Genotype-Phenotype Relationships in U.S. Melanoma-Prone Families With CDKN2A and CDK4 Mutations

Goldstein, Alisa M.; Struewing, Jeffery P.; Chidambaram, Abirami; Fraser, Mary C.; Tucker, Margaret A.

doi:10.1093/jnci/92.12.1006

Cited by 174 publications

(112 citation statements)

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“…c.-34G>T, p.R24P, p.M53I, p.P75fs, p.G101W, p.R112_L113insR, p.V126D) have shown that the majority result from single genetic origins, i.e. common founders or ancestors (Gruis et al, 1995a(Gruis et al, , 1995bBorg et al, 1996;Platz et al, 1997;Pollock et al, 1998;Liu et al, 1999;Ciotti et al, 2000;Goldstein et al, 2000Goldstein et al, , 2001Auroy et al, 2001;Hashemi et al, 2001;) rather than mutation hotspots in the CDKN2A gene. To date, only one recurrent mutation has been shown to have multiple origins (c.24_47dup24) (Pollock et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…The distribution of pancreatic cancer in these families differed significantly (p=0.02); the frequency of pancreatic cancer varied from > 30% in p.G101W, p.P75fs, p.R112_L113insR, and p.V126D families to <10% in p.R24P and p.M53I families (figure 1). Fargnoli et al, 1998;MacKie et al, 1998;Soufir et al, 1998;Holland et al, 1999;Newton-Bishop et al, 1999;Della Torre et al, 2001;Mantelli et al, 2002;Lynch et al, 2002 1α c.78insG Fitzgerald et al, 1996;Flores et al, 1997;MacKie et al, 1998;Monzon et al, 1998;Soufir et al, 1998;Holland et al, 1999; Gruis et al, 1995aGruis et al, , 1995bHolland et al, 1999;Goldstein et al, 2000;Vasen et Hussussian et al, 1994;Whelan et al, 1995;Soufir et al, 1998;Ghiorzo et al, 1999;Holland et al, 1999; Codon numbering for the mutations is taken from table 1. Insertions, deletions, and frameshift mutations are shown at the codon in which the mutation.…”

Section: Methodsmentioning

confidence: 99%

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Familial melanoma, pancreatic cancer and germline CDKN2A mutations

Goldstein

2004

Hum. Mutat.

119

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Germline CDKN2A mutations have been observed in approximately 20 percent of familial melanoma kindreds from North America, Europe and Australasia. There is also an increased risk of pancreatic cancer in a subset of families with mutations, however, the precise relationship between the CDKN2A gene and pancreatic cancer remains unknown. The relationships between familial melanoma, pancreatic cancer and germline CDKN2A mutations were examined using published data. There were 67 different CDKN2A mutations in 189 melanoma-prone families. Forty-two families (18 mutations) had pancreatic cancer reported. For families without reported pancreatic cancer, the most common types of mutations were missense (56%), frameshift (12%), and deletions (12%). For families with pancreatic cancer, missense (56%), splicing (17%), and frameshift (11%) mutations were most common. Seventy percent of the mutations were observed only once, while the remainder recurred in different families. Comparison of 147 melanoma-prone families without pancreatic cancer to the 42 families that had pancreatic cancer reported showed no significant differences in the types or locations of mutations. However, there was a significant difference (p=0.002) in the distribution of families across the four ankyrin repeats. This finding primarily resulted from the six most frequent mutations where the distribution of pancreatic cancer varied significantly (p=0

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Familial melanoma, pancreatic cancer and germline CDKN2A mutations

Goldstein

2004

Hum. Mutat.

119

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“…Further details about the melanoma patients and their families are provided elsewhere. 3,[18][19][20][21][22][23][24][25] …”

Section: Subjectsmentioning

confidence: 99%

Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries

Goldstein

Chaudru

Ghiorzo

et al. 2007

Intl Journal of Cancer

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The G101W founder mutation is the most common CDKN2A mutation in Italy, Spain, and France. As the background of modifying genes, environmental exposures, and sun behavior vary across countries, studying G101W carriers from distinct countries offers a unique opportunity to evaluate possible modifying factors in melanoma development. We evaluated 76 G101W cases and 59 carrier controls from France, Italy, Spain, and the United States. Hair color and dysplastic nevi distributions differed significantly in cases and controls across the 4 study groups. Cases also varied significantly for eye color, freckling, and nevi. The distribution of MC1R variants in cases differed significantly across study groups because 12% of Italian melanoma patients had 2 MC1R variants vs. >50% for the other case groups. Several MC1R covariates showed significant associations with melanoma risk in all groups combined and in the American, French, and Spanish samples; no significant findings were observed in the Italian sample. In multiple-case families, the number and type of MC1R variants varied significantly between multiple-primary-melanoma and single-primary-melanoma patients from the 4 groups; there was also a significant decrease in median age at melanoma diagnosis as the number or type of MC1R variants increased. The variation in the effects of the cutaneous phenotypic and MC1R factors across the study sample suggests that these factors differentially contribute to development of melanoma even on a common genetic background of a germline CDKN2A mutation. Differences in melanoma risk across geographic regions justify the need for individual studies in each country before counseling should be considered. ' 2007 Wiley-Liss, Inc.Key words: melanoma; CDKN2A; MC1R; G101W Germline mutations within the coding region of the CDKN2A gene (9p21) have been observed in affected members of melanoma-prone families. 1,2 G101W is one of the most common CDKN2A missense mutations identified to date. It is the most common mutation observed in Italy, Spain, and France. G101W also has a high occurrence in the United States. Similar to most of the other frequent recurrent CDKN2A mutations, G101W appears to have resulted from a single mutational event. Previous evaluation of 20 melanoma-prone families with G101W mutations from France, Italy, and the United States provided compelling evidence for a single genetic origin for G101W; the mutation was estimated to have originated about 97 generations ago (1 LODunit support interval 70-133 generations). 3 Although CDKN2A mutations confer substantial risk for melanoma, not all carriers of mutations develop melanoma. Other host/ clinical, environmental, and genetic factors also modulate risk. It is well known that the incidence of melanoma varies worldwide and even in the context of familial melanoma, penetrance of CDKN2A mutations differs between Europe and the United States. 4 These differences could be related to different genetic backgrounds or to variation in host/clinical characteristics and/or sun behavior. Pr...

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“…INK4a are implicated in pancreatic cancer in familial atypical multiple-mole melanoma syndrome (15) and STK11 mutations in Peutz-Jeghers syndrome (16). Other germ line mutations associated with sporadic incidences of pancreatic cancer include those of the FANCG gene (17).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the 4q32-34 Locus in European Familial Pancreatic Cancer

Earl

Li²,

Vitone³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Familial pancreatic cancer (FPC) describes a group of families where the inheritance of pancreatic cancer is consistent with an autosomal-dominant mode of inheritance. The 4q32-34 region has been previously identified as a potential locus for FPC in a large American family. Methods: The region was allelotyped in 231 individuals from 77 European families using nine microsatellite markers, and haplotyping was possible in 191 individuals from 41 families. Families were selected based on at least two affected first-degree relatives with no other cancer syndromes. Results: Linkage to most of the locus was excluded based on LOD scores less than À2.0. Eight families were excluded from linkage to 4q32-34 based on haplotypes not segregating

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Genotype-Phenotype Relationships in U.S. Melanoma-Prone Families With CDKN2A and CDK4 Mutations

Cited by 174 publications

References 17 publications

Familial melanoma, pancreatic cancer and germline CDKN2A mutations

Familial melanoma, pancreatic cancer and germline CDKN2A mutations

Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries

Evaluation of the 4q32-34 Locus in European Familial Pancreatic Cancer

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