FoxO3a gene is a target of deletion in mouse lung adenocarcinoma

Lung adenocarcinomas (LAC) of smokers and never-smokers differ from one another in epidemiology, and clinical and molecular characteristics. The pathogenetic differences between these tumors are potential biomarkers and therapeutic targets. Mouse carcinogenesis models of human LAC are proven tools applicable for the identification of these molecular changes. Allelic loss frequency on human chromosome 6q is higher in LAC of smokers compared with never smokers. We analyzed the orthologous region on mouse chromosome 10 and found this region similarly was a more frequent site of allelic loss in carcinogen-induced LAC compared with non-induced or spontaneous LAC. We then conducted high resolution quantitative PCR-based deletion mapping of this region and identified the FoxO3a gene as the focus of bi-allelic or homozygous deletion (HD). HDs were detected in 5 out of 15 (33.3%) LAC cell lines and in 6 out of 75 (8%) carcinogen-induced primary LAC. FoxO3a was exclusively affected by HD in 7 of the samples examined, as loss of both alleles did extend to the nearest flanking genes of FoxO3a. Deletion of FoxO3a, either by HD or subclonal loss was detected in 38 out of 75 (50.7%) of carcinogen-induced LAC in contrast to only 1 out of 10 (10%) of LAC of untreated mice. Several of the samples also were subjected to direct sequence analysis; however, no intragenic mutations were detected. These results implicate FoxO3a as a selective target of deletion in mouse LAC. Significant association with carcinogenic induction suggests that deletion of FoxO3a contributes to the development of carcinogen-initiated tumors.