The M53I Mutation in CDKN2A Is a Founder Mutation That Predominates in Melanoma Patients with Scottish Ancestry Julie Lang, 1,2 * Nicholas Hayward, 3 David Goldgar, 4 Hensin Tsao, 5 David Hogg, 6 Jane Palmer, 3 Mitchell Stark, 3 Edward S. Tobias, 1,2 and Rona MacKie 1,2,7 1 Duncan Guthrie Institute,Glasgow,UK 2 University of Glasgow,Glasgow,UK 3 Queensland Institute of Medical Research, P.O.Royal Brisbane Hospital, Herston,Qld, Australia 4 Department of Dermatology,University of Utah, Salt Lake City,UT 5 Department of Dermatology, Massachusetts General Hospital,Boston, MA 6 Departments of Medicine and Medical Biophysics, Medical Sciences Building,University of Toronto,Toronto,Ont,Canada 7 Department of Public Health,University of Glasgow,Glasgow,UK Germline mutations in the tumor suppressor gene CDKN2A have been shown to predispose to cutaneous malignant mela- noma. The M53I mutation is the most common CDKN2A mutation identified in Scottish melanoma patients and is also found in a small number of families in other countries. The aim of this study was to determine whether the occurrence of this mutation is due to a common ancestor originating from Scotland, and if so, to estimate how long ago the mutation arose. We examined 18 families carrying the M53I mutation: six from Scotland, five from Canada, four from Australia, and three from America. Hap- lotypes derived from segregation of seven informative microsatellite markers flanking CDKN2A were constructed in each fam- ily. Our findings show that 14 of 18 families carry a common ancestral haplotype on which the mutation arose *88 genera- tions ago (1-LOD-unit support interval 44-198 generations). This haplotype is very rare in controls, which supports the idea that it is a common founder mutation haplotype. The four M53I families that do not share the consensus haplotype may in fact have arisen from the same founder, but this is potentially obscured by presumed replication slippage for some of the microsa- tellite markers tested. V V C 2006 Wiley-Liss, Inc. INTRODUCTION The majority of cutaneous melanomas are spo- radic, but up to 10% of melanoma patients have one or more first-degree relatives also affected (MIM no. 155,600). Genetic analysis of these mela- noma families demonstrates germline mutations of CDKN2A (MIM no. 600,160) (Kamb et al., 1994; Nobori et al., 1994) in 20–30% of patients (Hussus- sian et al., 1994; Dracopoli and Fountain, 1996; Zuo et al., 1996; Harland et al., 1997). The CDKN2A locus is unique in the genome, because it encodes two overlapping tumor suppressor genes, CDKN2A and the alternative reading frame ARF . These genes encode two distinct cell cycle regula- tory proteins, P16INK4A and P14ARF. Both of these proteins have a crucial role in cell cycle con- trol and apoptosis via the retinoblastoma pathway for P16INK4A and the TP53 pathway for P14ARF. The P16INK4A protein acts as a tumor suppressor and a cell-cycle regulator that induces G1 cell- cycle arrest by binding to and inhibiting the kinase activities of the CDK4/cyclin D and CDK6/cyclin D complexes. When CDK4 and cyclin D are active in this complex, they initiate the phosphorylation of the retinoblastoma protein, thereby permitting cells to enter the DNA replication stage in the S- phase of the cell cycle. P14ARF is also a tumor suppressor protein but acts through a different pathway from P16INK4A by arresting the cell cycle in a TP53-dependent manner. P14ARF is involved in the stabilization and accumulation of TP53 by binding to MDM2, which promotes the rapid degradation of MDM2 (Zhang et al., 1998). A variety of germline mutations within the cod- ing sequence of CDKN2A have now been observed in affected members of more than 100 malignant melanoma families worldwide. The international *Correspondence to: Dr. Julie Lang, Duncan Guthrie Institute of Medical Genetics, Royal Hospital for Sick Children and University of Glasgow, Glasgow G3 8SJ, UK. E-mail: j.lang@clinmed.gla.ac.uk Supported by: Shaw Melanoma Trust, Leverhulme Trust, the Australian National Health and Medical Research Council, and GlaxoSmithKline. Received 12 July 2006; Accepted 9 November 2006 DOI 10.1002/gcc.20410 Published online 14 December 2006 in Wiley InterScience (www.interscience.wiley.com). V V C 2006 Wiley-Liss, Inc. GENES, CHROMOSOMES & CANCER 46:277–287 (2007)