Hepatocyte nuclear factor 1 alpha (HNF-1?) mutations in maturity-onset diabetes of the young

Ellard, Sian

doi:10.1002/1098-1004(200011)16:5<377::aid-humu1>3.0.co;2-2

Cited by 107 publications

(53 citation statements)

References 41 publications

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“…The codon 291 substitution located in a polyC-8 tract is the most frequent mutation found in MODY3 patients, whereas the codon 206 mutation, which was not contained in a repeated sequence motif, was specific to adenomas. 33 Lesions containing HNF1␣ mutations were mainly adenomas with a firm diagnosis (37 of the 44 cases; 84%). The other tumors were diagnosed as borderline lesion between adenoma and HCC (2 cases), or between adenoma and FNH (4 cases); in 1 additional case, part of the adenoma was associated with an HCC (Table 2).…”

Section: Molecular Analysesmentioning

confidence: 99%

Genotype–phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC

et al. 2006

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Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1␣ (HNF1␣) and ␤-catenin were sequenced. No tumors were mutated in both HNF1␣ and ␤-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1␣ mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10 ؊4 ), lack of cytological abnormalities (P < 10 ؊6 ), and no inflammatory infiltrates (P < 10 ؊4 ). In contrast, the group of tumors defined by ␤-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (P < 10 ؊5 ). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P ‫؍‬ 10 ؊3 ), ductular reaction (P < 10 ؊2 ), and dystrophic vessels (P ‫؍‬ .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the ␤-catenin-mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1␣ mutated tumors (P ‫؍‬ .004). In conclusion, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with ␤-catenin activation have a higher risk of malignant transformation. (

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Section: Molecular Analysesmentioning

confidence: 99%

Genotype–phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC

et al. 2006

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“…HNF1A mutations have been reported mainly in the maturityonset diabetes of the young (MODY) type 3 form of diabetes, which is characterized by an absolute deficiency in insulin secretion and nonobese anthropometry (10). Some HNF1A mutations completely abolished the ability of HNF-1␣ to promote transcription, and a few resulted in partial loss of activity and had a dominant negative effect on the activity of wild-type HNF-1␣ (10-13).…”

mentioning

confidence: 99%

HNF-1α G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community

Triggs-Raine

Kirkpatrick

Kelly

et al. 2002

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

106

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The prevalence of type 2 diabetes mellitus in the Oji-Cree of northwestern Ontario is the third highest in the world. A private mutation, G319S, in HNF1A, which encodes hepatic nuclear factor-1␣ (HNF-1␣), was associated with Oji-Cree type 2 diabetes and was found in Ϸ40% of affected subjects. The G319S mutation reduced the in vitro ability of HNF-1␣ to activate transcription by Ϸ50%, with no effect on DNA binding or protein stability. There was no evidence of a dominant negative effect of the mutant protein. The impact of the G319S mutation at the population level was assessed by classifying subjects with type 2 diabetes according to HNF1A genotype and plotting the cumulative age of onset of diabetes. Disease onset was modeled satisfactorily by two-parameter sigmoidal functions for all diabetic subjects and all three HNF1A genotypes. Pairwise statistical comparisons showed significant between-genotype differences in t50 (all P < 0.00001), corresponding to the age at which half the subjects had become diabetic. Each dose of G319S accelerated median disease onset by Ϸ7 years. Thus, the transactivation-deficient HNF1A G319S mutation affects the dynamics of disease onset. The demonstration of a functional consequence for HNF1A G319S provides a mechanistic basis for its strong association with Oji-Cree type 2 diabetes and its unparalleled specificity for diabetes prediction in these people, in whom diabetes presents a significant public health dilemma. The findings also show that HNF1A mutations can be associated with typical adult-onset insulin-resistant obesity-related diabetes in addition to maturity-onset diabetes of the young.

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“…Positive hMSH2 immunostaining was observed in all cases ( Table 1). Loss of hMLH1 expression was observed in Figure 3 summary of HNF1a mutations found in adenoma and HCC (Bluteau et al, 2002), MSI-H colon cancer (Laurent-Puig et al, 2003), endometrial tumors (present work) and MODY3 (Ellard, 2000). HNF1a mutations are represented by triangles, rhombus or boxes in white (germline), in black (biallelic somatic) and in gray (monoallelic somatic).…”

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confidence: 68%

Mutation of TCF1 encoding hepatocyte nuclear factor 1α in gynecological cancer

et al. 2004

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TCF1 (transcription factor 1) encoding hepatocyte nuclear factor 1a (HNF1a) is mutated in 50% of liver cell adenomas, a benign tumor closely associated with oral contraceptive use. These genetic alterations inactivate both alleles, leading to the absence of wild-type HNF1a expression in liver cell adenomas. To search for a role of HNF1a in other hormone-related neoplasias, we screened for HNF1a mutations in a series of 36 endometrial carcinomas, 29 breast carcinomas and 20 ovarian epithelial tumors. HNF1a mutations were identified in 4/ 36 (11%) of endometrial tumors. No mutation was found in ovarian and breast tumors. HNF1a mutations were somatic in all cases, monoallelic in three cases and biallelic in one case. These results suggest that HNF1a may contribute to endometrial carcinogenesis through complete HNF1a inactivation like in liver cell adenoma or by haploinsufficiency like in MSI-H colorectal cancer.

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Hepatocyte nuclear factor 1 alpha (HNF-1?) mutations in maturity-onset diabetes of the young

Cited by 107 publications

References 41 publications

Genotype–phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC

Genotype–phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC

HNF-1α G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community

Mutation of TCF1 encoding hepatocyte nuclear factor 1α in gynecological cancer

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