Association between INK4a-ARF and p53 mutations in skin carcinomas of xeroderma pigmentosum patients. 
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.  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.  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.  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.