TY - JOUR
TI - Genomic instability, mutations and expression analysis of the tumour
suppressor genes p14(ARF), p15(INK4b), p16(INK4a) and p53 in actinic
keratosis
AU - Kanellou, P.
AU - Zaravinos, A.
AU - Zioga, M.
AU - Stratigos, A. and
AU - Baritaki, S.
AU - Soufla, G.
AU - Zoras, O.
AU - Spandidos, D. A.
JO - Cancer Letter
PY - 2008
VL - 264
TODO - 1
SP - 145-161
PB - Elsevier Ireland Ltd
SN - null
TODO - 10.1016/j.canlet.2008.01.042
TODO - actinic keratosis; CDKN2A; CDKN2B; mRNA expression; MSI/LOH; mutations
TODO - Actinic keratosis (AK) is a well-established pre-cancerous skin lesion
that has the potential to progress to squamous cell carcinoma (SCC). We
investigated the involvement of the CDKN2A, CDKN2B and p53 genes in AK
and in the progression of AK to SCC. Mutational analysis on exons 1a, 1b
and 2 of the CDKN2A locus and exon I of the CDKN2B locus as well as
allelic imbalance was performed in 26 AK specimens. Expression levels of
the genes p14(ARF), p15(INK4b), p16(INK4a) and p53 were examined in 16
AKs and 12 SCCs by real-time RT-PCR. A previously described polymorphism
of p16(INK4a) (Ala148Thr) was detected at an allelic frequency of 12%.
Six samples carried novel mutations at codon 71 of the CDKN2A locus and
one sample presented an additional mutation at codon 65. Two AK samples
carried a not-previously described non-UV type missense mutation at
codon 184 (Val184Glu) of exon 1b in the p14(ARF) gene. Regarding the
CDKN2B locus a new mutation at codon 50 (Ala50Thr) and another at codon
24 (Arg24Arg), were detected. Microsatellite instability (MSI) was found
in 15% of AKs in at least one marker, indicating that genetic
instability has some implication in the development of AK.
Down-regulation of p16(INK4a) and p53 mRNA levels was noted in SCC
compared to AK. TSGs expression levels in sun-exposed morphologically
normal-appearing skin, suggests that abnormal growth stimuli might exist
in these tissues as well. Furthermore, we suggest a possible role of
p15(INK4b), independently from the intracellular pathway mediated by
p16(INK4a), and of p14(ARF) in AK development, as well as in the
progression of AK to SCC. The deregulation of the expression profiles of
the CDKN2A, CDKN2B and p53 genes may, independently of mutations and LOH
at 9p21, play a significant role in AK and progression of AK to SCC. (C)
2008 Elsevier Ireland Ltd. All rights reserved.
ER -