In: Twin research and human genetics: the official journal of the International Society for Twin Studies (ISTS) and the Human Genetics Society of Australasia, Band 18, Heft 2, S. 126-133
Mutations in Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A)and Cyclin-Dependent Kinase 4 (CDK4) contribute to susceptibility in approximately 40% of high-density cutaneous melanoma (CMM) families and about 2% of unselected CMM cases. BRCA-1 associated protein-1 (BAP1)has been more recently shown to predispose to CMM and uveal melanoma (UMM) in some families; however, its contribution to CMM development in the general population is unreported. We sought to determine the contribution of these genes to CMM susceptibility in a population-based sample of cases from Australia. We genotyped 1,109 probands from Queensland families and found that approximately 1.31% harbored mutations inCDKN2A, including some with novel missense mutations (p.R22W, p.G35R and p.I49F).BAP1missense variants occurred in 0.63% of cases but noCDK4variants were observed in the sample. This is the first estimate of the contribution ofBAP1andCDK4to a population-based sample of CMM and supports the previously reported estimate ofCDKN2Agermline mutation prevalence.
Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis. ; European Commission under the 6th and 7th Framework Programme ; Cancer Research UK Programme ; Cancer Research UK ; US National Institutes of Health ; NIH, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics ; National Health and Medical Research Council of Australia ; Cancer Council New South Wales ; Cancer Institute New South Wales ; Cancer Council Victoria ; Cancer Council Queensland ; CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior) ; FAPESP (Fundacao para o Amparo da Pesquisa do Estado de Sao Paulo)-SP, Brazil ; National Health and Medical Research Council of Australia ; NCI ; Cancer Research Foundations of Radiumhemmet ; Swedish Cancer Society ; Paulsson Trust ; Lund University ; European Research Council ; Fondo de Investigaciones Sanitarias, Spain ; CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain ; Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, Una manera de hacer Europa ; Catalan Government, Spain ; Fundacio La Marato de TV3, Catalonia, Spain ; Italian Association for Cancer research (AIRC) ; Italian Ministry of Health ; Programme Hospitalier de Recherche Clinique ; Institut National du Cancer (INCA) ; Comision Honoraria de Lucha Contra el Cancer, Montevideo, Uruguay ; Dutch Cancer Society ; CONACYT, Mexico ; NHMRC ; Cancer Institute NSW ; National Institutes of Health ; Texas A&M Hlth Sci Ctr, Dept Epidemiol & Biostat, College Stn, TX USA ; Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA USA ; Natl Canc Inst, Div Canc Epidemiol & Genet, Human Genet Program, Bethesda, MD USA ; Hop Cochin, AP HP, Paris, France ; Univ Paris 05, Paris, France ; Tel Aviv Univ, Sackler Fac Med, Sheba Med Ctr, Dept Dermatol, Tel Aviv, Israel ; Leiden Univ, Med Ctr, Dept Dermatol, Leiden, Netherlands ; St James Univ Hosp, Canc Res UK Clin Ctr Leeds, Leeds Inst Canc & Pathol, Sect Epidemiol & Biostat, Leeds, W Yorkshire, England ; Univ Paris Saclay, Gustave Roussy, Dept Biol & Pathol Med, INSERM,U1186, Villejuif, France ; Univ Genoa, Dept Internal Med & Med Specialties, Genoa, Italy ; IRCCS, AOU San Martino IST, Genoa, Italy ; Maurizio Bufalini Hosp, Dermatol Unit, Cesena, Italy ; Univ Utah, Dept Genet Epidemiol, Salt Lake City, UT USA ; Univ Utah, Dept Biomed Informat, Salt Lake City, UT USA ; Hosp Clin Barcelona, IDIBAPS, Dermatol Dept, Melanoma Unit, Barcelona, Spain ; CIBER Enfermedades Raras, Barcelona, Spain ; Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW, Australia ; Melanoma Inst Australia, Westmead, NSW, Australia ; Univ Paris Diderot, Univ Sorbonne Paris Cite, INSERM, Genet Variat & Human Dis Unit,UMR 946, Paris, France ; Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA USA ; Univ Copenhagen Hosp, Dept Clin Genet, Copenhagen, Denmark ; Univ Fed Ciencias Sau Porto Alegre, Porto Alegre, RS, Brazil ; Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden ; QIMR Berghofer Med Res Inst, Herston, Qld, Australia ; Inst Oncol Ljubljana, Ljubljana, Slovenia ; Lund Univ, Dept Clin Sci, Lund, Sweden ; Lund Univ, Dept Surg, Lund, Sweden ; Univ Fed Sao Paulo, Escola Paulista Med, Dept Pathol, Sao Paulo, Brazil ; Univ Republica, Hosp Clin, Unidad Lesiones Pigmentadas Catedra Dermatol, Montevideo, Uruguay ; Oregon Hlth & Sci Univ, Dept Dermatol, Portland, OR 97201 USA ; Univ Sydney, Westmead Millennium Inst, Westmead Inst Canc Res, Sydney, NSW, Australia ; Inst Valenciano Oncol, Dept Dermatol, Valencia, Spain ; Latvian Biomed Res & Study Ctr, Riga, Latvia ; H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA ; Univ Fed Sao Paulo, Escola Paulista Med, Dept Pathol, Sao Paulo, Brazil ; European Commission under the 6th and 7th Framework Programme: LSH-CT-2006-018702 ; Cancer Research UK Programme: C588/A4994 ; Cancer Research UK Programme: C588/ A10589 ; Cancer Research UK: C8216/A6129 ; US National Institutes of Health: R01-CA83115 ; US National Institutes of Health: R01CA5558-01A2 ; US National Institutes of Health: 5R25-CA147832-04 ; National Health and Medical Research Council of Australia: NHMRC 107359 ; National Health and Medical Research Council of Australia: 402761 ; National Health and Medical Research Council of Australia: 633004 ; National Health and Medical Research Council of Australia: 566946 ; National Health and Medical Research Council of Australia: 211172 ; Cancer Council New South Wales: 77/00 ; Cancer Council New South Wales: 06/10 ; Cancer Institute New South Wales: CINSW 05/TPG/1-01 ; |Cancer Institute New South Wales: 10/TPG/1-02 ; Cancer Council Queensland: 371 ; FAPESP: 2007/04313-2 ; NCI: CA88363 ; European Research Council: ERC-2011-294576 ; Fondo de Investigaciones Sanitarias, Spain: P.I. 09/01393 ; Fondo de Investigaciones Sanitarias, Spain: P.I. 12/ 00840 ; Catalan Government, Spain: AGAUR 2009 SGR 1337 ; Catalan Government, Spain: AGAUR 2014_SGR_603 ; Fundacio La Marato de TV3, Catalonia, Spain: 201331-30 ; Italian Association for Cancer research (AIRC): 15460 ; Programme Hospitalier de Recherche Clinique: PHRC-AOM-07-195 ; Dutch Cancer Society: UL 2012-5489 ; CONACYT, Mexico: 152256/158706 ; NHMRC: 1063593 ; Cancer Institute NSW: 15/CDF/1-14 ; National Institutes of Health: P30CA042014 ; Web of Science
