Low prevalence of p53, p16(INK4a) and Ha-ras tumour-specific mutations in low-graded actinic keratosis.
BACKGROUND
Ultraviolet radiation induces DNA damage and is the major risk factor for the development of non-melanoma skin cancer (NMSC). Different mutation rates of p53, p16(INK4a) and Ha-ras in cutaneous squamous cell carcinoma (SCC) and the earlier stage actinic keratosis (AK) have been reported.


OBJECTIVE
To assess the presence of missense mutations in hotspot exons of p53, p16(INK4a) and Ha-ras in low-graded AK.


METHODS
Cryo-biopsies of 75 sun-exposed AK lesions and 75 sun-shielded areas of normal skin from 75 AK patients were analysed to identify mutations in p53 (exons 7 and 8), p16(INK4a) (exon 2) and Ha-ras (exon 1) using polymerase chain reaction (PCR) followed by direct sequencing. As a representative subset of the specimens, ten mutation-negative AK were also micro-dissected in order to exclude the possibility that additional mutations were undetected.


RESULTS
Eight missense and one nonsense point mutations were found in the 75 AK lesions examined (12%), of which seven (9%) were tumour-specific (i.e. present in AK lesions only) and two (3%) were p16(INK4a) mutations (i.e. also detected in normal skin). Three of the tumour-specific mutations (42%) were cytosine (C) to thymine (T) transitions at pyrimidine-rich sequences. Tumour-specific mutations were identified in 1% of p16(INK4a) (exon 2), 1% of Ha-ras (exon 1) and at a higher rate of 7% in p53 (exons 7 and 8), including one nonsense mutation.


CONCLUSIONS
The evaluation of a large number of AK specimens in this study have found a low gene mutation rate in low-graded AK lesions. p53 mutations rather than p16(INK4a) and/or Ha-ras mutations may be an early event in the development of AK to cutaneous SCC.
Nindl
I
I
Department of Dermatology, Charité, Skin Cancer Center Charité, University Hospital of Berlin, Berlin, Germany. ingo.nindl@charite.de
Gottschling
M
M
Krawtchenko
N
N
Lehmann
M D
MD
Röwert-Huber
J
J
Eberle
J
J
Stockfleth
E
E
Forschner
T
T
D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007642:Keratosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017354:Point Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16