Identification of Las2, a major modifier gene affecting the Pas1 mouse lung tumor susceptibility locus.
Identification of Las2, a major modifier gene affecting the Pas1 mouse lung tumor susceptibility locus.
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DOI：
10.1158/0008-5472.can-09-0782
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发表时间：
2009-08
期刊：
影响因子：
11.2
通讯作者：
Pengyuan Liu;H. Vikis;Michael R. James;Yan Lu;Dao-long Wang;Hongbo Liu;Weidong Wen;Yian Wang;M. You
中科院分区：
文献类型：
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作者：
Pengyuan Liu;H. Vikis;Michael R. James;Yan Lu;Dao-long Wang;Hongbo Liu;Weidong Wen;Yian Wang;M. You
肺癌是全球癌症死亡的主要原因。在这里，我们描述了一个全基因组的关联研究化学诱导的肺肿瘤的593只小鼠从21个近交系使用115,904基因型和1,952,918插补单核苷酸多态性（SNP）。使用遗传背景控制的基因组搜索，我们确定了一个新的肺肿瘤易感基因Las 2（肺腺瘤易感性2）远端染色体18。Las 2与肿瘤诱导抗性（rs30245983; P = 1.87 x 10（-9））以及与肺腺瘤易感性1基因座的上位相互作用（P = 1.71 x 10（-3））密切相关，肺腺瘤易感性1基因座是影响小鼠肺肿瘤发展的主要基因座（rs 13459098，P = 5.64 x 10（-27））。测序分析显示4个非同义SNP和2个插入/缺失的易感等位基因的Las 2，导致在细胞集落形成和裸鼠致瘤性测定的肿瘤抑制活性的损失。在大约40%的人肺腺癌中观察到LAS 2的缺失，这意味着LAS 2功能的丧失可能是肺肿瘤发生的关键步骤。
Lung cancer is the leading cause of cancer death worldwide. Here, we describe a genome-wide association study of chemically induced lung tumorigenesis on 593 mice from 21 inbred strains using 115,904 genotyped and 1,952,918 imputed single nucleotide polymorphisms (SNPs). Using a genetic background-controlled genome search, we identified a novel lung tumor susceptibility gene Las2 (Lung adenoma susceptibility 2) on distal chromosome 18. Las2 showed strong association with resistance to tumor induction (rs30245983; P = 1.87 x 10(-9)) as well as epistatic interactions (P = 1.71 x 10(-3)) with the pulmonary adenoma susceptibility 1 locus, a major locus affecting mouse lung tumor development (rs13459098, P = 5.64 x 10(-27)). Sequencing analysis revealed four nonsynonymous SNPs and two insertions/deletions in the susceptible allele of Las2, resulting in the loss of tumor suppressor activities in both cell colony formation and nude mouse tumorigenicity assays. Deletion of LAS2 was observed in approximately 40% of human lung adenocarcinomas, implying that loss of function of LAS2 may be a key step for lung tumorigenesis.