Carcinogen‐induced amplification of SV40 DNA inserted at 9q12‐21.1 associated with chromosome breakage, deletions, and translocations in human uroepithelial cell transformation in vitro

Chinghai Kao, Shi‐Qi ‐Q Wu, Sandy Devries, William S. Reznikoff, Frederic M. Waldman, Catherine A. Reznikoff

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Abstract

The fate of integrated SV40 viral genome in SV40‐immortalized human uroepithelial cells (SV‐HUC) during multistep chemical transformation in vitro was studied. We previously reported that exposure of SV‐HUC at passage (P) 15 to the chemical carcinogens 3‐methylcholanthrene (MCA), 4‐aminobiphenyl (ABP), or the N‐hydroxy metabolites of ABP causes tumorigenic transformation and/or neoplastic progression. We report now that these same chemical carcinogens induce amplification of SV40 DNA in SV‐HUC. We used fluorescence in situ hybridization (FISH) to show that this amplification occurs at the SV40 integration site, which was mapped near a common fragile site at 9q12‐21.1 on the der(9)t(8;9) chromosome that is present in all SV‐HUC at the earliest passage studied. Karyotypic analysis, along with FISH, also revealed that all carcinogen‐induced tumors (T‐SV‐HUCs) had breaks at 9q12‐21.1, deletions of 9q12‐21.1→pter, and new derivative chromosomes containing SV40 in the segment 9q12‐21.1→9q34::8q22→8qter. Southern blot analysis, along with FISH, confirmed SV40 genome rearrangements in T‐SV‐HUCs. In contrast, no 9q12‐21.1 breaks were observed in control SV‐HUC. Thus, these results associate 9q 12‐21.1→pter alterations with HUC tumorigenic transformation. In addition, these results indicate for the first time that (carcinogen‐induced) amplification of chromosome‐integrated viral genes may create sites that are prone to breakage, deletions, and translocations. These results suggest a new mechanism by which chemical carcinogens in synergy with a DNA tumor virus could initiate a cascade of events that contribute to the genomic instability associated with tumorigenesis. © 1993 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)155-166
Number of pages12
JournalGenes, Chromosomes and Cancer
Volume8
Issue number3
DOIs
StatePublished - Nov 1993

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ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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