Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer.
Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer.
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作者：
Gill RK;Yang SH;Meerzaman D;Mechanic LE;Bowman ED;Jeon HS;Roy Chowdhuri S;Shakoori A;Dracheva T;Hong KM;Fukuoka J;Zhang JH;Harris CC;Jen J
LKB 1/STK 11是一种肿瘤抑制因子，也是哺乳动物雷帕霉素靶蛋白信号传导的负调节因子。它在30%的肺癌细胞系中失活，但仅在5-15%的原发性肺腺癌中失活。有证据表明，LKB基因座处染色体19 p的纯合缺失（HD）有助于原发性人类肺癌中基因的失活。在这里，我们使用了几种互补的遗传学方法来评估原发性非小细胞肺癌（NSCLC）中的LKB 1基因座。我们首先使用染色体19 p上的8个微卫星标记分析了124例NSCLC患者的等位基因失衡，结果显示杂合性丢失（洛）的总发生率为65%（80/124）。我们接下来使用显色原位杂交（CISH）直接检查LKB 1基因座的染色体状态。124例洛合性缺失（LOH）检测样本中有65例可用于CISH检测，其中58例（89%）表现为染色体19 p的一个拷贝缺失（洛合性缺失，40/65例，62%）或两个拷贝缺失（HD 18/65例，28%）。白人（35%）的HD发生率显著高于非裔美国人（6%）（P=0.04）。通过直接测序完整的编码区，对124个在LKB 1基因侧翼的一个或两个标记处具有洛缺失的样品中的总共62个进行了进一步分析，其鉴定了62个肿瘤中的7个（11%）具有基因中的体细胞突变。此外，我们的数据表明，在39%的受试样本中，HD或洛导致LKB 1基因完全失活，而在90%的NSCLC中，HD或LKB 1区域的洛导致染色体19 p区域丢失。
LKB1/STK11 is a tumor suppressor and a negative regulator of mammalian target of rapamycin signaling. It is inactivated in 30% of lung cancer cell lines but only 5–15% of primary lung adenocarcinomas. There is evidence that homozygous deletion (HD) of chromosome 19p at the LKB locus contributes to the inactivation of the gene in primary human lung cancers. Here, we used several complementary genetic approaches to assess the LKB1 locus in primary non-small cell lung cancers (NSCLCs). We first analyzed 124 NSCLC cases for allelic imbalance using eight microsatellite markers on chromosome 19p, which revealed an overall rate of 65% (80 of 124) loss of heterozygosity (LOH). We next used chromogenic in situ hybridization (CISH) to directly examine the chromosomal status of the LKB1 locus. In all, 65 of 124 LOH tested samples were available for CISH and 58 of those (89%) showed either loss of one copy of chromosome 19p (LOH, 40 of 65 cases, 62%) or both copies (HD 18 of 65 cases, 28%). The occurrence of HD was significantly more frequent in Caucasian (35%) than in African-American patients (6%) (P=0.04). A total of 62 of 124 samples with LOH at one or both markers immediately flanking the LKB1 gene were further analyzed by directly sequencing the complete coding region, which identified 7 of 62 (11%) tumors with somatic mutations in the gene. Jointly, our data identified total inactivation of the LKB1 gene by either HD or LOH with somatic mutation in 39% of tested samples, whereas loss of chromosome 19p region by HD or LOH at the LKB1 region occured in 90% of NSCLC.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
8
作者：
Carretero, J;Medina, PP;Sanchez-Cespedes, M
通讯作者：
Sanchez-Cespedes, M
影响因子：
64.8
作者：
Ji, Hongbin;Ramsey, Matthew R.;Wong, Kwok-Kin
通讯作者：
Wong, Kwok-Kin
影响因子：
8
作者：
Matsumoto, S.;Iwakawa, R.;Yokota, J.
通讯作者：
Yokota, J.
影响因子：
56.9
作者：
Hahn, SA;Schutte, M;Kern, SE
通讯作者：
Kern, SE