Populations of p53 codon 270 CGT to TGT mutant cells in SKH-1 mouse skin tumors induced by simulated solar light.
The p53 codon 270 CGT to TGT mutation was investigated as a biomarker of sunlight-induced mutagenesis and carcinogenesis. The relationship between tumor development and abundance of this hotspot mutation was analyzed in mouse skin tumors induced by chronic exposure to simulated solar light (SSL). The 24 tumors analyzed had similar growth kinetics, with an average doubling time of approximately 16.4 d. Levels of the p53 codon 270 mutation were quantified in the 24 mouse skin tumors using allele-specific competitive blocker-polymerase chain reaction (ACB-PCR). All tumors contained measurable amounts of the mutation. The p53 codon 270 CGT to TGT mutant fraction (MF) ranged from 2.29 x 10(-3) to 9.42 x 10(-2), with 3.26 x 10(-2) as the median. These p53 MF measurements are lower than expected for an initiating mutation involved in the development of tumors of monoclonal origin. There was no evidence of a correlation between p53 codon 270 MF and either tumor area or an estimate of tumor cell number. Thus, the data do not support the idea that p53 mutation accumulates linearly during tumor development. To investigate how p53 mutation was distributed within tumors, 19 needle biopsies from seven different tumors were analyzed by ACB-PCR. This analysis demonstrated that p53 codon 270 mutation is heterogeneously distributed within tumors. The long-term goal of this research is to combine morphological and p53 MF measurements from tissues corresponding to the various stages of tumor development, in order to derive mathematical models relating the p53 codon 270 mutation to the development of SSL-induced skin tumors.
Verkler
Tracie L
TL
Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, USFDA, Jefferson, Arkansas 72079, USA.
Delongchamp
Robert R
RR
Couch
Letha H
LH
Miller
Barbara J
BJ
Warbritton
Alan
A
Mellick
Paul W
PW
Howard
Paul C
PC
Parsons
Barbara L
BL
D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D003062:Codon / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D013472:Sunlight; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D003062:Codon; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53