Association between INK4a-ARF and p53 mutations in skin carcinomas of xeroderma pigmentosum patients.
BACKGROUND
The INK4a-ARF locus encodes two tumor suppressor proteins, p16(INK4a) and p14(ARF), that act through the Rb-CDK4 and p53 pathways, respectively. Data from murine models and sporadic human skin carcinomas implicate p16(INK4a) and p14(ARF) in the development of skin carcinomas. We examined the frequency of INK4a-ARF, p53, and CDK4 mutations in skin carcinomas from patients with xeroderma pigmentosum (XP), a rare autosomal disease that is associated with a defect in DNA repair and that predisposes patients to skin cancer.


METHODS
DNA from skin cancers of 28 unrelated XP patients was screened for mutations in p53, INK4a-ARF, and CDK4 coding exons by single-strand conformation polymorphism analysis and automated sequencing. Data were evaluated with the use of the exact unconditional test derived from Fisher's test. All statistical tests were two-sided.


RESULTS
Eight of 28 XP-associated tumors had mutations in the INK4a-ARF locus. Three XP-associated tumors had multiple mutations at this locus. In all, 13 mutations in the INK4a-ARF locus were detected in XP-associated tumors, of which seven (54%) were signature UV radiation-induced mutations, i.e., tandem CC : GG-->TT : AA transitions. p53 mutations, mostly of the type induced by UV radiation, were present in 12 tumors (43%). Statistically significant positive associations were found between the frequency of mutations in p53 and in p16(INK4a) (P =.008) and between the frequency of mutations in p53 and in p14(ARF) (P<.001). No mutations were detected within the CDK4 gene.


CONCLUSIONS
We have demonstrated for the first time the occurrence of UV radiation-induced mutations in INK4a-ARF in XP-associated skin carcinomas. The simultaneous inactivation of p53 and INK4a-ARF may be linked to the genetic instability caused by XP and could be advantageous for tumor progression.
Soufir
N
N
Institut de Recherche sur la Peau, Institut National de la Santé et de la Recherche Medicale [INSERM] U532), P. de La Salmonière, Hôpital Saint-Louis, Paris, France.
Daya-Grosjean
L
L
de La Salmonière P
Moles
J P
JP
Dubertret
L
L
Sarasin
A
A
Basset-Seguin
N
N
D000352:Africa, Northern / Q000208:ethnology; D002277:Carcinoma / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004249:DNA Damage / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF; D014466:Ultraviolet Rays / Q000009:adverse effects; D044465:White People / Q000235:genetics*; D014983:Xeroderma Pigmentosum / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF; D018844:Cyclin-Dependent Kinases