Emanuel Yakobson on BBC Беседы с генетиком Эммануилом Якобсоном Part 1 2

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents.
Goldstein AM, Chan M, Harland M, Hayward NK, Demenais F, Bishop DT, Azizi E, Bergman W, Bianchi-scarra G, Bruno W, Calista D, Albright LA, Chaudru V, Chompret A, Cuellar F, Elder DE, Ghiorzo P, Gillanders EM, Gruis NA, Hansson J... expand author list, Hogg D, Holland EA, Kanetsky PA, Kefford RF, Landi MT, Lang J, Leachman SA, Mackie RM, Magnusson V, Mann GJ, Bishop JN, Palmer JM, Puig S, Puig-butille JA, Stark M, Tsao H, Tucker MA, Whitaker L, Yakobson E, Lund Melanoma Study Group, Melanoma Genetics Consortium (GenoMEL) collapse author list
Journal of medical genetics 2007 Feb; 44(2)
BACKGROUND: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary... expand abstract melanomas (MPM) or pancreatic cancer. METHODS: These four features were examined in 385 families with > or =3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. RESULTS: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, > or =2 patients with MPM, median age at melanoma diagnosis < or =40 years and > or =6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only > or =1 patient with MPM and age at diagnosis < or =40 years simultaneously predicted the mutation risk. CONCLUSIONS: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer-CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed. collapse abstract
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Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents.
Goldstein AM, Chan M, Harland M, Hayward NK, Demenais F, Bishop DT, Azizi E, Bergman W, Bianchi-scarra G, Bruno W, Calista D, Albright LA, Chaudru V, Chompret A, Cuellar F, Elder DE, Ghiorzo P, Gillanders EM, Gruis NA, Hansson J... expand author list, Hogg D, Holland EA, Kanetsky PA, Kefford RF, Landi MT, Lang J, Leachman SA, Mackie RM, Magnusson V, Mann GJ, Bishop JN, Palmer JM, Puig S, Puig-butille JA, Stark M, Tsao H, Tucker MA, Whitaker L, Yakobson E, Lund Melanoma Study Group, Melanoma Genetics Consortium (GenoMEL) collapse author list
Journal of medical genetics 2007 Feb; 44(2)
BACKGROUND: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary... expand abstract melanomas (MPM) or pancreatic cancer. METHODS: These four features were examined in 385 families with > or =3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. RESULTS: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, > or =2 patients with MPM, median age at melanoma diagnosis < or =40 years and > or =6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only > or =1 patient with MPM and age at diagnosis < or =40 years simultaneously predicted the mutation risk. CONCLUSIONS: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer-CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed. collapse abstract #[Gene silencing RNAi technology: possible application to therapy] Vestin A, Weinstein J, Davidov E, Sidi Y, Yakobson EA Harefuah 2006 Feb; 145(2) RNA interference (RNAi), i.e. gene silencing, or gene expression down-regulation is the process whereby a double-stranded RNA (dsRNA) induces the homology-dependent degradation of cognate messenger RNA (mRNA). When dsRNA is introduced into cells, an ... expand abstractRNA-induced silencing complex (RISC) is assembled. RISC serves as cellular machinery that is responsible for the specific mRNA degradation. This process results in the subsequent reduction of the specific protein translated from appropriate mRNA. Short RNA duplexes (21 nucleotide), called small interfering RNA (siRNA), have become the major tool for induction of gene silencing. With the human genome mapped and sequenced, attempts are currently being made to manipulate the expression of genes involved in viral diseases, carcinogenesis and other disorders with the aim of developing novel therapies. collapse abstract # Search for germline alterations in CDKN2A/ARF and CDK4 of 42 Jewish melanoma families with or without neural system tumours. Marian C, Scope A, Laud K, Friedman E, Pavlotsky F, Yakobson E, Bressac-de paillerets B, Azizi E British journal of cancer 2005 Jun; 92(12) To gain insight into the molecular mechanisms involved in the inherited predisposition to melanoma and associated neural system tumours, 42 Jewish, mainly Ashkenazi, melanoma families with or without neural system tumours were genotyped for germline ... expand abstractpoint mutations and genomic deletions at the CDKN2A/ARF and CDK4 loci. CDKN2A/ARF deletion detection was performed using D9S1748, an intragenic microsatellite marker. Allele dosage at the p14ARF locus was analysed by quantitative real-time PCR employing a TaqMan probe that anneals specifically to exon 1beta of the p14ARF gene. For detecting point mutations, dHPLC and direct sequencing of the coding sequences of CDKN2A/ARF and CDK4 was used. No germline alterations in any of the tested genes were detected among the families under study. We conclude that in the majority of Ashkenazi Jewish families, the genes tested are unlikely to be implicated in the predisposition to melanoma and associated neural system tumours. collapse abstract # Search for genetic variants associated with cutaneous malignant melanoma in the Ashkenazi Jewish population. Loo JC, Paterson AD, Hao A, Shennan M, Peretz H, Sidi Y, Hogg D, Yakobson E Journal of medical genetics 2005 May; 42(5) # A single Mediterranean, possibly Jewish, origin for the Val59Gly CDKN2A mutation in four melanoma-prone families. Yakobson E, Eisenberg S, Isacson R, Halle D, Levy-lahad E, Catane R, Safro M, Sobolev V, Huot T, Peters G, Ruiz A, Malvehy J, Puig S, Chompret A, Avril MF, Shafir R, Peretz H, Bressac-de paillerets B European journal of human genetics : EJHG 2003 Apr; 11(4) We have screened for CDKN2A germline mutations in 49 Jewish families with two or more cases of melanoma. The Val59Gly mutation, one of the three different alterations identified among these families, was also detected independently in two kindreds fr... expand abstract
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