Fhit loss in lung preneoplasia: Relation to DNA damage response checkpoint activation

Abstract 

Loss of heterozygosity at the FHIT locus is coincident with activation of DNA damage response checkpoint proteins; thus damage at fragile loci may trigger checkpoint activation. We examined preneoplastic lesions adjacent to non-small cell lung carcinomas for alterations to expression of Fhit and activated checkpoint proteins. Expression scores were analyzed for pair-wise associations and correlations among proteins and type of lesion. Hyperplastic and dysplastic lesions were positive for nuclear γH2AX expression; 12/20 dysplastic lesions were negative for Fhit expression. Fhit positive lesions showed expression of most checkpoint proteins examined, while Fhit negative lesions showed absence of expression of Chk1 and phosphoChk1. The results show that loss of expression of Fhit is significantly directly correlated with absence of activated Chk1 in dysplasia, and suggest a connection between loss of Fhit and modulation of checkpoint activity.

Abbreviations: Fhit, fragile histidine triad protein, Wwox, WW-domain and oxidoreductase containing protein, γH2AX, gamma histone 2AX, ATM, ataxia telangiectasia gene, ATR, ataxia telangiectasia related gene, Chk1/2, checkpoint kinase proteins 1 and 2, 53BP1, p53 binding protein 1, NSCLC, non-small cell lung cancer, AAH, atypical adenomatous hyperplasia, DSBs, double-strand breaks, FISH, fluorescent in situ hybridization, LOH, loss of heterozygosity

Keywords: Fhit, Preneoplastic lesions of lung, DNA damage response checkpoint, Chromosome fragile sites, Squamous dysplasia