High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.

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.

[1]  L. Cannon-Albright,et al.  Population-based prevalence of CDKN2A mutations in Utah melanoma families. , 2006, The Journal of investigative dermatology.

[2]  R. MacKie,et al.  CDKN2A mutations in Scottish families with cutaneous melanoma: results from 32 newly identified families , 2005, The British journal of dermatology.

[3]  J. Barrett,et al.  Prevalence of 9p21 deletions in UK melanoma families , 2005, Genes, chromosomes & cancer.

[4]  R. Millikan,et al.  Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. , 2005, Journal of the National Cancer Institute.

[5]  N. Hayward,et al.  A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation , 2005, Genes, chromosomes & cancer.

[6]  J. A. Bishop,et al.  A mutation hotspot at the p14ARF splice site , 2005, Oncogene.

[7]  A. Scope,et al.  Search for germline alterations in CDKN2A/ARF and CDK4 of 42 Jewish melanoma families with or without neural system tumours , 2005, British Journal of Cancer.

[8]  M. Tucker,et al.  Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma , 2005, Journal of Medical Genetics.

[9]  M. Tucker,et al.  16 ink 4 a / p 14 arf ) and cdkn 2 b genes in 53 melanoma index cases considered to be at heightened risk of melanoma , 2005 .

[10]  Guang Yang,et al.  A novel methionine-53-valine mutation of p16 in a hereditary melanoma kindred. , 2004, The Journal of investigative dermatology.

[11]  A. Goldstein,et al.  Genetic susceptibility in familial melanoma from northeastern Italy , 2004, Journal of Medical Genetics.

[12]  A. Goldstein.  Familial melanoma, pancreatic cancer and germline CDKN2A mutations , 2004, Human mutation.

[13]  E. Schwinger,et al.  Detection of 53 novel DNA variations within the tyrosinase gene and accumulation of mutations in 17 patients with albinism , 2004, Human mutation.

[14]  J. Struewing,et al.  Prospective risk of cancer in CDKN2A germline mutation carriers , 2004, Journal of Medical Genetics.

[15]  K. Nielsen,et al.  Melanoma and nonmelanoma skin cancer in patients with multiple tumours—evidence for new syndromes in a population‐based study , 2004, The British journal of dermatology.

[16]  G. Lenoir,et al.  CDKN2A as a uveal and cutaneous melanoma susceptibility gene , 2003, Genes, chromosomes & cancer.

[17]  J. Disario,et al.  Pancreatic carcinoma surveillance in patients with familial melanoma. , 2003, Archives of dermatology.

[18]  J. Bond,et al.  Detailed computational study of p53 and p16: using evolutionary sequence analysis and disease-associated mutations to predict the functional consequences of allelic variants , 2003, Oncogene.

[19]  Florence Demenais,et al.  Geographical variation in the penetrance of CDKN2A mutations for melanoma. , 2002, Journal of the National Cancer Institute.

[20]  A. Howell,et al.  Germline mutation of ARF in a melanoma kindred. , 2002, Human molecular genetics.

[21]  M. Miller,et al.  Understanding human disease mutations through the use of interspecific genetic variation. , 2001, Human molecular genetics.

[22]  J. Malvehy,et al.  A melanoma-associated germline mutation in exon 1β inactivates p14ARF , 2001, Oncogene.

[23]  J. Struewing,et al.  A common founder for the V126D CDKN2A mutation in seven North American melanoma-prone families , 2001, British Journal of Cancer.

[24]  M. Genuardi,et al.  CDKN2A germline splicing mutation affecting both p16ink4 and p14arf RNA processing in a melanoma/neurofibroma kindred , 2001, Genes, chromosomes & cancer.

[25]  Å. Borg,et al.  Haplotype analysis and age estimation of the 113insR CDKN2A founder mutation in Swedish melanoma families , 2001, Genes, chromosomes & cancer.

[26]  D. Bishop,et al.  A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. , 2001, Human molecular genetics.

[27]  N. Gruis,et al.  Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16‐Leiden) , 2000, International journal of cancer.

[28]  Å. Borg,et al.  High Frequency of Multiple Melanomas and Breast and Pancreas Carcinomas in CDKN2A Mutation-Positive Melanoma Families , 2000 .

[29]  J. Struewing,et al.  A single genetic origin for the G101W CDKN2A mutation in 20 melanoma-prone families. , 2000, American journal of human genetics.

[30]  J. Struewing,et al.  Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. , 2000, Journal of the National Cancer Institute.

[31]  D. Bishop,et al.  Mutation screening of the CDKN2A promoter in melanoma families , 2000, Genes, chromosomes & cancer.

[32]  Kerstin,et al.  High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. , 2000, Journal of the National Cancer Institute.

[33]  P. Bruzzi,et al.  Characterization of ligurian melanoma families and risk of occurrence of other neoplasia , 1999, International journal of cancer.

[34]  G. Mann,et al.  CDKN2A (P16INK4a) and CDK4 mutation analysis in 131 Australian melanoma probands: Effect of family history and multiple primary melanomas , 1999, Genes, chromosomes & cancer.

[35]  X. Estivill,et al.  CDKN2A mutations in Spanish cutaneous malignant melanoma families and patients with multiple melanomas and other neoplasia , 1999, Journal of medical genetics.

[36]  D. Bishop,et al.  Mutation testing in melanoma families: INK4A, CDK4 and INK4D , 1999, British Journal of Cancer.

[37]  D. Duffy,et al.  CDKN2A variants in a population-based sample of Queensland families with melanoma. , 1999, Journal of the National Cancer Institute.

[38]  J. Hansson,et al.  Melanoma development in relation to non-functional p16/INK4A protein and dysplastic naevus syndrome in Swedish melanoma kindreds. , 1999, Melanoma research.

[39]  David Hogg,et al.  Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma , 1999, Nature Genetics.

[40]  R. MacKie,et al.  CDKN2A germline mutations in U.K. patients with familial melanoma and multiple primary melanomas. , 1998, The Journal of investigative dermatology.

[41]  J. Cayuela,et al.  Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. , 1998, Cancer research.

[42]  Ken Chen,et al.  The Ink4a Tumor Suppressor Gene Product, p19Arf, Interacts with MDM2 and Neutralizes MDM2's Inhibition of p53 , 1998, Cell.

[43]  Yue Xiong,et al.  ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways , 1998, Cell.

[44]  D. Stoppa-Lyonnet,et al.  Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. , 1998, Human molecular genetics.

[45]  L. Chin,et al.  The Ink4a Tumor Suppressor Gene Product, p19 Arf , Interacts with MDM2 and Neutralizes , 1998 .

[46]  J. Hansson,et al.  Screening of germline mutations in the CDK4, CDKN2C and TP53 genes in familial melanoma: a clinic-based population study. , 1998, International journal of cancer.

[47]  P. Pollock,et al.  Analysis of the CDKN2A, CDKN2B and CDK4 genes in 48 Australian melanoma kindreds , 1997, Oncogene.

[48]  N. Hayward,et al.  Germline CDKN2A mutations in childhood melanoma. , 1997, Journal of the National Cancer Institute.

[49]  G. Mann,et al.  Differential expression of p16INK4a and p16β transcripts in B-lymphoblastoid cells from members of hereditary melanoma families without CDKN2A exon mutations , 1997, Oncogene.

[50]  M. Inganäs,et al.  Screening of germline mutations in the CDKN2A and CDKN2B genes in Swedish families with hereditary cutaneous melanoma. , 1997, Journal of the National Cancer Institute.

[51]  Å. Borg,et al.  Novel germline p16 mutation in familial malignant melanoma in southern Sweden. , 1996, Cancer research.

[52]  N. Hayward,et al.  Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma , 1996, Nature Genetics.

[53]  A M Goldstein,et al.  Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. , 1995, The New England journal of medicine.

[54]  L. Sandkuijl,et al.  Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds , 1995, Nature Genetics.

[55]  R. DePinho,et al.  Inhibition of ras-induced proliferation and cellular transformation by p16INK4 , 1995, Science.

[56]  Genes, chromosomes & cancer , 1995 .

[57]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[58]  W. Clark,et al.  Germline p16 mutations in familial melanoma , 1994, Nature Genetics.

[59]  M. Skolnick,et al.  Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus , 1994, Nature Genetics.

[60]  G. Hannon,et al.  A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 , 1993, Nature.

[61]  S. Henikoff,et al.  Amino acid substitution matrices from protein blocks. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[62]  C. Mecucci,et al.  Cytogenetic and molecular studies of the Philadelphia translocation in myelodysplastic syndromes. Report of two cases and review of the literature. , 1992, Cancer genetics and cytogenetics.

[63]  N. Gruis,et al.  The Dutch FAMMM family material: clinical and genetic data. , 1992, Cytogenetics and cell genetics.

[64]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[65]  Shona M. Barcus.  The guide to mental health for nurses in primary care , 2003, International Journal of Integrated Care.

[66]  Eugene W. Myers,et al.  Basic local alignment search tool. Journal of Molecular Biology , 1990 .

[67]  R. Grantham.  Amino Acid Difference Formula to Help Explain Protein Evolution , 1974, Science.