Future studies will require follow up work to determine whether the changes in mRNA level are reflective of NFkB protein levels. Similarly, while changes in global and repeat element DNA methylation were observed, there was a lack of consensus among the four unstable clones. However, the common LINE-1 DNA BI-D1870 hypermethylation observed for the CS9 and LS12 clones and the common Alu element DNA hypomethylation observed for the 115 and Fe5.0–8 emerged as the first evidence of a compelling story. While it is possible that our data are merely correlative, the persistence of these unique groupings among the clones is also quite clear at the level of mRNA and miR expression. We have only evaluated one clonally expanded single cell survivor of high LET irradiation so no conclusions can be drawn, but some observations might be made. The Fe5.0–8 cell line was exposed to 5 Gy of Fe ions as compared to 10 Gy of X-rays for the other clones. This might lead one to expect differences in phenotype based on radiation quality. However, the types of epigenetic and genetic changes that we observed for the Fe clone. High LET radiation exposure causes a different spectrum of DNA damage and generally has a higher relative biological effectiveness for cell killing than low LET irradiation. In the original study that generated the Fe5.0–8 cell line Limoli and colleagues reported that the RBE of Fe ions for cell killing was 2, while the RBE for inducing chromosomal instability was only 1.3. For this reason, the Fe5.0–8 cell line may have differences in endogenous DNA damage without differences in other aspects of their phenotype or genomic instability. The results of this study also reinforce the role of oxidative stress and mitochondrial function in the radiation response and genomic instability. Oxidative stress has been clearly shown to persist in these chromosomally unstable cell lines. In the current paper KEGG pathway analyses were performed based on the three different clone groups, CS9-LS12, 115-Fe5.0-8, and 114-118. These analyses demonstrate significant enrichment of pathways related to oxidative stress, mitochondria and cellular metabolism. While the CS9 and LS12 clones showed the fewest common mRNA changes as a pair, these are probably the two best characterized clones with respect to documentation of persistent oxidative stress and mitochondrial dysfunction. When evaluated independently in a separate proteomics study the LS12 clone had significant enrichment for electron transport chain and cellular redox homeostasis pathway proteins, and some of those genes were shown to be under epigenetic regulation by miR. If the enrichment of the mRNA for similar mitochondrial genes, and oxidative stress and cellular metabolism pathways identified in our current study also translate into altered protein levels and activities, then they are likely to represent deficiencies as well as compensatory strategies.