene–environment interactions for nevi. One hundred and three monozygous (MZ) and 118 dizygous (DZ) twin pairs aged 10–18 y were examined in Yorkshire and Surrey, U.K. Nevus counts were, on average, higher in boys (mean = 98.6) than girls (83.8) (p =0.009) and higher in Australia (110.4) than in the U.K. (79.2, adjusted to age 12 y, p <0.0001), and nevus densities were higher on sun-exposed sites (92 per m2) than sun-protected sites (58 per m2) (p <0.0001). Correlations in sex and age adjusted nevus density were higher in MZ pairs (0.94, 95%CI 0.92–0.96) than in DZ pairs (0.61, 95%CI 0.49–0.72), were notably similar to those of the Australian study (MZ = 0.94, DZ = 0.60), and were consistent with high heritability (65% in the U.K., 68% in Australia). We conclude that emergence of nevi in adolescents is under strong genetic control, whereas environmental exposures affect the mean number of nevi.Keywords: genes, heritability, melanoma, nevi, twins
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