Telomerase reactivation is a critical event during neoplastic transformation and occurs in most human cancers. Through a combination of genetic and gene expression analyses, we identified a small region on chromosome 3p21 that is lost at 82% in lung adenocarcinomas from patients who were diagnosed at ages before 50 but only lost in 30% tumors of patients who were diagnosed at age 80 or later. This region overlaps with a previously reported telomerase suppressor locus in renal cell carcinoma cells carrying a wild type chromosome 3. Based on gene expression, we identified a novel gene, LELA1 (loss in early age lung adenocarcinoma), that is inactivated in 70% of primary lung cancers and lung cancer cell lines via methylation at the CpG island 5 of the gene. Functionally, increased expression of LELA1 either by exogenous expression or reactivation after 5-azacytosine treatment reduced hTERT message levels in lung cancer cell lines. Genetically, we identified six unique somatic and germline changes among 19 early age onset patients but none in patients who had cancer at later ages . Our results suggest that loss of LELA1 contributes to early lung cancer onset through hTERT dysregulation.
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