DNA double-strand breaks (DSBs) are the most deleterious lesion inflicted by 
ionizing radiation. Although DSBs are potentially carcinogenic, it is not clear 
whether complex DSBs that are refractory to repair are more potently tumorigenic 
compared with simple breaks that can be rapidly repaired, correctly or 
incorrectly, by mammalian cells. We previously demonstrated that complex DSBs 
induced by high-linear energy transfer (LET) Fe ions are repaired slowly and 
incompletely, whereas those induced by low-LET gamma rays are repaired 
efficiently by mammalian cells. To determine whether Fe-induced DSBs are more 
potently tumorigenic than gamma ray-induced breaks, we irradiated 'sensitized' 
murine astrocytes that were deficient in Ink4a and Arf tumor suppressors and 
injected the surviving cells subcutaneously into nude mice. Using this model 
system, we find that Fe ions are potently tumorigenic, generating tumors with 
significantly higher frequency and shorter latency compared with tumors 
generated by gamma rays. Tumor formation by Fe-irradiated cells is accompanied 
by rampant genomic instability and multiple genomic changes, the most 
interesting of which is loss of the p15/Ink4b tumor suppressor due to deletion 
of a chromosomal region harboring the CDKN2A and CDKN2B loci. The additional 
loss of p15/Ink4b in tumors derived from cells that are already deficient in 
p16/Ink4a bolsters the hypothesis that p15 plays an important role in tumor 
suppression, especially in the absence of p16. Indeed, we find that reexpression 
of p15 in tumor-derived cells significantly attenuates the tumorigenic potential 
of these cells, indicating that p15 loss may be a critical event in 
tumorigenesis triggered by complex DSBs.