|
Genetic alterations
in p16INK4a and p14ARF genes in
human non melanoma skin cancer.
Pacifico, Alessia1,3,
Ouhtit, Allal1, Goldberg, Leonard2,
Bolshakov, Svetlana1, Peris, Ketty3,
Chimenti, Sergio4 and Ananthaswamy, Honnavara1
M.D. Anderson Cancer Center, Houston, Texas1
DermSurgery Associates, P.A., Houston, Texas2
University of l'Aquila, l'Aquila, Italy3
University of Tor Vergata, Rome, Italy4
Abstract-
The INK-ARF locus on human chromosome 9p21 encodes two proteins, p16
and p14, known to function as tumor suppressors via the retinoblastoma
or the p53 pathway. Genetic abnormalities in p16INK4a
and p14ARF genes have been well documented in human
melanoma, but their involvement in non-melanoma skin cancer (NMSC) is
less clear. To determine whether human NMSC exhibit genetic abnormalities
in p16INK4a and/or p14ARF genes,
we analyzed 40 NMSC (21 primary human squamous cell carcinomas, 17 basal
cell carcinomas and 2 actinic keratoses) for deletions in p16INK4a and/or
p14ARF genes by PCR. The results indicated that about 85% of tumors
had deletions in exon 2 of the p16INK4a gene. In addition,
methylation-specific PCR experiments revealed that about 45% of the
tumors had hypermethylation in the p16INK4a and p14ARF
promoter regions. Immunohistochemical analysis revealed loss of expression
of p16 and p14 proteins in 97% of NMSC. As expected, about 80% of human
NMSC analyzed contained UV signature mutations in the p53 gene and almost
all of them were strongly positive for p53 immunostaining. These results
indicate that in addition to mutations in the p53 gene, loss of expression
of p16INK4a and p14ARF genes via
deletion and promoter hypermethylation also plays an important role
in the pathogenesis of human NMSC.
Keywords: deletion,
hypermethylation
|
