Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer

Abstract

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.

Activation of AMP-activated protein kinase sensitizes lung cancer cells and H1299 xenografts to erlotinib

“…It was shown that metformin, a biguanide antidiabetic drug and activator of the AMPK signaling, decreases the risk for cancer in diabetes patients (Evans et al, 2005). Furthermore, LKB1, a known upstream activator of AMPK signaling, has been described as tumor suppressor in lung cancer cells and mouse tumors (Ji et al, 2007;Gill et al, 2011).…”

Tobacco Smoking and Lung Cancer : Perception Changing Facts = تدخين التبغ و سرطان الرئة : إدراك تغير الحقائق

“…Homozygous deletion or loss of heterozygosity (LOH) of chromosome 19p at the LKB1 locus occurred in 90% of the tested specimen in primary lung cancers. 50 The mutation is more frequent in lung cancers in smokers than neversmokers (P 0.007), and commonly occurs with K-Ras mutations (P 0.042) but infrequently with EGFR mutations (P 0.002). T790M (substitution of methionine for threonine at aa position 790) in tumours that progress on TKIs are more common in smokers and ex-smokers than in never-smokers.…”

Immunohistochemical Loss of LKB1 Is a Biomarker for More Aggressive Biology in KRAS-Mutant Lung Adenocarcinoma

“…Several types of somatic mutations in LKB1 in sporadic cancers have been identified, including insertions, deletions (including large intragenic deletions), nonsense, frameshift, missense, and splice site alterations, and more infrequently hypermethylation of the promoter (28). Moreover, homozygous deletions of LKB1 have been frequently reported in NSCLC (29,30). Detection of genomic loss by DNA sequencing of clinical specimens is challenging because of the admixture with DNA from nontumor cells.…”