Carcinogen-specific induction of genetic instability
A Bardelli1, D P Cahill, G Lederer
1The Johns Hopkins Oncology Center, Howard Hughes Medical Institute, and Graduate Program in Human Genetics and Molecular Biology, 1650 Orleans Street, Baltimore, MD 21231, USA.
Summary
Specific carcinogens select for distinct cancer genetic instabilities. Cells resistant to the bulky-adduct agent PhIP showed chromosomal instability (CIN), while those resistant to the methylating agent MNNG showed microsatellite instability (MIN).
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Cancer cells exhibit various forms of genetic instability.
- The relationship between carcinogen exposure and specific instability types is under investigation.
Purpose of the Study:
- To test the hypothesis that carcinogen exposure selects for distinct genetic instability phenotypes in cancer cells.
- To investigate the reciprocal relationship between carcinogen resistance and genetic instability.
Main Methods:
- Treatment of immortal human cells with representative carcinogens: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).
- Assessment of genetic instability types: chromosomal instability (CIN) and microsatellite instability (MIN) associated with mismatch repair defects.
- Experimental induction of CIN and MIN phenotypes to test for carcinogen resistance.
Main Results:
- Cells resistant to PhIP (bulky-adduct agent) developed CIN.
- Cells resistant to MNNG (methylating agent) developed MIN.
- Induced CIN cells showed resistance to PhIP, and induced MIN cells showed resistance to MNNG.
Conclusions:
- Specific carcinogens can select for tumor cells with distinct genetic instability profiles.
- The type of genetic instability in cancer cells can reflect the selective pressures of specific carcinogens.
- A reciprocal relationship exists between carcinogen exposure and the development of specific genetic instabilities.
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