Genetic analysis in early age of onset lung cancer patients

端粒酶重新激活是肿瘤转化过程中的一个关键事件，在大多数人类癌症中都会发生。通过结合遗传和基因表达分析，我们发现了3p21染色体上的一个小区域，该区域在50岁之前确诊的肺腺癌患者中丢失了82%，但在80岁或更晚确诊的患者中只有30%的肿瘤丢失。这一区域与先前报道的携带野生型3号染色体的肾癌细胞中的端粒酶抑制基因重叠。基于基因表达，我们发现了一个新的基因LELA1(Lost In Lead Are Al Adamoma)，该基因在70%的原发肺癌和肺癌细胞系中通过该基因CpG岛5的甲基化而失活。在功能上，通过外源表达或5-氮胞嘧啶处理后重新激活的LELA1的表达增加，降低了肺癌细胞系中hTERT的信息水平。在遗传学上，我们在19名早发性患者中发现了6种独特的体细胞和生殖系变化，但在晚年患癌症的患者中没有发现。我们的结果表明，LELA1的缺失可能通过hTERT调节失调导致早期肺癌的发生。

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.