Specific Allelic Loss of p16 INK4A Tumor Suppressor Gene after Weeks of Iron-Mediated Oxidative Damage during Rat Renal Carcinogenesis

• Published in: The American journal of pathology Vol. 160; no. 2; pp. 419 - 424
• Main Authors: Hiroyasu, Makoto, Ozeki, Munetaka, Kohda, Haruyasu, Echizenya, Michiko, Tanaka, Tomoyuki, Hiai, Hiroshi, Toyokuni, Shinya
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-02-2002; ASIP; American Society for Investigative Pathology
• Subjects: Short Communications
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)64860-2

Oxidative tissue damage has been shown to be associated with carcinogenesis. In human cancers
p16
INK4A
is one of the most frequently mutated tumor suppressor genes. The present study used the ferric nitrilotriacetate (Fe-NTA)-induced rat renal carcinogenesis model to determine whether oxidative damage can cause specific allelic loss of
p16
INK4A
. By the use of fluorescent
in situ hybridization in combination with imprint cytology at single-cell resolution, we found that the number of renal tubular cells with aneuploidy (1 or 3 signals) at the
p16
INK4A
locus was significantly and specifically increased (1 week, 37.2 ± 2.3%; 3 weeks, 37.8 ± 1.3%
vs control, 22.5 ± 1.9%; mean ± SE,
N = 8;
P < 0.001 and
P < 0.0001, respectively) after repeated intraperitoneal administration of 5 to10 mg of iron/kg in the form of Fe-NTA for 3 weeks. No increase in aneuploidy was observed at the loci of either the
p53 or
vhl tumor suppressor gene. Furthermore, the increase in the cells with 3 signals was followed by a continuous increase in those with 1 signal. Therefore, the
p16
INK4A
locus is specifically vulnerable to oxidative damage, leading to its allelic loss within weeks, presumably due to a deficiency in the replication of both the alleles.