Peutz-Jeghers syndrome(PJS) is an autosomal dominant inherited disease, which is characterized by mucocutaneous pigmentation and multiple gastrointestinal hamartoma polyps. The germline mutation of LKB1/STK11 gene on ...Peutz-Jeghers syndrome(PJS) is an autosomal dominant inherited disease, which is characterized by mucocutaneous pigmentation and multiple gastrointestinal hamartoma polyps. The germline mutation of LKB1/STK11 gene on chromosome 19 p13.3 is considered to be the hereditary cause of PJS. However, must a patient with PJS have the LKB1/STK11 gene mutation? We here report a case of a male patient who had typical manifestations of PJS and a definite family history, but did not have LKB1/STK11 gene mutation. By means of high-throughput sequencing technology, only mutations in APC gene(c.6662 T > C: p.Met2221 Thr) and MSH6 gene(c.3488 A > T: p.Glu1163 Val) were detected. The missense mutations in APC and MSH6 gene may lead to abnormalities in structure and function of their expression products, and may result in the occurrence of PJS. This study suggests that some other genetic disorders may cause PJS besides LKB1/STK11 gene mutation.展开更多
Genetic alterations to serine-threonine kinase 11(STK11)have been implicated in Peutz-Jeghers syndrome and tumorigenesis.Further exploration of the context-specific roles of liver kinase B1(LKB1;encoded by STK11)obser...Genetic alterations to serine-threonine kinase 11(STK11)have been implicated in Peutz-Jeghers syndrome and tumorigenesis.Further exploration of the context-specific roles of liver kinase B1(LKB1;encoded by STK11)observed that it regulates AMP-activated protein ki-nase(AMPK)and AMPK-related kinases.Given that both migration and proliferation are enhanced with the loss of LKB1 activity combined with the prevalence of STK11 genetic alter-ations in cancer biopsies,LKB1 was markedas a tumor suppressor.However,the roleof LKB1 in tumorigenesis is paradoxical as LKB1 activates autophagy and reactive oxygen species scav-enging while dampening anoikis,which contribute to cancer cell survival.Due to the pro-tumor-igenic properties of LKB1,targeting LKB1 pathways is now relevant for cancer treatment.With the recent successes of targeting LKB1 signaling in research and clinical settings,and enhanced cytotoxicity of chemical compounds in LKB1-deficient tumors,there is now a need for LKB1 in-hibitors.However,validating LKB1 inhibitors is challenging as LKB1 adaptor proteins,nucleocy-toplasmic shuttling,and splice variants all manipulate LKB1 activity.Furthermore,STE-20-related kinase adaptor protein(STRAD)and mouse protein 25 dictate LKB1 cellular localization and kinase activity.For these reasons,prior to assessing the efficacy and potency of pharmaco-logical candidates,the functional status of LKB1 needs to be defined.Therefore,to improve the understanding of LKB1 in physiology and oncology,this review highlights the role of LKB1 in tumorigenesis and addresses the therapeutic relevancy of LKB1 inhibitors..展开更多
BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare disease with clinical manifestations of pigmented spots on the lips,mucous membranes and extremities,scattered gastrointestinal polyps,and susceptibility to tumors.The c...BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare disease with clinical manifestations of pigmented spots on the lips,mucous membranes and extremities,scattered gastrointestinal polyps,and susceptibility to tumors.The clinical heterogeneity of PJS is obvious,and the relationship between clinical phenotype and genotype is still unclear.AIM To investigate the mutation status of hereditary colorectal tumor-associated genes in hamartoma polyp tissue of PJS patients and discuss its relationship with the clinicopathological data of PJS.METHODS Twenty patients with PJS were randomly selected for this study and were treated in the Air Force Medical Center(former Air Force General Hospital)PLA between 2008 and 2017.Their hamartoma polyp tissues were used for APC,AXIN2,BMPR1A,EPCAM,MLH1,MLH3,MSH2,MSH6,MUTYH,PMS1,PMS2,PTEN,SMAD4,and LKB1/STK11 gene sequencing using next-generation sequencing technology.The correlations between the sequencing results and clinical pathological data of PJS were analyzed.RESULTS Fourteen types of LKB1/STK11 mutations were detected in 16 cases(80.0%),of which 8 new mutations were found(3 types of frameshift deletion mutations:c.243delG,c.363_364delGA,and c.722delC;2 types of frameshift insertions:c.144_145insGCAAG,and c.454_455insC;3 types of splice site mutations:c.464+1G>T,c.464+1G>A,and c.598-1G>A);9 cases(45.0%)were found to have 18 types of heterozygous mutations in the remaining 13 genes except LKB1/STK11.Of these,MSH2:c.792+1G>A,MSH6:c.3689C>G,c.4001+13C>CTTAC,PMS1:c.46C>t,and c.922G>A were new mutations.CONCLUSION The genetic mutations in hamartoma polyp tissue of PJS are complex and diverse.Moreover,other gene mutations in PJS hamartoma polyp tissue were observed,with the exception of LKB1/STK11 gene,especially the DNA mismatch repair gene(MMR).Colorectal hamartoma polyps with LKB1/STK11 mutations were larger in diameter than those with other gene mutations.展开更多
Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by the development of hamartomatous polyposis in the gastrointestinal tract and melanin-pigmented macules on the skin mucosa. The responsibl...Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by the development of hamartomatous polyposis in the gastrointestinal tract and melanin-pigmented macules on the skin mucosa. The responsible gene is a tumor suppressor, STK11/LKB1, on chromosome 19p13.3. PJS complicates with benign and malignant tumors in various organs. In gynecology, there has been a particular focus on complications of PJS with sex cord tumor with annular tubules (SCTAT) and minimal deviation adenocarcinoma (MDA), which are rare diseases. Approximately 36% of patients with SCTAT are complicated with PJS and these patients are characterized by multifocal, bilateral, small and benign lesions that develop into tumors with mucinous to serous ratios of 8:1. In addition, 10% of cases of MDA are complicated with PJS and mutation of STK11, the gene responsible for PJS, has a major effect on onset and prognosis. The disease concept of lobular endocervical glandular hyper-plasia (LEGH) has recently been proposed and LEGH is thought to be a potential premalignant lesion of MDA, however, the relationship between PJS and LEGH remains unclear. Several case reports of PJS patients complicated with gynecological tumors have been published and further studies are needed to determine the underlying展开更多
基金Supported by Major Projects of Chinese PLA"13th Five-Year Plan"Logistics Research Subject,No.AKJ15J003
文摘Peutz-Jeghers syndrome(PJS) is an autosomal dominant inherited disease, which is characterized by mucocutaneous pigmentation and multiple gastrointestinal hamartoma polyps. The germline mutation of LKB1/STK11 gene on chromosome 19 p13.3 is considered to be the hereditary cause of PJS. However, must a patient with PJS have the LKB1/STK11 gene mutation? We here report a case of a male patient who had typical manifestations of PJS and a definite family history, but did not have LKB1/STK11 gene mutation. By means of high-throughput sequencing technology, only mutations in APC gene(c.6662 T > C: p.Met2221 Thr) and MSH6 gene(c.3488 A > T: p.Glu1163 Val) were detected. The missense mutations in APC and MSH6 gene may lead to abnormalities in structure and function of their expression products, and may result in the occurrence of PJS. This study suggests that some other genetic disorders may cause PJS besides LKB1/STK11 gene mutation.
文摘Genetic alterations to serine-threonine kinase 11(STK11)have been implicated in Peutz-Jeghers syndrome and tumorigenesis.Further exploration of the context-specific roles of liver kinase B1(LKB1;encoded by STK11)observed that it regulates AMP-activated protein ki-nase(AMPK)and AMPK-related kinases.Given that both migration and proliferation are enhanced with the loss of LKB1 activity combined with the prevalence of STK11 genetic alter-ations in cancer biopsies,LKB1 was markedas a tumor suppressor.However,the roleof LKB1 in tumorigenesis is paradoxical as LKB1 activates autophagy and reactive oxygen species scav-enging while dampening anoikis,which contribute to cancer cell survival.Due to the pro-tumor-igenic properties of LKB1,targeting LKB1 pathways is now relevant for cancer treatment.With the recent successes of targeting LKB1 signaling in research and clinical settings,and enhanced cytotoxicity of chemical compounds in LKB1-deficient tumors,there is now a need for LKB1 in-hibitors.However,validating LKB1 inhibitors is challenging as LKB1 adaptor proteins,nucleocy-toplasmic shuttling,and splice variants all manipulate LKB1 activity.Furthermore,STE-20-related kinase adaptor protein(STRAD)and mouse protein 25 dictate LKB1 cellular localization and kinase activity.For these reasons,prior to assessing the efficacy and potency of pharmaco-logical candidates,the functional status of LKB1 needs to be defined.Therefore,to improve the understanding of LKB1 in physiology and oncology,this review highlights the role of LKB1 in tumorigenesis and addresses the therapeutic relevancy of LKB1 inhibitors..
基金Supported by Major Projects of the Chinese PLA"Thirteenth Five-Year Plan"Logistics Research Subject,No.AKJ15J003No.AKJ15J001+1 种基金Incubation Project of Military Medical Science and Technology Youth Cultivation Program,No.17QNP023Beijing Capital Medical Development Research Fund,No.Shoufa2020-2-5122.
文摘BACKGROUND Peutz-Jeghers syndrome(PJS)is a rare disease with clinical manifestations of pigmented spots on the lips,mucous membranes and extremities,scattered gastrointestinal polyps,and susceptibility to tumors.The clinical heterogeneity of PJS is obvious,and the relationship between clinical phenotype and genotype is still unclear.AIM To investigate the mutation status of hereditary colorectal tumor-associated genes in hamartoma polyp tissue of PJS patients and discuss its relationship with the clinicopathological data of PJS.METHODS Twenty patients with PJS were randomly selected for this study and were treated in the Air Force Medical Center(former Air Force General Hospital)PLA between 2008 and 2017.Their hamartoma polyp tissues were used for APC,AXIN2,BMPR1A,EPCAM,MLH1,MLH3,MSH2,MSH6,MUTYH,PMS1,PMS2,PTEN,SMAD4,and LKB1/STK11 gene sequencing using next-generation sequencing technology.The correlations between the sequencing results and clinical pathological data of PJS were analyzed.RESULTS Fourteen types of LKB1/STK11 mutations were detected in 16 cases(80.0%),of which 8 new mutations were found(3 types of frameshift deletion mutations:c.243delG,c.363_364delGA,and c.722delC;2 types of frameshift insertions:c.144_145insGCAAG,and c.454_455insC;3 types of splice site mutations:c.464+1G>T,c.464+1G>A,and c.598-1G>A);9 cases(45.0%)were found to have 18 types of heterozygous mutations in the remaining 13 genes except LKB1/STK11.Of these,MSH2:c.792+1G>A,MSH6:c.3689C>G,c.4001+13C>CTTAC,PMS1:c.46C>t,and c.922G>A were new mutations.CONCLUSION The genetic mutations in hamartoma polyp tissue of PJS are complex and diverse.Moreover,other gene mutations in PJS hamartoma polyp tissue were observed,with the exception of LKB1/STK11 gene,especially the DNA mismatch repair gene(MMR).Colorectal hamartoma polyps with LKB1/STK11 mutations were larger in diameter than those with other gene mutations.
文摘Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by the development of hamartomatous polyposis in the gastrointestinal tract and melanin-pigmented macules on the skin mucosa. The responsible gene is a tumor suppressor, STK11/LKB1, on chromosome 19p13.3. PJS complicates with benign and malignant tumors in various organs. In gynecology, there has been a particular focus on complications of PJS with sex cord tumor with annular tubules (SCTAT) and minimal deviation adenocarcinoma (MDA), which are rare diseases. Approximately 36% of patients with SCTAT are complicated with PJS and these patients are characterized by multifocal, bilateral, small and benign lesions that develop into tumors with mucinous to serous ratios of 8:1. In addition, 10% of cases of MDA are complicated with PJS and mutation of STK11, the gene responsible for PJS, has a major effect on onset and prognosis. The disease concept of lobular endocervical glandular hyper-plasia (LEGH) has recently been proposed and LEGH is thought to be a potential premalignant lesion of MDA, however, the relationship between PJS and LEGH remains unclear. Several case reports of PJS patients complicated with gynecological tumors have been published and further studies are needed to determine the underlying
