Human Molecular Genetics, 2002, Vol. 11, No. 11 1273-1279
© 2002 Oxford University Press
Germline mutation of ARF in a melanoma kindred
1University of Manchester Department of Medical Genetics and Regional Genetic Service, Central Manchester Healthcare Trust, St. Mary's Hospital, Manchester, M13 OJH, UK, 2Centre for Cancer Epidemiology, Christie Hospital, Manchester, M20 4BX, UK, 3Department of Stomatology, University of California San Francisco, San Francisco, CA 94143-0424, USA and 4University of Manchester Dental Hospital, Manchester, M15 6FH, UK
Received December 3, 2001; Accepted March 13, 2002
Familial melanoma predisposition is associated with germline mutations at the CDKN2A/ARF locus in up to 40% of families. The exact role of the two proteins encoded by this complex locus in this predisposition is unclear. Most mutations affect either CDKN2A only or products of both genes. Recently a deletion affecting ARF-specific exon 1ß was reported in a family with melanoma and neural tumours. However, the possibility of this deletion also altering the CDKN2A transcript could not be excluded. More convincingly, a 16 base pair insertion in exon 1ß has been reported in an individual with multiple melanomas suggesting a direct role for ARF in melanoma predisposition. We report here a splice mutation in exon 1ß in a family with melanoma that results in ARF haploinsufficiency. The mutation was observed in a mother and daughter with melanoma. A sibling of the mother with breast cancer also had this mutation. Analysis of the melanoma from one individual revealed a 62 bp deletion in exon 3 of the wildtype allele and loss of the mutant allele; these somatic changes would affect both CDKN2A and ARF. These somatic events suggest that concomitant inactivation of both ARF and CDKN2A may be necessary for melanoma development and that mutations in ARF and CDKN2A possibly confer different levels of susceptibility to melanoma, with the former associated with lesser predisposition. In this situation, the events follow a ‘three-hit’ model as observed in tumours from FAP patients with an attenuated phenotype. Overall, the data suggest a direct role for ARF haploinsufficiency in melanoma predisposition and co-operation between ARF and CDKN2A in tumour formation, consistent with recent observations in Cdkn2a-specific knockout mice.
* To whom correspondence should be addressed. Tel:+44 161276 6604/6720; Fax:+44 161 276 6606; Email: nthakker{at}man.ac.uk
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. E. Freedberg, S. H. Rigas, J. Russak, W. Gai, M. Kaplow, I. Osman, F. Turner, J. A. Randerson-Moor, A. Houghton, K. Busam, et al. Frequent p16-Independent Inactivation of p14ARF in Human Melanoma J Natl Cancer Inst, June 4, 2008; 100(11): 784 - 795. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Pasmant, I. Laurendeau, D. Heron, M. Vidaud, D. Vidaud, and I. Bieche Characterization of a Germ-Line Deletion, Including the Entire INK4/ARF Locus, in a Melanoma-Neural System Tumor Family: Identification of ANRIL, an Antisense Noncoding RNA Whose Expression Coclusters with ARF Cancer Res., April 15, 2007; 67(8): 3963 - 3969. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Goldstein, M. Chan, M. Harland, E. M. Gillanders, N. K. Hayward, M.-F. Avril, E. Azizi, G. Bianchi-Scarra, D. T. Bishop, B. Bressac-de Paillerets, et al. High-risk Melanoma Susceptibility Genes and Pancreatic Cancer, Neural System Tumors, and Uveal Melanoma across GenoMEL. Cancer Res., October 15, 2006; 66(20): 9818 - 9828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Falchi, T. D. Spector, U. Perks, B. S. Kato, and V. Bataille Genome-wide search for nevus density shows linkage to two melanoma loci on chromosome 9 and identifies a new QTL on 5q31 in an adult twin cohort Hum. Mol. Genet., October 15, 2006; 15(20): 2975 - 2979. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Ghiorzo, S. Gargiulo, L. Pastorino, S. Nasti, R. Cusano, W. Bruno, S. Gliori, M. R. Sertoli, A. Burroni, V. Savarino, et al. Impact of E27X, a novel CDKN2A germ line mutation, on p16 and p14ARF expression in Italian melanoma families displaying pancreatic cancer and neuroblastoma Hum. Mol. Genet., September 15, 2006; 15(18): 2682 - 2689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Chin, L. A. Garraway, and D. E. Fisher Malignant melanoma: genetics and therapeutics in the genomic era. Genes & Dev., August 15, 2006; 20(16): 2149 - 2182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Laud, C Marian, M F Avril, M Barrois, A Chompret, A M Goldstein, M A Tucker, P A Clark, G Peters, V Chaudru, et al. Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma J. Med. Genet., January 1, 2006; 43(1): 39 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Payne and C. J. Kemp Tumor suppressor genetics Carcinogenesis, December 1, 2005; 26(12): 2031 - 2045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. H. Tolleson, J. C. Doss, J. Latendresse, A. R. Warbritton, W. B. Melchior Jr, L. Chin, R. R. Dubielzig, and D. M. Albert Spontaneous Uveal Amelanotic Melanoma in Transgenic Tyr-RAS+ Ink4a/Arf-/- Mice Arch Ophthalmol, August 1, 2005; 123(8): 1088 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Puig, J. Malvehy, C. Badenas, A. Ruiz, D. Jimenez, F. Cuellar, A. Azon, U. Gonzalez, T. Castel, A. Campoy, et al. Role of the CDKN2A Locus in Patients With Multiple Primary Melanomas J. Clin. Oncol., May 1, 2005; 23(13): 3043 - 3051. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Lens and J. A. Newton-Bishop An association between cutaneous melanoma and non-Hodgkin's lymphoma: pooled analysis of published data with a review Ann. Onc., March 1, 2005; 16(3): 460 - 465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Ghiorzo, L. Pastorino, L. Bonelli, R. Cusano, A. Nicora, S. Zupo, P. Queirolo, M. Sertoli, V. Pugliese, and G. Bianchi-Scarra INK4/ARF germline alterations in pancreatic cancer patients Ann. Onc., January 1, 2004; 15(1): 70 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A H Prowse, D C Schultz, S Guo, L Vanderveer, J Dangel, B Bove, P Cairns, M Daly, and A K Godwin Identification of a splice acceptor site mutation in p16INK4A/p14ARF within a breast cancer, melanoma, neurofibroma prone kindred J. Med. Genet., August 1, 2003; 40(8): e102 - 102. [Full Text] [PDF]
|
|
|
|
|
|
K. Laud, C. Kannengiesser, M.-F. Avril, A. Chompret, D. Stoppa-Lyonnet, L. Desjardins, A. Eychene, F. Demenais, French Hereditary Melanoma Study Group, G. M. Lenoir, et al. BRAF as a Melanoma Susceptibility Candidate Gene? Cancer Res., June 15, 2003; 63(12): 3061 - 3065. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Rizos, E. Diefenbach, P. Badhwar, S. Woodruff, T. M. Becker, R. J. Rooney, and R. F. Kefford Association of p14ARF with the p120E4F Transcriptional Repressor Enhances Cell Cycle Inhibition J. Biol. Chem., February 7, 2003; 278(7): 4981 - 4989. [Abstract] [Full Text] [PDF]
|
|