The Experts below are selected from a list of 9588 Experts worldwide ranked by ideXlab platform
Michael Goggins - One of the best experts on this subject based on the ideXlab platform.
-
a novel mutation of STK11 lkb1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma
Oncogene, 2006Co-Authors: Wanglong Qiu, Frank Schönleben, Harshwardhan M. Thaker, Michael GogginsAbstract:To investigate whether genetic alteration of the STK11 (serine/threonine kinase 11)/LKB1 tumor-suppressor gene is involved in the carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the entire encoding exons and flanking intronic sequences of the STK11/LKB1 gene were analysed with direct genomic sequencing of 15 HNSCC specimens. A novel missense mutation with presumed loss of heterozygosity (LOH) and 10 polymorphisms were identified in these samples. The novel mutation of STK11/LKB1 at nucleotide position 613 G --> A, which causes the amino-acid substitution from alanine to threonine at residue 205 within the catalytic kinase domain, was identified in cell line RPMI 2650. To further determine whether this point mutation affects the gene function, constructs of the wild type and A205T mutant of the STK11/LKB1 gene expression vectors were created and transfected into RPMI 2650 cells. Our results showed that the reintroduction of the wild-type but not the mutant STK11/LKB1 construct into RPMI 2650 cells induced suppression of the cell growth. The mutation also affected the kinase activity of the STK11/Lkb1 protein. This led us to conclude that the A205T point mutation of the STK11/LKB1 gene produces functionally inactive proteins. This is the first described mutation of the STK11/LKB1 gene in HNSCC. While the mutation frequency of the STK11/LKB1 gene in HNSCC remains to be determined in future studies, our data strongly suggests that STK11/LKB1 is involved in the carcinogenesis of HNSCC.
-
A novel mutation of STK11 / LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma
Oncogene, 2006Co-Authors: Wanglong Qiu, Frank Schönleben, Harshwardhan M. Thaker, Michael GogginsAbstract:To investigate whether genetic alteration of the STK11 (serine/threonine kinase 11)/LKB1 tumor-suppressor gene is involved in the carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the entire encoding exons and flanking intronic sequences of the STK11/LKB1 gene were analysed with direct genomic sequencing of 15 HNSCC specimens. A novel missense mutation with presumed loss of heterozygosity (LOH) and 10 polymorphisms were identified in these samples. The novel mutation of STK11/LKB1 at nucleotide position 613 G --> A, which causes the amino-acid substitution from alanine to threonine at residue 205 within the catalytic kinase domain, was identified in cell line RPMI 2650. To further determine whether this point mutation affects the gene function, constructs of the wild type and A205T mutant of the STK11/LKB1 gene expression vectors were created and transfected into RPMI 2650 cells. Our results showed that the reintroduction of the wild-type but not the mutant STK11/LKB1 construct into RPMI 2650 cells induced suppression of the cell growth. The mutation also affected the kinase activity of the STK11/Lkb1 protein. This led us to conclude that the A205T point mutation of the STK11/LKB1 gene produces functionally inactive proteins. This is the first described mutation of the STK11/LKB1 gene in HNSCC. While the mutation frequency of the STK11/LKB1 gene in HNSCC remains to be determined in future studies, our data strongly suggests that STK11/LKB1 is involved in the carcinogenesis of HNSCC.
-
loss of STK11 lkb1 expression in pancreatic and biliary neoplasms
Modern Pathology, 2003Co-Authors: Fikret Sahin, Anirban Maitra, Pedram Argani, Norihiro Sato, Naoki Maehara, Elizabeth A. Montgomery, Michael Goggins, Ralph H. HrubanAbstract:We have documented previously somatic mutations of STK11/LKB11, the gene responsible for Peutz-Jeghers syndrome (PJS), in a small proportion of sporadic pancreatic adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and biliary adenocarcinomas. In this report, we characterize the expression of STK11, the protein product of the STK11 gene, in a larger series of pancreatic and biliary neoplasms. First, the specificity of the STK11 antibody was established in 23 neoplasms (22 IPMNs and 1 biliary adenocarcinoma) with known STK11 gene status. Complete absence of labeling was seen in the neoplastic cells of 3 of the 3 (100%) cases with previously documented biallelic inactivation of the STK11 gene, whereas 16 of the 20 (80%) IPMNs, presumably with at least one wild-type STK11 gene, retained STK11 expression in the neoplastic cells. The marked decrease or absence of STK11 expression in four neoplasms with wild-type STK11 suggests that additional mechanisms may account for the lack of STK11 expression. Subsequently, to further evaluate STK11 expression in pancreatic and biliary neoplasms, tissue microarrays (TMAs) were constructed from a series of nearly 100 ductal adenocarcinomas and biliary neoplasms. STK11 expression was lost in 4 of the 56 (7%) pancreatic adenocarcinomas and 1 of the 38 (2.6%) biliary cancers by immunohistochemistry; the absence of labeling was confirmed by repeated immunohistochemical labeling of complete tissue sections for the same cases. Thus, STK11 expression is abrogated in a small proportion of pancreatic and biliary neoplasms. The inactivation of STK11 in 27% (6/22) of IPMNs versus 7% (4/56) of pancreatic adenocarcinomas suggests genetic disparities in the pathogenesis of these closely related neoplasms. Immunohistochemical analysis for STK11 expression may be a valid surrogate for genetic analysis of STK11 gene mutations in cancers.
-
Loss of STK11/Lkb1 Expression in Pancreatic and Biliary
2003Co-Authors: Neoplasms Sahin, Anirban Maitra, Pedram Argani, Norihiro Sato, Naoki Maehara, Elizabeth A. Montgomery, Michael Goggins, Ralph H. HrubanAbstract:We have documented previously somatic mutations of STK11/LKB11, the gene responsible for PeutzJeghers syndrome (PJS), in a small proportion of sporadic pancreatic adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and biliary adenocarcinomas. In this report, we characterize the expression of STK11, the protein product of the STK11 gene, in a larger series of pancreatic and biliary neoplasms. First, the specificity of the STK11 antibody was established in 23 neoplasms (22 IPMNs and 1 biliary adenocarcinoma) with known STK11 gene status. Complete absence of labeling was seen in the neoplastic cells of 3 of the 3 (100%) cases with previously documented biallelic inactivation of the STK11 gene, whereas 16 of the 20 (80%) IPMNs, presumably with at least one wild-type STK11 gene, retained STK11 expression in the neoplastic cells. The marked decrease or absence of STK11 expression in four neoplasms with wild-type STK11 suggests that additional mechanisms may account for the lack of STK11 expression. Subsequently, to further evaluate STK11 expression in pancreatic and biliary neoplasms, tissue microarrays (TMAs) were constructed from a series of nearly 100 ductal adenocarcinomas and biliary neoplasms. STK11 expression was lost in 4 of the 56 (7%) pancreatic adenocarcinomas and 1 of the 38 (2.6%) biliary cancers by immunohistochemistry; the absence of labeling was confirmed by repeated immunohistochemical labeling of complete tissue sections for the same cases. Thus, STK11 expression is abrogated in a small proportion of pancreatic and biliary neoplasms. The inactivation of STK11 in 27% (6/22) of IPMNs versus 7% (4/56) of pancreatic adenocarcinomas suggests genetic disparities in the pathogenesis of these closely related neoplasms. Immunohistochemical analysis for STK11 expression may be a valid surrogate for genetic analysis of STK11 gene mutations in cancers.
-
Loss of STK11/Lkb1 Expression in Pancreatic and Biliary Neoplasms
Modern pathology : an official journal of the United States and Canadian Academy of Pathology Inc, 2003Co-Authors: Fikret Sahin, Anirban Maitra, Pedram Argani, Norihiro Sato, Naoki Maehara, Elizabeth A. Montgomery, Michael Goggins, Ralph H. HrubanAbstract:We have documented previously somatic mutations of STK11/LKB11, the gene responsible for Peutz-Jeghers syndrome (PJS), in a small proportion of sporadic pancreatic adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and biliary adenocarcinomas. In this report, we characterize the expression of STK11, the protein product of the STK11 gene, in a larger series of pancreatic and biliary neoplasms. First, the specificity of the STK11 antibody was established in 23 neoplasms (22 IPMNs and 1 biliary adenocarcinoma) with known STK11 gene status. Complete absence of labeling was seen in the neoplastic cells of 3 of the 3 (100%) cases with previously documented biallelic inactivation of the STK11 gene, whereas 16 of the 20 (80%) IPMNs, presumably with at least one wild-type STK11 gene, retained STK11 expression in the neoplastic cells. The marked decrease or absence of STK11 expression in four neoplasms with wild-type STK11 suggests that additional mechanisms may account for the lack of STK11 expression. Subsequently, to further evaluate STK11 expression in pancreatic and biliary neoplasms, tissue microarrays (TMAs) were constructed from a series of nearly 100 ductal adenocarcinomas and biliary neoplasms. STK11 expression was lost in 4 of the 56 (7%) pancreatic adenocarcinomas and 1 of the 38 (2.6%) biliary cancers by immunohistochemistry; the absence of labeling was confirmed by repeated immunohistochemical labeling of complete tissue sections for the same cases. Thus, STK11 expression is abrogated in a small proportion of pancreatic and biliary neoplasms. The inactivation of STK11 in 27% (6/22) of IPMNs versus 7% (4/56) of pancreatic adenocarcinomas suggests genetic disparities in the pathogenesis of these closely related neoplasms. Immunohistochemical analysis for STK11 expression may be a valid surrogate for genetic analysis of STK11 gene mutations in cancers.
Ralph H. Hruban - One of the best experts on this subject based on the ideXlab platform.
-
loss of STK11 lkb1 expression in pancreatic and biliary neoplasms
Modern Pathology, 2003Co-Authors: Fikret Sahin, Anirban Maitra, Pedram Argani, Norihiro Sato, Naoki Maehara, Elizabeth A. Montgomery, Michael Goggins, Ralph H. HrubanAbstract:We have documented previously somatic mutations of STK11/LKB11, the gene responsible for Peutz-Jeghers syndrome (PJS), in a small proportion of sporadic pancreatic adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and biliary adenocarcinomas. In this report, we characterize the expression of STK11, the protein product of the STK11 gene, in a larger series of pancreatic and biliary neoplasms. First, the specificity of the STK11 antibody was established in 23 neoplasms (22 IPMNs and 1 biliary adenocarcinoma) with known STK11 gene status. Complete absence of labeling was seen in the neoplastic cells of 3 of the 3 (100%) cases with previously documented biallelic inactivation of the STK11 gene, whereas 16 of the 20 (80%) IPMNs, presumably with at least one wild-type STK11 gene, retained STK11 expression in the neoplastic cells. The marked decrease or absence of STK11 expression in four neoplasms with wild-type STK11 suggests that additional mechanisms may account for the lack of STK11 expression. Subsequently, to further evaluate STK11 expression in pancreatic and biliary neoplasms, tissue microarrays (TMAs) were constructed from a series of nearly 100 ductal adenocarcinomas and biliary neoplasms. STK11 expression was lost in 4 of the 56 (7%) pancreatic adenocarcinomas and 1 of the 38 (2.6%) biliary cancers by immunohistochemistry; the absence of labeling was confirmed by repeated immunohistochemical labeling of complete tissue sections for the same cases. Thus, STK11 expression is abrogated in a small proportion of pancreatic and biliary neoplasms. The inactivation of STK11 in 27% (6/22) of IPMNs versus 7% (4/56) of pancreatic adenocarcinomas suggests genetic disparities in the pathogenesis of these closely related neoplasms. Immunohistochemical analysis for STK11 expression may be a valid surrogate for genetic analysis of STK11 gene mutations in cancers.
-
Loss of STK11/Lkb1 Expression in Pancreatic and Biliary
2003Co-Authors: Neoplasms Sahin, Anirban Maitra, Pedram Argani, Norihiro Sato, Naoki Maehara, Elizabeth A. Montgomery, Michael Goggins, Ralph H. HrubanAbstract:We have documented previously somatic mutations of STK11/LKB11, the gene responsible for PeutzJeghers syndrome (PJS), in a small proportion of sporadic pancreatic adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and biliary adenocarcinomas. In this report, we characterize the expression of STK11, the protein product of the STK11 gene, in a larger series of pancreatic and biliary neoplasms. First, the specificity of the STK11 antibody was established in 23 neoplasms (22 IPMNs and 1 biliary adenocarcinoma) with known STK11 gene status. Complete absence of labeling was seen in the neoplastic cells of 3 of the 3 (100%) cases with previously documented biallelic inactivation of the STK11 gene, whereas 16 of the 20 (80%) IPMNs, presumably with at least one wild-type STK11 gene, retained STK11 expression in the neoplastic cells. The marked decrease or absence of STK11 expression in four neoplasms with wild-type STK11 suggests that additional mechanisms may account for the lack of STK11 expression. Subsequently, to further evaluate STK11 expression in pancreatic and biliary neoplasms, tissue microarrays (TMAs) were constructed from a series of nearly 100 ductal adenocarcinomas and biliary neoplasms. STK11 expression was lost in 4 of the 56 (7%) pancreatic adenocarcinomas and 1 of the 38 (2.6%) biliary cancers by immunohistochemistry; the absence of labeling was confirmed by repeated immunohistochemical labeling of complete tissue sections for the same cases. Thus, STK11 expression is abrogated in a small proportion of pancreatic and biliary neoplasms. The inactivation of STK11 in 27% (6/22) of IPMNs versus 7% (4/56) of pancreatic adenocarcinomas suggests genetic disparities in the pathogenesis of these closely related neoplasms. Immunohistochemical analysis for STK11 expression may be a valid surrogate for genetic analysis of STK11 gene mutations in cancers.
-
Loss of STK11/Lkb1 Expression in Pancreatic and Biliary Neoplasms
Modern pathology : an official journal of the United States and Canadian Academy of Pathology Inc, 2003Co-Authors: Fikret Sahin, Anirban Maitra, Pedram Argani, Norihiro Sato, Naoki Maehara, Elizabeth A. Montgomery, Michael Goggins, Ralph H. HrubanAbstract:We have documented previously somatic mutations of STK11/LKB11, the gene responsible for Peutz-Jeghers syndrome (PJS), in a small proportion of sporadic pancreatic adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and biliary adenocarcinomas. In this report, we characterize the expression of STK11, the protein product of the STK11 gene, in a larger series of pancreatic and biliary neoplasms. First, the specificity of the STK11 antibody was established in 23 neoplasms (22 IPMNs and 1 biliary adenocarcinoma) with known STK11 gene status. Complete absence of labeling was seen in the neoplastic cells of 3 of the 3 (100%) cases with previously documented biallelic inactivation of the STK11 gene, whereas 16 of the 20 (80%) IPMNs, presumably with at least one wild-type STK11 gene, retained STK11 expression in the neoplastic cells. The marked decrease or absence of STK11 expression in four neoplasms with wild-type STK11 suggests that additional mechanisms may account for the lack of STK11 expression. Subsequently, to further evaluate STK11 expression in pancreatic and biliary neoplasms, tissue microarrays (TMAs) were constructed from a series of nearly 100 ductal adenocarcinomas and biliary neoplasms. STK11 expression was lost in 4 of the 56 (7%) pancreatic adenocarcinomas and 1 of the 38 (2.6%) biliary cancers by immunohistochemistry; the absence of labeling was confirmed by repeated immunohistochemical labeling of complete tissue sections for the same cases. Thus, STK11 expression is abrogated in a small proportion of pancreatic and biliary neoplasms. The inactivation of STK11 in 27% (6/22) of IPMNs versus 7% (4/56) of pancreatic adenocarcinomas suggests genetic disparities in the pathogenesis of these closely related neoplasms. Immunohistochemical analysis for STK11 expression may be a valid surrogate for genetic analysis of STK11 gene mutations in cancers.
-
STK11 lkb1 peutz jeghers gene inactivation in intraductal papillary mucinous neoplasms of the pancreas
American Journal of Pathology, 2001Co-Authors: Norihiro Sato, Ralph H. Hruban, Christophe Rosty, Marnix Jansen, Noriyoshi Fukushima, Takashi Ueki, John L Cameron, Christine A Iacobuziodonahue, Michael GogginsAbstract:Despite the growing awareness of intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas among clinicians, the molecular features of IPMNs have not been well characterized. Previous reports suggest that inactivation of the STK11/LKB1 , a tumor-suppressor gene responsible for Peutz-Jeghers syndrome (PJS), plays a role in the pathogenesis of gastrointestinal hamartomas as well as several cancers, including pancreatic adenocarcinoma. Using polymerase chain reaction amplification of five microsatellite markers from the 19p13.3 region harboring the STK11/LKB1 gene, we analyzed DNA from 22 IPMNs for loss of heterozygosity (LOH). LOH at 19p13.3 was identified in 2 of 2 (100%) IPMNs from patients with PJS and 5 of 20 (25%) from patients lacking features of PJS (7 of 22, 32% overall). Sequencing analysis of the STK11/LKB1 gene in these IPMNs with LOH revealed a germline mutation in one IPMN that arose in a patient with PJS and a somatic mutation in 1 of the 20 sporadic IPMNs. None of the 22 IPMNs showed hypermethylation of the STK11/LKB1 gene. These results suggest that the STK11/LKB1 gene is involved in the pathogenesis of some IPMNs.
-
STK11/LKB1 Peutz-Jeghers Gene Inactivation in Intraductal Papillary-Mucinous Neoplasms of the Pancreas
The American journal of pathology, 2001Co-Authors: Norihiro Sato, Ralph H. Hruban, Charles J. Yeo, Christophe Rosty, Marnix Jansen, Noriyoshi Fukushima, Takashi Ueki, John L Cameron, Christine A. Iacobuzio-donahue, Michael GogginsAbstract:Despite the growing awareness of intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas among clinicians, the molecular features of IPMNs have not been well characterized. Previous reports suggest that inactivation of the STK11/LKB1, a tumor-suppressor gene responsible for Peutz-Jeghers syndrome (PJS), plays a role in the pathogenesis of gastrointestinal hamartomas as well as several cancers, including pancreatic adenocarcinoma. Using polymerase chain reaction amplification of five microsatellite markers from the 19p13.3 region harboring the STK11/LKB1 gene, we analyzed DNA from 22 IPMNs for loss of heterozygosity (LOH). LOH at 19p13.3 was identified in 2 of 2 (100%) IPMNs from patients with PJS and 5 of 20 (25%) from patients lacking features of PJS (7 of 22, 32% overall). Sequencing analysis of the STK11/LKB1 gene in these IPMNs with LOH revealed a germline mutation in one IPMN that arose in a patient with PJS and a somatic mutation in 1 of the 20 sporadic IPMNs. None of the 22 IPMNs showed hypermethylation of the STK11/LKB1 gene. These results suggest that the STK11/LKB1 gene is involved in the pathogenesis of some IPMNs.
John Gásdal Karstensen - One of the best experts on this subject based on the ideXlab platform.
-
Two cases of somatic STK11 mosaicism in Danish patients with Peutz–Jeghers syndrome
Familial Cancer, 2020Co-Authors: Anne Marie Jelsig, Birgitte Bertelsen, Isabel Forss, John Gásdal KarstensenAbstract:Peutz–Jeghers syndrome (PJS) is a hereditary polyposis syndrome characterized by hamartomatous Peutz–Jeghers polyps in the gastrointestinal tract, mucocutaneous pigmentations, and increased risk for intestinal and extraintestinal cancer. In more than two-third of patients it is possible to detect pathogenic variants in the serine/threonine kinase 11 ( STK11 ) gene, but so far is knowledge about genetic causes in the remaining part of patients limited. Reports of STK11 mosaicism are rare but may be an explanation in some patients without initial findings of pathogenic variants in STK11 . We report two Danish patients with STK11 mosaicism detected in blood when using Next-Generation Sequencing. This is only the sixth and seventh patient reported in the literature, and we compare phenotypes of the reported cases. The results indicate that STK11 mosaicism is more frequent than anticipated and highlight that mosaicism should be considered in patients with clinical suspicion of PJS or patients fulfilling the diagnostic criteria.
-
Two cases of somatic STK11 mosaicism in Danish patients with Peutz-Jeghers syndrome.
Familial cancer, 2020Co-Authors: Anne Marie Jelsig, Birgitte Bertelsen, Isabel Forss, John Gásdal KarstensenAbstract:Peutz-Jeghers syndrome (PJS) is a hereditary polyposis syndrome characterized by hamartomatous Peutz-Jeghers polyps in the gastrointestinal tract, mucocutaneous pigmentations, and increased risk for intestinal and extraintestinal cancer. In more than two-third of patients it is possible to detect pathogenic variants in the serine/threonine kinase 11 (STK11) gene, but so far is knowledge about genetic causes in the remaining part of patients limited. Reports of STK11 mosaicism are rare but may be an explanation in some patients without initial findings of pathogenic variants in STK11. We report two Danish patients with STK11 mosaicism detected in blood when using Next-Generation Sequencing. This is only the sixth and seventh patient reported in the literature, and we compare phenotypes of the reported cases. The results indicate that STK11 mosaicism is more frequent than anticipated and highlight that mosaicism should be considered in patients with clinical suspicion of PJS or patients fulfilling the diagnostic criteria.
Nicoletta Resta - One of the best experts on this subject based on the ideXlab platform.
-
Molecular and Clinical Characteristics in 46 Families Affected with Peutz–Jeghers Syndrome
Digestive Diseases and Sciences, 2007Co-Authors: Hamid Mehenni, Louisa Mota-vieira, Mohammed Peyman, Kim A. Chong, Larbi Aissa, Ali Ince, Aaron Lerner, Nicoletta Resta, Giuseppe Guanti, Angel CosmeAbstract:Germline mutations of the tumor suppressor gene LKB1/STK11 are responsible for the Peutz–Jeghers syndrome (PJS), an autosomal-dominant disorder characterized by mucocutaneous pigmentation, hamartomatous polyps, and an increased risk of associated malignancies. In this study, we assessed the presence of pathogenic mutations in the LKB1/STK11 gene in 46 unrelated PJS families, and also carried genotype–phenotype correlation in regard of the development of cancer in 170 PJS patients belonging to these families. All LKB1/STK11 variants detected with single-strand conformational polymorphism were confirmed by direct sequencing, and those without LKB1/STK11 mutation were further submitted to Southern blot analysis for detection of deletions/rearrangements. Statistical analysis for genotype–phenotype correlation was performed. In 59% (27/46) of unrelated PJS cases, pathogenic mutations in the LKB1/STK11 gene, including 9 novel mutations, were identified. The new mutations were 2 splice site deletion–insertions, 2 missenses, 1 nonsense, and 4 abnormal splice sites. Genotype–phenotype analysis did not yield any significant differences between patients carrying mutations in LKB1/STK11 versus those without mutations, even with respect to primary biliary adenocarcinoma. This study presents the molecular characterization and cancer occurrence of a large cohort of PJS patients, increases the mutational spectrum of LKB1/STK11 allelic variants worldwide, and provides a new insight useful for clinical diagnosis and genetic counseling of PJS families.
-
molecular and clinical characteristics in 46 families affected with peutz jeghers syndrome
Digestive Diseases and Sciences, 2007Co-Authors: Hamid Mehenni, Mohammed Peyman, Kim A. Chong, Larbi Aissa, Aaron Lerner, Nicoletta Resta, Ginevra Guanti, Louisa Motavieira, Ali Tuzun Ince, Angel CosmeAbstract:Germline mutations of the tumor suppressor gene LKB1/STK11 are responsible for the Peutz-Jeghers syndrome (PJS), an autosomal-dominant disorder characterized by mucocutaneous pigmentation, hamartomatous polyps, and an increased risk of associated malignancies. In this study, we assessed the presence of pathogenic mutations in the LKB1/STK11 gene in 46 unrelated PJS families, and also carried genotype-phenotype correlation in regard of the development of cancer in 170 PJS patients belonging to these families. All LKB1/STK11 variants detected with single-strand conformational polymorphism were confirmed by direct sequencing, and those without LKB1/STK11 mutation were further submitted to Southern blot analysis for detection of deletions/rearrangements. Statistical analysis for genotype-phenotype correlation was performed. In 59% (27/46) of unrelated PJS cases, pathogenic mutations in the LKB1/STK11 gene, including 9 novel mutations, were identified. The new mutations were 2 splice site deletion-insertions, 2 missenses, 1 nonsense, and 4 abnormal splice sites. Genotype-phenotype analysis did not yield any significant differences between patients carrying mutations in LKB1/STK11 versus those without mutations, even with respect to primary biliary adenocarcinoma. This study presents the molecular characterization and cancer occurrence of a large cohort of PJS patients, increases the mutational spectrum of LKB1/STK11 allelic variants worldwide, and provides a new insight useful for clinical diagnosis and genetic counseling of PJS families.
-
functional analysis of lkb1 STK11 mutants and two aberrant isoforms found in peutz jeghers syndrome patients
Human Mutation, 2003Co-Authors: Jérôme Boudeau, Alessandro Stella, Agnieszka Kieloch, Dario R. Alessi, Ginevra Guanti, Nicoletta RestaAbstract:Peutz-Jeghers Syndrome (PJS) is thought to be caused by mutations occurring in the widely expressed serine/threonine protein kinase named LKB1/STK11. Recent work has led to the identification of four mutants (R304W, I177N, K175-D176del, L263fsX286) and two novel aberrant LKB1/STK11 cDNA isoforms (r291-464del, r485-1283del) in a group of PJS Italian patients. Three of the four mutations only change 1 or 2 amino acids in the LKB1/STK11 catalytic domain. Here we demonstrate that all six LKB1/STK11 variants analysed are completely inactive in vitro as they were unable to autophosphorylate at Thr336, the major LKB1/STK11 autophosphorylation site, and to phosphorylate the p53 tumour suppressor protein. We also show that 5 out of the 6 variants are entirely localised in the nucleus in contrast to the wild type LKB1/STK11, which is detected in both the nucleus and cytoplasm. Finally we demonstrate that all 6 LKB1/STK11 variants, in contrast to wild type LKB1/STK11, are unable to suppress the growth of melanoma G361 cells. Taken together, these results demonstrate that the LKB1 mutations investigated in this study lead to the loss of serine/threonine kinase activity and are therefore likely to be the primary cause of PJS development in the patients that they were isolated from.
-
Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers Syndrome patients.
Human mutation, 2003Co-Authors: Jérôme Boudeau, Alessandro Stella, Agnieszka Kieloch, Dario R. Alessi, Ginevra Guanti, Nicoletta RestaAbstract:Peutz-Jeghers Syndrome (PJS) is thought to be caused by mutations occurring in the widely expressed serine/threonine protein kinase named LKB1/STK11. Recent work has led to the identification of four mutants (R304W, I177N, K175-D176del, L263fsX286) and two novel aberrant LKB1/STK11 cDNA isoforms (r291-464del, r485-1283del) in a group of PJS Italian patients. Three of the four mutations only change 1 or 2 amino acids in the LKB1/STK11 catalytic domain. Here we demonstrate that all six LKB1/STK11 variants analysed are completely inactive in vitro as they were unable to autophosphorylate at Thr336, the major LKB1/STK11 autophosphorylation site, and to phosphorylate the p53 tumour suppressor protein. We also show that 5 out of the 6 variants are entirely localised in the nucleus in contrast to the wild type LKB1/STK11, which is detected in both the nucleus and cytoplasm. Finally we demonstrate that all 6 LKB1/STK11 variants, in contrast to wild type LKB1/STK11, are unable to suppress the growth of melanoma G361 cells. Taken together, these results demonstrate that the LKB1 mutations investigated in this study lead to the loss of serine/threonine kinase activity and are therefore likely to be the primary cause of PJS development in the patients that they were isolated from.
-
STK11 mutations in peutz jeghers syndrome and sporadic colon cancer
Cancer Research, 1998Co-Authors: Nicoletta Resta, Cristiano Simone, Cristina Mareni, Mariapina Montera, Mattia Gentile, Francesco Susca, Roberto Gristina, Sarah Pozzi, Lucio Bertario, Pantaleo BufoAbstract:A potential tumor suppressor gene, STK11 , encoding a serine threonine kinase, has recently been identified on chromosome 19p13. Germ-line mutations of this gene have been found in patients with Peutz-Jeghers syndrome (PJS). To further investigate the relevance of STK11 mutations in PJS, we analyzed its coding sequence in nine patients and identified two deletions and three missense mutations. Because intestinal carcinomas have been observed to develop in association with PJS, we analyzed tumors from 71 patients for allelic deletions (loss of heterozygosity) and STK11 gene mutations, to elucidate the etiological role of STK11 gene in sporadic colorectal cancer. Loss of heterozygosity, evaluated using the microsatellite D19S886, was observed in 10 of 52 informative cases. No somatic mutations were detected except for a missense alteration in one tumor. Our data indicate the heterogeneity of PJS and the infrequent involvement of the STK11 gene in colorectal cancer.
Charles J. Yeo - One of the best experts on this subject based on the ideXlab platform.
-
STK11/LKB1 Peutz-Jeghers Gene Inactivation in Intraductal Papillary-Mucinous Neoplasms of the Pancreas
The American journal of pathology, 2001Co-Authors: Norihiro Sato, Ralph H. Hruban, Charles J. Yeo, Christophe Rosty, Marnix Jansen, Noriyoshi Fukushima, Takashi Ueki, John L Cameron, Christine A. Iacobuzio-donahue, Michael GogginsAbstract:Despite the growing awareness of intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas among clinicians, the molecular features of IPMNs have not been well characterized. Previous reports suggest that inactivation of the STK11/LKB1, a tumor-suppressor gene responsible for Peutz-Jeghers syndrome (PJS), plays a role in the pathogenesis of gastrointestinal hamartomas as well as several cancers, including pancreatic adenocarcinoma. Using polymerase chain reaction amplification of five microsatellite markers from the 19p13.3 region harboring the STK11/LKB1 gene, we analyzed DNA from 22 IPMNs for loss of heterozygosity (LOH). LOH at 19p13.3 was identified in 2 of 2 (100%) IPMNs from patients with PJS and 5 of 20 (25%) from patients lacking features of PJS (7 of 22, 32% overall). Sequencing analysis of the STK11/LKB1 gene in these IPMNs with LOH revealed a germline mutation in one IPMN that arose in a patient with PJS and a somatic mutation in 1 of the 20 sporadic IPMNs. None of the 22 IPMNs showed hypermethylation of the STK11/LKB1 gene. These results suggest that the STK11/LKB1 gene is involved in the pathogenesis of some IPMNs.
-
Short Communication STK11/LKB1 Peutz-Jeghers Gene Inactivation in Intraductal Papillary-Mucinous Neoplasms of the Pancreas
2001Co-Authors: Norihiro Sato, Ralph H. Hruban, Charles J. Yeo, Christophe Rosty, Marnix Jansen, Noriyoshi Fukushima, Takashi Ueki, John L Cameron, Christine A. Iacobuzio-donahue, Michael S GogginsAbstract:Despite the growing awareness of intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas among clinicians, the molecular features of IPMNs have not been well characterized. Previous reports suggest that inactivation of the STK11/LKB1, a tumorsuppressor gene responsible for Peutz-Jeghers syndrome (PJS), plays a role in the pathogenesis of gastrointestinal hamartomas as well as several cancers, including pancreatic adenocarcinoma. Using polymerase chain reaction amplification of five microsatellite markers from the 19p13.3 region harboring the STK11/LKB1 gene, we analyzed DNA from 22 IPMNs for loss of heterozygosity (LOH). LOH at 19p13.3 was identified in 2 of 2 (100%) IPMNs from patients with PJS and 5 of 20 (25%) from patients lacking features of PJS (7 of 22, 32% overall). Sequencing analysis of the STK11/LKB1 gene in these IPMNs with LOH revealed a germline mutation in one IPMN that arose in a patient with PJS and a somatic mutation in 1 of the 20 sporadic IPMNs. None of the 22 IPMNs showed hypermethylation of the STK11/LKB1 gene. These results suggest that the STK11/LKB1 gene is involved in the pathogenesis of some IPMNs. (Am J Pathol 2001, 159:2017–2022)
-
germline and somatic mutations of the STK11 lkb1 peutz jeghers gene in pancreatic and biliary cancers
American Journal of Pathology, 1999Co-Authors: Ralph H. Hruban, Michael Goggins, Ravi K. Bansal, David J. Tang, Manu C. Shekher, Anne Marie Westerman, Mark M. Entius, Charles J. Yeo, Steven G Bova, Scott E KernAbstract:Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder characterized by hamartomatous polyps in the gastrointestinal tract and by pigmented macules of the lips, buccal mucosa, and digits. Less appreciated is the fact that PJS also predisposes patients to an increased risk of gastrointestinal cancer, and pancreatic cancer has been reported in many PJS patients. It was recently shown that germline mutations of the STK11/LKB1 gene are responsible for PJS. We investigated the role of STK11/LKB1 in the development of pancreatic and biliary cancer in patients with and without the PJS. In a PJS patient having a germline splice site mutation in the STK11/LKB1 gene, sequencing analysis of an intestinal polyp and pancreatic cancer from this patient revealed loss of the wild-type allele of the STK11/LKB1 gene in the cancer. Inactivation of STK11/LKB1, by homozygous deletions or somatic sequence mutations coupled with loss of heterozygosity, was also demonstrated in 4-6% of 127 sporadic pancreatic and biliary adenocarcinomas. Our results demonstrate that germline and somatic genetic alterations of the STK11/LKB1 gene may play a causal role in carcinogenesis and that the same gene contributes to the development of both sporadic and familial forms of cancer.
-
Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers.
The American journal of pathology, 1999Co-Authors: Ralph H. Hruban, Michael Goggins, Ravi K. Bansal, G. Steven Bova, David J. Tang, Manu C. Shekher, Anne Marie Westerman, Mark M. Entius, Charles J. YeoAbstract:Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder characterized by hamartomatous polyps in the gastrointestinal tract and by pigmented macules of the lips, buccal mucosa, and digits. Less appreciated is the fact that PJS also predisposes patients to an increased risk of gastrointestinal cancer, and pancreatic cancer has been reported in many PJS patients. It was recently shown that germline mutations of the STK11/LKB1 gene are responsible for PJS. We investigated the role of STK11/LKB1 in the development of pancreatic and biliary cancer in patients with and without the PJS. In a PJS patient having a germline splice site mutation in the STK11/LKB1 gene, sequencing analysis of an intestinal polyp and pancreatic cancer from this patient revealed loss of the wild-type allele of the STK11/LKB1 gene in the cancer. Inactivation of STK11/LKB1, by homozygous deletions or somatic sequence mutations coupled with loss of heterozygosity, was also demonstrated in 4-6% of 127 sporadic pancreatic and biliary adenocarcinomas. Our results demonstrate that germline and somatic genetic alterations of the STK11/LKB1 gene may play a causal role in carcinogenesis and that the same gene contributes to the development of both sporadic and familial forms of cancer.
