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

J Natl Cancer Inst. 2000 Nov 15;92(22):1841-7. doi: 10.1093/jnci/92.22.1841.

Abstract

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.

MeSH terms

  • Africa, Northern / ethnology
  • Carcinoma / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • DNA Damage / radiation effects
  • DNA, Neoplasm / genetics*
  • Genes, Tumor Suppressor / genetics
  • Genes, p53 / genetics*
  • Humans
  • Mutation*
  • Polymorphism, Single-Stranded Conformational
  • Proteins / genetics*
  • Sequence Analysis, DNA
  • Skin Neoplasms / genetics*
  • Tumor Suppressor Protein p14ARF
  • Ultraviolet Rays / adverse effects
  • Whites / genetics*
  • Xeroderma Pigmentosum / genetics*

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA, Neoplasm
  • Proteins
  • Tumor Suppressor Protein p14ARF
  • Cyclin-Dependent Kinases