A mutation hotspot at the p14ARF splice site.
Germline mutations of CDKN2A that affect the p16INK4a transcript have been identified in numerous melanoma pedigrees worldwide. In the UK, over 50% of pedigrees with three or more cases of melanoma have been found to carry mutations of CDKN2A. Mutations that affect p14ARF exon 1beta exclusively are very rare. This has led to the suggestion that it is p16INK4a and not p14ARF that plays the critical role in melanoma predisposition. We report the identification of a cluster of five different germline mutations at the p14ARF exon 1beta splice donor site in melanoma pedigrees. All the five splice site variants showed evidence of being causal mutations. Three of the variants were demonstrated to result in aberrant splicing of the p14ARF mRNA, confirming their role in melanoma predisposition. No other point mutations were identified in the coding region of p14ARF. The p14ARF transcript of CDKN2A is clearly important in disease predisposition in a subset of melanoma pedigrees. Curiously, the only mutations so far reported to affect p14ARF exon 1beta exclusively have been knockout mutations. Further investigation into the spectrum of mutations observed in this gene may help clarify the exact role of p14ARF in melanoma predisposition.
Harland
Mark
M
Genetic Epidemiology Division, Cancer Research UK Clinical Centre, St James's University Hospital, Beckett Street, Leeds LS9 7TF, England.
Taylor
Claire F
CF
Chambers
Philip A
PA
Kukalizch
Kairen
K
Randerson-Moor
Juliette A
JA
Gruis
Nelleke A
NA
de Snoo
Femke A
FA
ter Huurne
Jeanet A C
JA
Goldstein
Alisa M
AM
Tucker
Margaret A
MA
Bishop
D Timothy
DT
Bishop
Julia A Newton
JA
D005091:Exons; D020022:Genetic Predisposition to Disease; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D022821:RNA Splice Sites; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
D022821:RNA Splice Sites; D025803:Tumor Suppressor Protein p14ARF