The Experts below are selected from a list of 723 Experts worldwide ranked by ideXlab platform
Pia Hoglund - One of the best experts on this subject based on the ideXlab platform.
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a serine threonine kinase gene defective in peutz jeghers syndrome
Nature, 1998Co-Authors: Akseli Hemminki, Graham R. Bignell, William H. Warren, David Markie, Ian Tomlinson, Egle Avizienyte, Stina Roth, Anu Loukola, Maria Aminoff, Pia HoglundAbstract:Studies of hereditary cancer syndromes have contributed greatly to our understanding of molecular events involved in tumorigenesis. Here we investigate the molecular background of the Peutz–Jeghers syndrome1,2 (PJS), a rare hereditary disease in which there is predisposition to benign and malignant tumours of many organ systems. A locus for this condition was recently assigned to Chromosome 19p (ref. 3). We have identified truncating germline mutations in a gene residing on Chromosome 19p in multiple individuals affected by PJS. This previously identified but unmapped gene, LKB1 (ref. 4), has strong homology to a cytoplasmic Xenopus serine/threonine protein kinase XEEK1 (ref. 5), and weaker similarity to many other protein kinases. Peutz–Jeghers syndrome is therefore the first cancer-susceptibility syndrome to be identified that is due to inactivating mutations in a protein kinase.
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A serine/threonine kinase gene defective in Peutz–Jeghers syndrome
Nature, 1998Co-Authors: Akseli Hemminki, Graham R. Bignell, David Markie, Ian Tomlinson, Egle Avizienyte, Stina Roth, Anu Loukola, Maria Aminoff, W. Warren, Pia HoglundAbstract:Studies of hereditary cancer syndromes have contributed greatly to our understanding of molecular events involved in tumorigenesis. Here we investigate the molecular background of the Peutz–Jeghers syndrome1,2 (PJS), a rare hereditary disease in which there is predisposition to benign and malignant tumours of many organ systems. A locus for this condition was recently assigned to Chromosome 19p (ref. 3). We have identified truncating germline mutations in a gene residing on Chromosome 19p in multiple individuals affected by PJS. This previously identified but unmapped gene, LKB1 (ref. 4), has strong homology to a cytoplasmic Xenopus serine/threonine protein kinase XEEK1 (ref. 5), and weaker similarity to many other protein kinases. Peutz–Jeghers syndrome is therefore the first cancer-susceptibility syndrome to be identified that is due to inactivating mutations in a protein kinase.
Montse Sanchezcespedes - One of the best experts on this subject based on the ideXlab platform.
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brg1 and lkb1 tales of two tumor suppressor genes on Chromosome 19p and lung cancer
Carcinogenesis, 2009Co-Authors: Salvador Rodrigueznieto, Montse SanchezcespedesAbstract: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.
Montserrat Sanchez-cespedes - One of the best experts on this subject based on the ideXlab platform.
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The role of LKB1 in lung cancer
Familial Cancer, 2011Co-Authors: Montserrat Sanchez-cespedesAbstract:In humans, the LKB1 gene is located on the short arm of Chromosome 19, which is frequently deleted in lung tumors. Unlike most cancers of sporadic origin, in non-small cell lung cancer (NSCLC) nearly half of the tumors harbor somatic and homozygous inactivating mutations in LKB1 . In NSCLC, LKB1 inactivation strongly predominates in adenocarcinomas from smokers and coexists with mutations at other important cancer genes, including KRAS and TP53. Remarkably, LKB1 alterations frequently occur simultaneously with inactivation at another important tumor suppressor gene , BRG1 (also called SMARCA4 ), which is also located on Chromosome 19p . The present review considers the frequency and pattern of LKB1 mutations in lung cancer and the distinct biological pathways in which the LKB1 protein is involved in the development of this type of cancer. Finally, the possible clinical applications in cancer management, especially in lung cancer treatment, associated with the presence of absence of LKB1 are discussed.
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Inactivation of LKB1/STK11 Is a Common Event in Adenocarcinomas of the Lung
Cancer Research, 2002Co-Authors: Montserrat Sanchez-cespedes, Paola Parrella, Manel Esteller, Shuji Nomoto, Barry Trink, James M. Engles, William H. Westra, James G. Herman, David SidranskyAbstract: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.
K-m Hong - One of the best experts on this subject based on the ideXlab platform.
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Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer
Oncogene, 2011Co-Authors: R K Gill, S-h Yang, D Meerzaman, L E Mechanic, E D Bowman, H-s Jeon, S Roy Chowdhuri, A Shakoori, T Dracheva, K-m HongAbstract: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.
Collette K. Hand - One of the best experts on this subject based on the ideXlab platform.
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A novel locus for restless legs syndrome maps to Chromosome 19p in an Irish pedigree
neurogenetics, 2012Co-Authors: Evelyn B. Skehan, Manal M. A. Abdulrahim, Nollaig A. Parfrey, Collette K. HandAbstract:Restless legs syndrome (RLS) is a common, sleep-related movement disorder. The symptoms follow a circadian pattern, worsening in the evening or night, leading to sleep disruption and daytime somnolence. Familial forms of RLS have been described and usually display an autosomal dominant pattern of inheritance. To date, linkage analysis has identified nine RLS loci, but no specific causative gene has been reported. Association mapping has highlighted a further four genomic areas of interest. We have conducted a genome-wide linkage analysis in an Irish autosomal dominant RLS pedigree with 11 affected members. Significant linkage was found on Chromosome 19p for a series of microsatellite markers, with a maximum two-point LOD score of 3.59 at θ = 0.0 for marker D19S878. Recombination events, identified by haplotype analysis, define a genetic region of 6.57 cM on Chromosome 19p13.3, corresponding to an interval of 2.5 Mb. This study provides evidence of a novel RLS locus and provides further evidence that RLS is a genetically heterogenous disorder.