N. Soufir et al., Association between INK4a-ARF and p53 mutations in skin carcinomas of xeroderma pigmentosum patients, J NAT CANC, 92(22), 2000, pp. 1841-1847
Background: The INK4a-ARF locus encodes two tumor suppressor proteins, p(16
INK4a) and p14(ARF), that act through the Rb-CDK4 and p53 pathways, respect
ively. Data from murine models and sporadic human skin carcinomas implicate
p16(INK4a) and p(14ARF) in the development of skin carcinomas. We examined
the frequency of INK4a-ARF, p53, and CDK4 mutations in skin carcinomas fro
m patients with xeroderma pigmentosum (XP), a rare autosomal disease that i
s associated with a defect in DNA repair and that predisposes patients to s
kin 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-s
trand conformation polymorphism analysis and automated sequencing. Data wer
e evaluated with the use of the exact unconditional test derived from Fishe
r's test. All statistical tests were two-sided. Results: Eight of 28 XP-ass
ociated tumors had mutations in the INK4a-ARF locus. Three XP-associated tu
mors had multiple mutations at this locus. In all, 13 mutations in the INK4
a-ARF locus were detected in XP-associated tumors, of which seven (54%) wer
e signature UV radiation-induced mutations, i.e., tandem CC:GG-->TT:AA tran
sitions. p53 mutations, mostly of the type induced by UV radiation, were pr
esent in 12 tumors (43%), Statistically significant positive associations w
ere found between the frequency of mutations in p53 and in p16(INK4a) (P =
.008) and between the frequency of mutations in p53 and in p(14ARF) (P<.001
). No mutations were detected within the CDK4 gene. Conclusions: We have de
monstrated for the first time the occurrence of UV radiation-induced mutati
ons in INK4a-ARF in XP-associated skin carcinomas. The simultaneous inactiv
ation of p53 and INK4a-ARF may be linked to the genetic instability caused
by XP and could be advantageous for tumor progression.