Clinical Spectrum Associated with Hepatocyte Nuclear Factor-1β Mutations

Bellanné‐Chantelot, Christine; Chauveau, Dominique; Gautier, Jean‐François; Dubois‐Laforgue, Danièle; Clauin, Séverine; Beaufils, Sandrine; Wilhelm, Jean-Marie; Boîtard, Christian; Nôël, Laure-Hélène; Velho, Gilberto; Timsit, José

doi:10.7326/0003-4819-140-7-200404060-00009

Cited by 322 publications

(296 citation statements)

References 33 publications

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“…Various mutations in the DNA-binding domain of HNF1B were identified in probands from eight different families who had a spectrum of structural renal abnormalities, diabetes, and in five of six patients who had undergone CT imaging, there was also diffuse atrophy of the exocrine pancreas. 21 Germ-line HNF1B mutations were found in two patients with chromophobe renal cell carcinoma with one patient incidentally discovered to have absence of the body and tail of the pancreas. 22 As ubiquitous as HNF1B expression may be for proper development of the pancreas and kidney its upregulation may be involved in the pathway to neoplastic conditions.…”

Section: Discussionmentioning

confidence: 99%

Clear cell carcinoma of the pancreas: histopathologic features and a unique biomarker: hepatocyte nuclear factor-1β

et al. 2008

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Clear cell carcinoma as a variant of ductal carcinoma of the pancreas is not well recognized. Hepatocyte nuclear factor-1b as a transcription factor has been identified as a specific biomarker of clear cell tumor of the female genital tract. The aim of this study was to systematically analyze clear cell carcinoma of the pancreas and its unique biomarker hepatocyte nuclear factor-1b. A total of 84 pancreatic adenocarcinomas were analyzed pathologically and with an immunohistochemical approach with hepatocyte nuclear factor-1b antibody. The identified clear cell carcinomas were further studied by PAS, DPAS, and mucicarmine stains. Pathologic features and clinical follow-up were documented. Of them, 20 (24%) pancreatic adenocarcinomas were identified with clear cell features, including 12 clear cell carcinomas and 8 ductal adenocarcinomas with clear cell component (defined as less than 75% of tumor with clear cells). Cytologically, the clear cell carcinomas exhibited clear cytoplasm with centrally located, atypical nuclei. PAS, DPAS, and mucicarmine stains confirmed that the clear cytoplasm was not due to accumulation of glycogen or mucin. The results of immunostaining showed that hepatocyte nuclear factor-1b is overexpressed in all clear cell carcinomas and in the clear cell components of eight ductal carcinomas with clear cell features. In contrast, in usual ductal adenocarcinoma, hepatocyte nuclear factor-1b exhibited overall weak or focally moderate staining; only eight cases were strongly positive (15%) of which 38% were high grade and 63% were moderate grade. However, when included with the strong staining cases in mixed and clear cell carcinoma, this group regardless of morphology appeared to correlate with worse survival compared to the group with weak hepatocyte nuclear factor-1b staining across morphologies (Po0.01). Thus, clear cell carcinoma of the pancreas is not an uncommon variant of pancreatic ductal adenocarcinoma. Hepatocyte nuclear factor-1b is a useful marker to identify these clear cell carcinomas, and its overexpression may aid in stratifying survival rate.

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Section: Discussionmentioning

confidence: 99%

Clear cell carcinoma of the pancreas: histopathologic features and a unique biomarker: hepatocyte nuclear factor-1β

et al. 2008

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“…In addition to these phenotypes, variable levels of pancreas atrophies have recently been associated with different TCF2 mutations (19,20). Remarkably, we have recently identified a severe pancreas hypoplasia in two fetuses carrying previously undescribed mutations in the TCF2 gene (A. L. Delezoide, C.H., and S.C., unpublished results).…”

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confidence: 86%

Lack of TCF2/vHNF1 in mice leads to pancreas agenesis

Haumaitre

Barbacci

Jenny

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

241

221

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Heterozygous mutations in the human POU-homeobox TCF2 (vHNF1, HNF1␤) gene are associated with maturity-onset diabetes of the young, type 5, and abnormal urogenital tract development. Recently, pancreas atrophies have been reported in several maturity-onset diabetes of the young type 5 patients, suggesting that TCF2 is required not only for adult pancreas function but also for its normal development. Tcf2-deficient mice die before gastrulation because of defective visceral endoderm formation. To investigate the role of this factor in pancreas development, we rescued this early lethality by tetraploid aggregation. We show that TCF2 has an essential function in the first steps of pancreas development, correlated with its expression domain that demarcates the entire pancreatic buds from the earliest stages. Lack of TCF2 results in pancreas agenesis by embryonic day 13.5. At earlier stages, only a dorsal bud rudiment forms transiently and expresses the transcription factors Ipf1 and Hlxb9 but lacks the key transcription factor involved in the acquisition of a pancreatic fate, Ptf1a, as well as all endocrine precursor cells. Regional specification of the gut also is perturbed in Tcf2 ؊/؊ embryos as manifested by ectopic expression of Shh and lack of Ihh and Ipf1 in the posterior stomach and duodenum. Our results highlight the requirement of Tcf2 for ensuring both accurate expression of key regulator molecules in the stomach-duodenal epithelium and proper acquisition of the pancreatic fate. This study provides further insights into early molecular events controlling pancreas development and may contribute to the development of cell-replacement strategies for diabetes.diabetes MODY5 ͉ homeodomain transcription factor ͉ pancreas development ͉ gut regionalization ͉ tetraploid aggregation I n mammals, the pancreas emerges as ventral and dorsal evaginations from the foregut-midgut junction that subsequently fused to form a complex organ. The signaling molecule Sonic Hedgehog (SHH) demarcates a molecular boundary between the prepancreatic endoderm and adjacent stomach and duodenal anlagen and exerts an inhibitory action on pancreas development (1-3). Genetic studies in mice have identified a hierarchical regulatory network involved in pancreas morphogenesis, with significant and sequential differences between ventral and dorsal pancreas. In the mouse, the dorsal bud appears at embryonic day 9.5 (E9.5) concomitantly with the first differentiated glucagon-producing cells. The homeobox gene Ipf1(Pdx1) is expressed before and during this budding, and all pancreatic cell types derive from IPF1 ϩ progenitors (4, 5). However, in Ipf1-deficient mice, pancreas development is arrested after budding (6, 7), implying that other factors promote pancreas specification. Recently, the transcription factor Ptf1a (P48) has been shown to be essential for the acquisition of a pancreatic fate by undifferentiated ventral foregut endoderm, being required for the specification of the ventral pancreas and robust outgrowth of the dorsal bud. In its a...

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“…Several of the patients had additional paramesonephric duct malformations (apart from common channel anomalies), such as fusion defects of the uterus and rudimentary uterine horns. Human dominant HNF1β mutations cause the Renal Cysts and Diabetes syndrome that always features a renal malformation (including congenital solitary and horseshoe kidney, renal cystic dysplasia and glomerulocystic disease); in addition, some females have defects of paramesonephric duct differentiation (bicornuate uterus, uterus didelphys and hemi-uterus) (27)(28)(29). The human clinical genetic observations, together with the fact that HNF1β is expressed during normal development of the mammalian kidney and uterus (25,26) led us to believe that HNF1β was another excellent candidate gene to screen in patients with persistent cloaca.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we screened three other genes, Sonic Hedgehog (SHH: 7q36), Ephrin B2 (EFNB2: 13q33) and Hepatocyte Nuclear Factor 1 β(HNF1β: 17cen-q21.3). As detailed in the Discussion, SHH (8,17,(21)(22)(23), EFNB2 (24) and HNF1β (25)(26)(27)(28)(29) are expressed in the developing renal, genital and alimentary tracts, and have been functionally implicated in the normal development of these structures.…”

Section: Introductionmentioning

confidence: 99%

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Jenkins

Bitner‐Glindzicz

Thomasson

et al. 2007

Journal of Pediatric Urology

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Objectives-'Persistent cloaca' is a severe malformation affecting females in which the urinary, genital and alimentary tracts share a single conduit. Previously, a Uroplakin IIIA (UPIIIA) mutation was reported in one individual with persistent cloaca, and UPIIIA, Sonic Hedgehog (SHH), Ephrin B2 (EFNB2) and Hepatocyte Nuclear Factor 1β (HNF1β) are expressed during the normal development of organs that are affected in this condition. HNF1β mutations have been associated with uterine malformations in humans, and mutations of genes homologous to human SHH or EFNB2 cause persistent cloaca in mice.Patients and Methods-We sought mutations of coding regions of UPIIIA, SHH, EFNB2 and HNF1β genes by direct sequencing in a group of 20 patients with persistent cloaca. Most had associated malformations of the upper renal tract and over half had impaired renal excretory function. The majority of patients had congenital anomalies outside the renal/genital tracts and two had the VACTERL association.Results-Apart from a previously described index case, we failed to find UPIIIA mutations, and no patient had a SHH, EFNB2 or HNF1β mutation.Conclusion-Persistent cloaca is only rarely associated with UPIIIA mutation. Despite the fact that SHH and EFNB2 are appealing candidate genes, based on their expression patterns and mutant mice phenotypes, they were not mutated in these humans with persistent cloaca. Although HNF1β mutations can perturb paramesonephric duct fusion in humans, HNF1β was not mutated in persistent cloaca.

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Clinical Spectrum Associated with Hepatocyte Nuclear Factor-1β Mutations

Cited by 322 publications

References 33 publications

Clear cell carcinoma of the pancreas: histopathologic features and a unique biomarker: hepatocyte nuclear factor-1β

Clear cell carcinoma of the pancreas: histopathologic features and a unique biomarker: hepatocyte nuclear factor-1β

Lack of TCF2/vHNF1 in mice leads to pancreas agenesis

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

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