66 research outputs found
Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas
Somatic STAT3 mutations present in a subset of inflammatory hepatocellular adenomas result in the generation of constitutively active STAT3 proteins that homodimerize independently of IL-6 stimulation
AmĂ©lioration de la classification molĂ©culaire des tumeurs hĂ©patocellulaires bĂ©nignes : vers la mise en place dâoutils diagnostiques
Hepatocellular adenomas (HCA) are rare benign tumors defined according to the presence of inactivating mutations of HNF1A, activating mutations of the CTNNB1 and IL6/JAK/STAT pathway activation. However, a small number of HCA remain without specific characteristics. We aim to refine the molecular classification of HCA and identify potential associations with the clinical and molecular characteristics of each subgroup of HCA. For this purpose, we collected of 533 HCA of 411 patients. We sequenced the 10 genes known to be mutated in HCA, and we analyzed by quantitative RT-PCR the expression of 20 genes significantly deregulated in the differents moleculars groups of HCA, allowing us to classify HCA according to their genetic and molecular alterations. However, 11% of HCA remained unclassified (U_HCA). In order to identify the genetic and molecular alterations involved in the tumorigenesis of these U_HCA, we analyzed the RNAseq profiles and compared the expression profiles of 4 normal livers and 36 adenomas from differents moleculars groups. A microdeletion of the INHBE gene leading to the formation of a gene fusion between the INHBE gene and exons 2 and 4 of the GLI1 gene, a transcription factor of the Sonic Hedgehog pathway (Hh), has been identified. In addition, the GSEA study, showed an enrichment of the Hh pathway genes in half of the U_HCA analized. We therefore identified a new subgroup of AHC (sh_HCA, 4%), characterized by the activation of the Hh pathway characterized to the presence of an INHBE-GLI1 gene fusion. The comparison of the histological, clinical and molecular characteristics of each of the HCA subgroup allowed us to refine our knowledge of the risk factors, clinical and histological characteristics related to each molecular group. We showed that the new sh_HCA adenoma subgroup was associated with a higher risk of histological and clinical bleeding. A proteomic study of HCA proposed ASS1 as a marker for HCA at high risk of bleeding. Interestingly, a study on hepatic metabolic zonation showed that ASS1 is a marker of the periportal zone of the hepatic lobule. We therefore sought to evaluate the importance of the level of expression of the ASS1 in the molecular classification of HCA and its involvement following the activation of the Hh pathway. In our series of HCA, we showed that the expression of ASS1 belonged to the periportal expression program that was maintained in sh_HCA while in the other subtypes of HCA, it was under-expressed. In addition, in contrast to sh_HCA, we identified the activation of the perivenous program in b_HCA with Wnt/ ÎČ-catenin activation. We performed a functional study by transfecting cell lines either by inhibiting the expression of the GLI1 gene. Inhibition by siRNA of GLI1 gene expression in cell lines induces negative regulation of the ASS1 gene. This study shows the importance of the molecular classification of HCA. Indeed, the improvement of this classification allowed the identification of a new subgroup of HCA, the sh_HCA, adenomas presenting a hemorrhagic risk. These findings highlight for the first time the involvement of the Sonic Hedgehog pathway in benign liver tumorigenesis and hepatic zonation in humans. Finally, this new classification could be useful in clinical practice to customize treatement to individual patients based on the molecular characteristics of the tumors.Les adĂ©nomes hĂ©patocellulaires (AHC) sont des tumeurs bĂ©nignes rares rĂ©partit selon la prĂ©sence de mutations inactivatrices dâHNF1A, de mutations activatrices du gĂšne CTNNB1 codant pour la Ă-catĂ©nine et lâactivation de la voie IL6/JAK/STAT. Toutefois, un faible nombre dâAHC reste sans caractĂ©ristiques spĂ©cifiques. Nous avons cherchĂ© Ă affiner la classification molĂ©culaire des AHC et Ă identifier les associations existantes entre les caractĂ©ristiques cliniques et molĂ©culaires de chaque sous-groupes dâAHC. Pour cela, un recrutement de 533 AHC pour 411 patients a Ă©tĂ© rĂ©alisĂ©. Nous avions procĂ©dĂ© au sĂ©quençage des 10 gĂšnes connus pour ĂȘtre mutĂ©s dans les AHC, et analysĂ© par RT-PCR quantitative lâexpression de 20 gĂšnes significativement dĂ©rĂ©guler dans les diffĂ©rents groupes molĂ©culaires dâAHC. Lâensemble de ces rĂ©sultats, a permis de classer les AHC selon leurs altĂ©rations gĂ©nĂ©tiques et molĂ©culaires. Cependant, 11% des AHC restaient inclassĂ©s (U_HCA). Afin dâidentifier les altĂ©rations gĂ©nĂ©tiques et molĂ©culaires impliquĂ©es dans la tumorigenĂšse de ces U_AHC, nous avons analysĂ© les profils RNAseq et comparĂ© les profils dâexpression de 4 foies normaux et 36 adĂ©nomes des diffĂ©rents groupes molĂ©culaires. Une micro dĂ©lĂ©tion du gĂšnes INHBE conduisant Ă la formation dâun gĂšne fusion entre le gĂšne INHBE et les exons 2 et 4 de du gĂšne GLI1, facteur de transcritption de la voie Hh, a Ă©tĂ© identifiĂ©. Par ailleurs, lâĂ©tude GSEA, des gĂšnes spĂ©cifiquement surexprimĂ©s dans ces AHC a montrĂ© un enrichissement des gĂšnes de la voie de la voie Sonic Hedgehog (Hh) dans la moitiĂ© des U_HCA Ă©tudiĂ©s. Nous avons donc identifiĂ© un nouveau sous-groupe dâAHC (sh_AHC, 4%), caractĂ©risĂ© par lâactivation de la voie Sonic Hedgehog secondaire Ă la prĂ©sence dâun gĂšne de fusion INHBE-GLI1. La confrontation des caractĂ©ristiques histologiques, cliniques et molĂ©culaires de chacun des 4 groupes dâAHC a permis dâaffiner notre connaissance des facteurs de risque, des caractĂ©ristiques cliniques, histologiques liĂ© Ă chaque groupe molĂ©culaire. Nous avons montrĂ© que le nouveau sous-groupe dâadĂ©nome sh_AHC est associĂ© un Ă risque plus Ă©levĂ© dâhĂ©morragie histologique et clinique. Une Ă©tude protĂ©omique des AHC a proposĂ© ASS1, comme marqueur des AHC prĂ©sentant un risque Ă©levĂ© dâhĂ©morragie. De maniĂšre intĂ©ressante, une Ă©tude sur la zonation mĂ©tabolique hĂ©patique, a dĂ©montrĂ© que ASS1 est un marqueur de la zone pĂ©riportale du lobule hĂ©patique. Nous avons donc cherchĂ© Ă Ă©valuer l'importance du niveau dâexpression du gĂšne ASS1 dans la classification molĂ©culaire des AHC et son implication suite Ă lâactivation de la voie Hh. Dans notre sĂ©rie dâAHC, nous avons montrĂ© que le niveau dâexpression dâASS1 appartenait au programme d'expression pĂ©riportal qui Ă©tait maintenu dans sh_AHC tandis que dans les autres sous-types de AHC, il Ă©tĂ© sous-exprimĂ©. De plus en opposition au sh_AHC, nous avons montrĂ© lâactivation du programme pĂ©riveineux dans les b_AHC activĂ©s pour la voie Wnt/ ÎČ-catenin car la voie est connue pour ĂȘtre impliquĂ© dans le zonation hĂ©patique et dans le maintien du niveau dâexpression des gĂšnes du rĂ©seau pĂ©riveineux. Nous avons effectuĂ© une Ă©tude fonctionnelle en transfectant des lignĂ©es cellulaires soit en inhibant lâexpression du gĂšne GLI1. Lâinhibition par siRNA de lâexpression du gĂšne GLI1 dans les lignĂ©es cellulaires, induit une rĂ©gulation nĂ©gative du gĂšne ASS1. Cette Ă©tude montre lâimportance de la classification molĂ©culaire des AHC. En effet, lâamĂ©lioration de cette classification a conduit Ă identifier un nouveau groupe dâAHC, les sh_AHC, adĂ©nomes prĂ©sentant un risque hĂ©morragique. Cette dĂ©couverte souligne pour la premiĂšre fois lâimplication de la voie Sonic Hedgehog dans la tumorigĂ©nĂšse hĂ©patique bĂ©nigne et dans la zonation hĂ©patique chez lâhomme. Lâidentification de ces tumeurs permettra de proposer des prises en charge Ă la carte adaptĂ©e au profil molĂ©culaire des tumeurs en pratique clinique
Improvement of the molecular classification of benign hepatocellular tumors : towards the implementation of diagnostic tools
Les adĂ©nomes hĂ©patocellulaires (AHC) sont des tumeurs bĂ©nignes rares rĂ©partit selon la prĂ©sence de mutations inactivatrices dâHNF1A, de mutations activatrices du gĂšne CTNNB1 codant pour la Ă-catĂ©nine et lâactivation de la voie IL6/JAK/STAT. Toutefois, un faible nombre dâAHC reste sans caractĂ©ristiques spĂ©cifiques. Nous avons cherchĂ© Ă affiner la classification molĂ©culaire des AHC et Ă identifier les associations existantes entre les caractĂ©ristiques cliniques et molĂ©culaires de chaque sous-groupes dâAHC. Pour cela, un recrutement de 533 AHC pour 411 patients a Ă©tĂ© rĂ©alisĂ©. Nous avions procĂ©dĂ© au sĂ©quençage des 10 gĂšnes connus pour ĂȘtre mutĂ©s dans les AHC, et analysĂ© par RT-PCR quantitative lâexpression de 20 gĂšnes significativement dĂ©rĂ©guler dans les diffĂ©rents groupes molĂ©culaires dâAHC. Lâensemble de ces rĂ©sultats, a permis de classer les AHC selon leurs altĂ©rations gĂ©nĂ©tiques et molĂ©culaires. Cependant, 11% des AHC restaient inclassĂ©s (U_HCA). Afin dâidentifier les altĂ©rations gĂ©nĂ©tiques et molĂ©culaires impliquĂ©es dans la tumorigenĂšse de ces U_AHC, nous avons analysĂ© les profils RNAseq et comparĂ© les profils dâexpression de 4 foies normaux et 36 adĂ©nomes des diffĂ©rents groupes molĂ©culaires. Une micro dĂ©lĂ©tion du gĂšnes INHBE conduisant Ă la formation dâun gĂšne fusion entre le gĂšne INHBE et les exons 2 et 4 de du gĂšne GLI1, facteur de transcritption de la voie Hh, a Ă©tĂ© identifiĂ©. Par ailleurs, lâĂ©tude GSEA, des gĂšnes spĂ©cifiquement surexprimĂ©s dans ces AHC a montrĂ© un enrichissement des gĂšnes de la voie de la voie Sonic Hedgehog (Hh) dans la moitiĂ© des U_HCA Ă©tudiĂ©s. Nous avons donc identifiĂ© un nouveau sous-groupe dâAHC (sh_AHC, 4%), caractĂ©risĂ© par lâactivation de la voie Sonic Hedgehog secondaire Ă la prĂ©sence dâun gĂšne de fusion INHBE-GLI1. La confrontation des caractĂ©ristiques histologiques, cliniques et molĂ©culaires de chacun des 4 groupes dâAHC a permis dâaffiner notre connaissance des facteurs de risque, des caractĂ©ristiques cliniques, histologiques liĂ© Ă chaque groupe molĂ©culaire. Nous avons montrĂ© que le nouveau sous-groupe dâadĂ©nome sh_AHC est associĂ© un Ă risque plus Ă©levĂ© dâhĂ©morragie histologique et clinique. Une Ă©tude protĂ©omique des AHC a proposĂ© ASS1, comme marqueur des AHC prĂ©sentant un risque Ă©levĂ© dâhĂ©morragie. De maniĂšre intĂ©ressante, une Ă©tude sur la zonation mĂ©tabolique hĂ©patique, a dĂ©montrĂ© que ASS1 est un marqueur de la zone pĂ©riportale du lobule hĂ©patique. Nous avons donc cherchĂ© Ă Ă©valuer l'importance du niveau dâexpression du gĂšne ASS1 dans la classification molĂ©culaire des AHC et son implication suite Ă lâactivation de la voie Hh. Dans notre sĂ©rie dâAHC, nous avons montrĂ© que le niveau dâexpression dâASS1 appartenait au programme d'expression pĂ©riportal qui Ă©tait maintenu dans sh_AHC tandis que dans les autres sous-types de AHC, il Ă©tĂ© sous-exprimĂ©. De plus en opposition au sh_AHC, nous avons montrĂ© lâactivation du programme pĂ©riveineux dans les b_AHC activĂ©s pour la voie Wnt/ ÎČ-catenin car la voie est connue pour ĂȘtre impliquĂ© dans le zonation hĂ©patique et dans le maintien du niveau dâexpression des gĂšnes du rĂ©seau pĂ©riveineux. Nous avons effectuĂ© une Ă©tude fonctionnelle en transfectant des lignĂ©es cellulaires soit en inhibant lâexpression du gĂšne GLI1. Lâinhibition par siRNA de lâexpression du gĂšne GLI1 dans les lignĂ©es cellulaires, induit une rĂ©gulation nĂ©gative du gĂšne ASS1. Cette Ă©tude montre lâimportance de la classification molĂ©culaire des AHC. En effet, lâamĂ©lioration de cette classification a conduit Ă identifier un nouveau groupe dâAHC, les sh_AHC, adĂ©nomes prĂ©sentant un risque hĂ©morragique. Cette dĂ©couverte souligne pour la premiĂšre fois lâimplication de la voie Sonic Hedgehog dans la tumorigĂ©nĂšse hĂ©patique bĂ©nigne et dans la zonation hĂ©patique chez lâhomme. Lâidentification de ces tumeurs permettra de proposer des prises en charge Ă la carte adaptĂ©e au profil molĂ©culaire des tumeurs en pratique clinique.Hepatocellular adenomas (HCA) are rare benign tumors defined according to the presence of inactivating mutations of HNF1A, activating mutations of the CTNNB1 and IL6/JAK/STAT pathway activation. However, a small number of HCA remain without specific characteristics. We aim to refine the molecular classification of HCA and identify potential associations with the clinical and molecular characteristics of each subgroup of HCA. For this purpose, we collected of 533 HCA of 411 patients. We sequenced the 10 genes known to be mutated in HCA, and we analyzed by quantitative RT-PCR the expression of 20 genes significantly deregulated in the differents moleculars groups of HCA, allowing us to classify HCA according to their genetic and molecular alterations. However, 11% of HCA remained unclassified (U_HCA). In order to identify the genetic and molecular alterations involved in the tumorigenesis of these U_HCA, we analyzed the RNAseq profiles and compared the expression profiles of 4 normal livers and 36 adenomas from differents moleculars groups. A microdeletion of the INHBE gene leading to the formation of a gene fusion between the INHBE gene and exons 2 and 4 of the GLI1 gene, a transcription factor of the Sonic Hedgehog pathway (Hh), has been identified. In addition, the GSEA study, showed an enrichment of the Hh pathway genes in half of the U_HCA analized. We therefore identified a new subgroup of AHC (sh_HCA, 4%), characterized by the activation of the Hh pathway characterized to the presence of an INHBE-GLI1 gene fusion. The comparison of the histological, clinical and molecular characteristics of each of the HCA subgroup allowed us to refine our knowledge of the risk factors, clinical and histological characteristics related to each molecular group. We showed that the new sh_HCA adenoma subgroup was associated with a higher risk of histological and clinical bleeding. A proteomic study of HCA proposed ASS1 as a marker for HCA at high risk of bleeding. Interestingly, a study on hepatic metabolic zonation showed that ASS1 is a marker of the periportal zone of the hepatic lobule. We therefore sought to evaluate the importance of the level of expression of the ASS1 in the molecular classification of HCA and its involvement following the activation of the Hh pathway. In our series of HCA, we showed that the expression of ASS1 belonged to the periportal expression program that was maintained in sh_HCA while in the other subtypes of HCA, it was under-expressed. In addition, in contrast to sh_HCA, we identified the activation of the perivenous program in b_HCA with Wnt/ ÎČ-catenin activation. We performed a functional study by transfecting cell lines either by inhibiting the expression of the GLI1 gene. Inhibition by siRNA of GLI1 gene expression in cell lines induces negative regulation of the ASS1 gene. This study shows the importance of the molecular classification of HCA. Indeed, the improvement of this classification allowed the identification of a new subgroup of HCA, the sh_HCA, adenomas presenting a hemorrhagic risk. These findings highlight for the first time the involvement of the Sonic Hedgehog pathway in benign liver tumorigenesis and hepatic zonation in humans. Finally, this new classification could be useful in clinical practice to customize treatement to individual patients based on the molecular characteristics of the tumors
AmĂ©lioration de la classification molĂ©culaire des tumeurs hĂ©patocellulaires bĂ©nignes : vers la mise en place dâoutils diagnostiques
Hepatocellular adenomas (HCA) are rare benign tumors defined according to the presence of inactivating mutations of HNF1A, activating mutations of the CTNNB1 and IL6/JAK/STAT pathway activation. However, a small number of HCA remain without specific characteristics. We aim to refine the molecular classification of HCA and identify potential associations with the clinical and molecular characteristics of each subgroup of HCA. For this purpose, we collected of 533 HCA of 411 patients. We sequenced the 10 genes known to be mutated in HCA, and we analyzed by quantitative RT-PCR the expression of 20 genes significantly deregulated in the differents moleculars groups of HCA, allowing us to classify HCA according to their genetic and molecular alterations. However, 11% of HCA remained unclassified (U_HCA). In order to identify the genetic and molecular alterations involved in the tumorigenesis of these U_HCA, we analyzed the RNAseq profiles and compared the expression profiles of 4 normal livers and 36 adenomas from differents moleculars groups. A microdeletion of the INHBE gene leading to the formation of a gene fusion between the INHBE gene and exons 2 and 4 of the GLI1 gene, a transcription factor of the Sonic Hedgehog pathway (Hh), has been identified. In addition, the GSEA study, showed an enrichment of the Hh pathway genes in half of the U_HCA analized. We therefore identified a new subgroup of AHC (sh_HCA, 4%), characterized by the activation of the Hh pathway characterized to the presence of an INHBE-GLI1 gene fusion. The comparison of the histological, clinical and molecular characteristics of each of the HCA subgroup allowed us to refine our knowledge of the risk factors, clinical and histological characteristics related to each molecular group. We showed that the new sh_HCA adenoma subgroup was associated with a higher risk of histological and clinical bleeding. A proteomic study of HCA proposed ASS1 as a marker for HCA at high risk of bleeding. Interestingly, a study on hepatic metabolic zonation showed that ASS1 is a marker of the periportal zone of the hepatic lobule. We therefore sought to evaluate the importance of the level of expression of the ASS1 in the molecular classification of HCA and its involvement following the activation of the Hh pathway. In our series of HCA, we showed that the expression of ASS1 belonged to the periportal expression program that was maintained in sh_HCA while in the other subtypes of HCA, it was under-expressed. In addition, in contrast to sh_HCA, we identified the activation of the perivenous program in b_HCA with Wnt/ ÎČ-catenin activation. We performed a functional study by transfecting cell lines either by inhibiting the expression of the GLI1 gene. Inhibition by siRNA of GLI1 gene expression in cell lines induces negative regulation of the ASS1 gene. This study shows the importance of the molecular classification of HCA. Indeed, the improvement of this classification allowed the identification of a new subgroup of HCA, the sh_HCA, adenomas presenting a hemorrhagic risk. These findings highlight for the first time the involvement of the Sonic Hedgehog pathway in benign liver tumorigenesis and hepatic zonation in humans. Finally, this new classification could be useful in clinical practice to customize treatement to individual patients based on the molecular characteristics of the tumors.Les adĂ©nomes hĂ©patocellulaires (AHC) sont des tumeurs bĂ©nignes rares rĂ©partit selon la prĂ©sence de mutations inactivatrices dâHNF1A, de mutations activatrices du gĂšne CTNNB1 codant pour la Ă-catĂ©nine et lâactivation de la voie IL6/JAK/STAT. Toutefois, un faible nombre dâAHC reste sans caractĂ©ristiques spĂ©cifiques. Nous avons cherchĂ© Ă affiner la classification molĂ©culaire des AHC et Ă identifier les associations existantes entre les caractĂ©ristiques cliniques et molĂ©culaires de chaque sous-groupes dâAHC. Pour cela, un recrutement de 533 AHC pour 411 patients a Ă©tĂ© rĂ©alisĂ©. Nous avions procĂ©dĂ© au sĂ©quençage des 10 gĂšnes connus pour ĂȘtre mutĂ©s dans les AHC, et analysĂ© par RT-PCR quantitative lâexpression de 20 gĂšnes significativement dĂ©rĂ©guler dans les diffĂ©rents groupes molĂ©culaires dâAHC. Lâensemble de ces rĂ©sultats, a permis de classer les AHC selon leurs altĂ©rations gĂ©nĂ©tiques et molĂ©culaires. Cependant, 11% des AHC restaient inclassĂ©s (U_HCA). Afin dâidentifier les altĂ©rations gĂ©nĂ©tiques et molĂ©culaires impliquĂ©es dans la tumorigenĂšse de ces U_AHC, nous avons analysĂ© les profils RNAseq et comparĂ© les profils dâexpression de 4 foies normaux et 36 adĂ©nomes des diffĂ©rents groupes molĂ©culaires. Une micro dĂ©lĂ©tion du gĂšnes INHBE conduisant Ă la formation dâun gĂšne fusion entre le gĂšne INHBE et les exons 2 et 4 de du gĂšne GLI1, facteur de transcritption de la voie Hh, a Ă©tĂ© identifiĂ©. Par ailleurs, lâĂ©tude GSEA, des gĂšnes spĂ©cifiquement surexprimĂ©s dans ces AHC a montrĂ© un enrichissement des gĂšnes de la voie de la voie Sonic Hedgehog (Hh) dans la moitiĂ© des U_HCA Ă©tudiĂ©s. Nous avons donc identifiĂ© un nouveau sous-groupe dâAHC (sh_AHC, 4%), caractĂ©risĂ© par lâactivation de la voie Sonic Hedgehog secondaire Ă la prĂ©sence dâun gĂšne de fusion INHBE-GLI1. La confrontation des caractĂ©ristiques histologiques, cliniques et molĂ©culaires de chacun des 4 groupes dâAHC a permis dâaffiner notre connaissance des facteurs de risque, des caractĂ©ristiques cliniques, histologiques liĂ© Ă chaque groupe molĂ©culaire. Nous avons montrĂ© que le nouveau sous-groupe dâadĂ©nome sh_AHC est associĂ© un Ă risque plus Ă©levĂ© dâhĂ©morragie histologique et clinique. Une Ă©tude protĂ©omique des AHC a proposĂ© ASS1, comme marqueur des AHC prĂ©sentant un risque Ă©levĂ© dâhĂ©morragie. De maniĂšre intĂ©ressante, une Ă©tude sur la zonation mĂ©tabolique hĂ©patique, a dĂ©montrĂ© que ASS1 est un marqueur de la zone pĂ©riportale du lobule hĂ©patique. Nous avons donc cherchĂ© Ă Ă©valuer l'importance du niveau dâexpression du gĂšne ASS1 dans la classification molĂ©culaire des AHC et son implication suite Ă lâactivation de la voie Hh. Dans notre sĂ©rie dâAHC, nous avons montrĂ© que le niveau dâexpression dâASS1 appartenait au programme d'expression pĂ©riportal qui Ă©tait maintenu dans sh_AHC tandis que dans les autres sous-types de AHC, il Ă©tĂ© sous-exprimĂ©. De plus en opposition au sh_AHC, nous avons montrĂ© lâactivation du programme pĂ©riveineux dans les b_AHC activĂ©s pour la voie Wnt/ ÎČ-catenin car la voie est connue pour ĂȘtre impliquĂ© dans le zonation hĂ©patique et dans le maintien du niveau dâexpression des gĂšnes du rĂ©seau pĂ©riveineux. Nous avons effectuĂ© une Ă©tude fonctionnelle en transfectant des lignĂ©es cellulaires soit en inhibant lâexpression du gĂšne GLI1. Lâinhibition par siRNA de lâexpression du gĂšne GLI1 dans les lignĂ©es cellulaires, induit une rĂ©gulation nĂ©gative du gĂšne ASS1. Cette Ă©tude montre lâimportance de la classification molĂ©culaire des AHC. En effet, lâamĂ©lioration de cette classification a conduit Ă identifier un nouveau groupe dâAHC, les sh_AHC, adĂ©nomes prĂ©sentant un risque hĂ©morragique. Cette dĂ©couverte souligne pour la premiĂšre fois lâimplication de la voie Sonic Hedgehog dans la tumorigĂ©nĂšse hĂ©patique bĂ©nigne et dans la zonation hĂ©patique chez lâhomme. Lâidentification de ces tumeurs permettra de proposer des prises en charge Ă la carte adaptĂ©e au profil molĂ©culaire des tumeurs en pratique clinique
MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations.: hepatocellular tumors miRNA profiling
International audienceMolecular classifications defining new tumor subtypes have been recently refined with genetic and transcriptomic analyses of benign and malignant hepatocellular tumors. Here, we performed microRNA (miRNA) profiling in two series of fully annotated liver tumors to uncover associations between oncogene/tumor suppressor mutations and clinical and pathological features. Expression levels of 250 miRNAs in 46 benign and malignant hepatocellular tumors were compared to those of 4 normal liver samples with quantitative reverse-transcriptase polymerase chain reaction. miRNAs associated with genetic and clinical characteristics were validated in a second series of 43 liver tumor samples and 16 nontumor samples. miRNA profiling unsupervised analysis classified samples in unique clusters characterized by histological features (tumor/nontumor, P < 0.001; benign/malignant tumors, P < 0.01; inflammatory adenoma and focal nodular hyperplasia, P < 0.01), clinical characteristics [hepatitis B virus (HBV) infection, P < 0.001; alcohol consumption, P < 0.05], and oncogene/tumor suppressor gene mutations [beta-catenin, P < 0.01; hepatocyte nuclear factor 1alpha (HNF1alpha), P < 0.01]. Our study identified and validated miR-224 overexpression in all tumors and miR-200c, miR-200, miR-21, miR-224, miR-10b, and miR-222 specific deregulation in benign or malignant tumors. Moreover, miR-96 was overexpressed in HBV tumors, and miR-126* was down-regulated in alcohol-related hepatocellular carcinoma. Down-regulations of miR-107 and miR-375 were specifically associated with HNF1alpha and beta-catenin gene mutations, respectively. miR-375 expression was highly correlated to that of beta-catenin-targeted genes as miR-107 expression was correlated to that of HNF1alpha in a small interfering RNA cell line model. Thus, this strongly suggests that beta-catenin and HNF1alpha could regulate miR-375 and miR-107 expression levels, respectively. CONCLUSION: Hepatocellular tumors may have a distinct miRNA expression fingerprint according to malignancy, risk factors, and oncogene/tumor suppressor gene alterations. Dissecting these relationships provides a new hypothesis to understand the functional impact of miRNA deregulation in liver tumorigenesis and the promising use of miRNAs as diagnostic markers
The beta-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules.
International audienceBACKGROUND/AIMS: Focal nodular hyperplasias (FNHs) are benign liver lesions considered to be a hyperplastic response to increased blood flow in normal liver. In contrast, FNH-like lesions/nodules occur in cirrhotic liver but share similar histopathological features. We conducted a transcriptome analysis to identify biological pathways deregulated in FNH. METHODS: Gene expression profiles obtained in FNH and normal livers were compared. Differentially-expressed genes were validated using quantitative-RT-PCR in 70 benign liver tumors including FNH-like lesions. RESULTS: Among the deregulated genes in FNHs, 19 displayed physiological restricted distribution in the normal liver. All six perivenous genes were up-regulated in FNH, whereas 13 periportal genes were down-regulated. Almost all these genes are known to be regulated by beta-catenin. Glutamine synthetase was markedly overexpressed in anastomosed areas usually centered on visible veins. Moreover, activated hypophosphorylated beta-catenin protein accumulated in FNH in the absence of activating mutations. These results suggest the zonated activation of the beta-catenin pathway in FNH, whereas the other benign hepatocellular tumors, including FNH-like lesions, demonstrated an entirely different pattern of beta-catenin expression. CONCLUSIONS: In FNH, increased activation of the beta-catenin pathway was found restricted to enlarged perivenous areas. FNH-like nodules may have a different pathogenetic origin
Immunogenomics of Metastatic Clear-Cell Renal Cell Carcinoma: Remarkable Response to Nivolumab in a Patient With a Pathogenic Germ Line BRCA1 Mutation
status: publishe
Immunogenomics of Metastatic Clear-Cell Renal Cell Carcinoma: Remarkable Response to Nivolumab in a Patient With a Pathogenic Germ Line BRCA1 Mutation
International audienc
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