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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivating germline mutations of the novel putative tumor-suppressor gene LKB1/STK11 at 19p13.3 have been shown to cause Peutz-Jeghers syndrome (PJS), an autosomal dominantly inherited disease characterized by a predisposition to mucocutaneous pigmentations, as well as various benign and malignant neoplasms. To elucidate the role of LKB1/STK11 in the carcinogenesis of primary and secondary human brain tumors, a total of 309 tumors were analyzed for loss of heterozygosity (LOH) at microsatellite loci D19S886, DI9S878, and D19S565. Low LOH rates were observed for glioma (17.3%, n = 139), meningioma (5.3%, n = 57), schwannoma (0%, n = 21), pituitary adenoma (18.8%, n = 16), primary CNS lymphoma, neuroblastoma, plasmocytoma, medulloblastoma, germinoma, and papilloma of the choroid plexus (6.6%, n = 15). In contrast, brain metastases exhibited a mean LOH frequency of 42.6% (n = 61), with breast (56.3%) and lung cancer metastases (58.3%) being most frequently affected. Genomic DNA sequencing of the complete coding region of LKB1/STK11 was performed in all brain metastases exhibiting LOH (n = 26); no mutation was revealed, but we did find a germline mutation in a PJS patient. Despite high LOH fiequencies at the 19p13.3 locus in carcinoma metastases to the brain and occasional mutations reported for certain primary carcinomas, there are no mutations in LKB1/STK11. This fact suggests that alterations of LKB1/STK11 occur relatively early in tumorigenesis and are rarely involved in the development of carcinoma metastases. Based on these findings, the genes adjacent to LKB1/STK11 may be relevant for the development of metastases to the brain from certain carcinomas.
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PMID:Frequent loss of heterozygosity at the 19p13.3 locus without LKB1/STK11 mutations in human carcinoma metastases to the brain. 1121 97

Frequent losses of chromosome 19p have recently been observed in sporadic lung adenocarcinomas, targeting the location of a critical tumor suppressor gene. Here we performed fine mapping of the short arm of chromosome 19 and found that the LKB1/STK11 gene mapped in the minimal-deleted region. Because germ-line mutations at LKB1/STK11 result in the Peutz-Jeghers syndrome and an increased risk of cancer, we performed a detailed genetic screen of the LKB1/STK11 gene in lung tumors. We detected a high frequency of somatic alterations (mainly nonsense mutations) in primary lung adenocarcinomas and in lung cancer cell lines. Thus, our findings demonstrate for the first time that LKB1/STK11 inactivation is a very common event and may be integrally involved in the development of sporadic lung adenocarcinoma.
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PMID:Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. 1209 71

Besides gastrointestinal hamartomatous polyposis and melanin spots in the skin and mucosa, patients with the Peutz-Jeghers syndrome (PJS) have repeatedly been observed with a variety of tumours, including lung cancer. Available data indicate an increased cancer risk among PJS patients, which suggests that the gene involved in PJS, STK11 on chromosome 19p13.3, may be a tumour suppressor gene. Herein, bronchioloalveolar carcinoma (BAC) of mucinous type is reported in a 22-year old male PJS patient with a novel germline frameshift insertion in exon 2 at codon 118 of the STK11 gene. Molecular studies of his BAC indicated loss of heterozygosity (LOH) in the region of STK11 on chromosome 19p13.3. This observation supports the hypothesis that STK11 is a tumour suppressor gene which is involved in the development of lung adenocarcinoma.
Lung Cancer 2005 Feb
PMID:Bronchioloalveolar carcinoma: a new cancer in Peutz-Jeghers syndrome. 1563 28

Research on developing molecular diagnostics for hereditary cancers resulted in establishing diagnostic services for familiar polyposis and non-polyposis patients (mutation determination of APC, MYH, STK11, SMAD4, MLH1, MSH2). In familiar testicular cancers the role of gr/gr gene on Y chromosome was identified. Molecular diagnostic tool was established to monitor the progression of follicular lymphoma using Bcl-2/IgH fusion sequences. Molecular diagnostic tools were developed to monitor circulating endothelial precursor cells (CEP) as well and the technique was tested in lung cancer patients. In malignant melanoma we have tested several potential novel markers among which ryanodine receptor seems to be a promising one, while the functional P2X7 receptor may serve as a therapeutic target. We have determined the tyrosine kinase "kinome" profile of HER-2-amplified breast cancers. Furthermore, the "kinome" profile was found to be characteristic for head and neck cancers of various anatomical location. Based on previous studies on the anti-migratory and antimetastatic potential of low-molecular-weight heparins, we have identified short heparin-derived oligosaccharides with maintained antimetastatic- but non-anticoagulant potentials. Pharmacogenomic studies on the role of polymorphism of the serine-hydroxymethyl-transferase (SHMT) gene in the efficacy of 5-FU and FOLFIRI protocols of colorectal cancer patients revealed a significant effect resulting in altered overall survival as well.
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PMID:[Developments in cancer management by innovative genomics. 2006 report of the National Cancer Consortium]. 1721 11

Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.
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PMID:LKB1 modulates lung cancer differentiation and metastasis. 1767 35

Mutation of the LKB1 gene (also known as STK11) is regarded as a cause of Peutz-Jeghers syndrome. In Caucasian patients, LKB1 somatic mutations occur in approximately one-third of lung adenocarcinomas. The aim of the present study was to examine the LKB1 gene in Japanese patients with lung cancer and to evaluate its clinical and pathological implications. We sequenced the LKB1 gene in 22 lung cancer cell lines and 100 Japanese patients with lung cancer (including 81 adenocarcinomas, 14 squamous cell carcinomas and five other histological types) who had undergone curative pulmonary resection. We also determined expression levels of the LKB1 gene by quantitative real-time reverse transcription-polymerase chain reaction and correlated these results with the clinical and pathological features of patients. Among the 22 cell lines, four had mutations and three of these were in adenocarcinoma cells. Of 100 primary lung cancers, only three had LKB1 gene mutations (3%). All of them were male smokers with adenocarcinomas. Hence, when confined to this subset of patients, the mutation frequency was 9% (3/33). No significant correlation was observed between the expression level of LKB1 and patient clinicopathological features. In conclusion, LKB1 gene mutations were relatively rare in Japanese patients with lung cancer compared with Caucasian patients. LKB1 gene mutations appear to be frequent in male, smoking patients of Caucasian origin, in contrast to EGFR or HER2 mutations that are frequent in non-smoking, female patients of Asian origin.
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PMID:LKB1 gene mutations in Japanese lung cancer patients. 1771 6

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies.
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PMID:LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. 1916 1

Losses of heterozygosity (LOH) of the short arm of chromosome 19 are frequent in lung cancer, suggesting that one or more tumor suppressor genes are present in this region. The LKB1 gene, also called STK11, is somatically inactivated through point mutations and large deletions in lung tumors, demonstrating that LKB1 is a target of the LOH of this chromosomal arm. Data from several independent groups have provided information about the profiles of lung tumors with LKB1 inactivation and it is generally agreed that this alteration strongly predominates in non-small cell lung cancer, in particular adenocarcinomas, in smokers. The LKB1 protein has serine-threonine kinase activity and is involved in the regulation of the cell energetic checkpoint through the phosphorylation and activation of adenosine monophosphate-dependent kinase (AMPK). LKB1 is also involved in other processes such as cell polarization, probably through substrates other than AMPK. Interestingly, another gene on chromosome 19p, BRG1, encoding a component of the SWI/SNF chromatin-remodeling complex, has emerged as a tumor suppressor gene that is altered in lung tumors. Similar to LKB1, BRG1 is somatically inactivated by point mutations or large deletions in lung tumors featuring LOH of chromosome 19p. These observations suggest an important role for BRG1 in lung cancer and highlight the need to further our understanding of the function of Brahma/SWI2-related gene 1 (BRG1) in cancer. Finally, simultaneous mutations at LKB1 and BRG1 are common in lung cancer cells, which exemplifies how a single event, LOH of chromosome 19p in this instance, targets two different tumor suppressors.
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PMID:BRG1 and LKB1: tales of two tumor suppressor genes on chromosome 19p and lung cancer. 1917 40

The paxillin gene (PXN) encodes a focal adhesion associated protein that could be involved in the progression of lung cancer through its interactions with the actin cytoskeleton and key signal transduction oncogenes. PXN mutations and PXN amplifications were recently identified in nonsmall-cell lung cancer (NSCLC) and amplifications were associated with MET increased copy number. The description of tumors with two to three mutations in the PXN gene and the overrepresentation of GC to AT transitions were unexpected and needed confirmation. The aim of this study was to validate the incidence of PXN somatic alterations in NSCLC and to correlate them to other common genetic alterations. PXN mutations and copy number changes at PXN, EGFR, and MET loci were analyzed on DNAs from frozen tumor samples (n = 159) that had been previously screened for mutations at EGFR, KRAS, BRAF, ERBB2, STK11, PIK3CA, and TP53. We found PXN polymorphisms including nonsynonymous ones but no PXN amplification and only 1/159 (<1%) somatic tumor mutation F416L. In conclusion, we do not deny the possible involvement of PXN in cancer but our findings do not support a major role for PXN somatic changes in lung carcinogenesis.
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PMID:No somatic genetic change in the paxillin gene in nonsmall-cell lung cancer. 1935 96

Lung cancer is the major cancer killer worldwide, and 5-yr survival is extremely poor (<or=15%), accentuating the need for more effective therapeutic strategies. Significant advances in lung cancer biology may lead to customised therapy based on targeting specific genes and pathways. The main signalling pathways that could provide roadmaps for therapy include the following: growth promoting pathways (Epidermal Growth Factor Receptor/Ras/PhosphatidylInositol 3-Kinase), growth inhibitory pathways (p53/Rb/P14(ARF), STK11), apoptotic pathways (Bcl-2/Bax/Fas/FasL), DNA repair and immortalisation genes. Epigenetic changes in lung cancer contribute strongly to cell transformation by modifying chromatin structures and the specific expression of genes; these include DNA methylation, histone and chromatin protein modification, and micro-RNA, all of which are responsible for the silencing of tumour suppressor genes while enhancing expression of oncogenes. The genetic and epigenetic pathways involved in lung tumorigenesis differ between smokers and nonsmokers, and are tools for cancer diagnosis, prognosis, clinical follow-up and targeted therapies.
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PMID:Pathogenesis of lung cancer signalling pathways: roadmap for therapies. 1948 50


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