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Liver: Adenoma

Written2006-03Jessica Zucman-Rossi
Inserm U674, Génomique Fonctionnelle des tumeurs solides, 27 rue Juliette Dodu, 75010 Paris, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C220 LIVER
ICD-Morpho 8170/0
Atlas_Id 5420
Phylum Digestive organs: Liver::Hepatic adenoma
Other namesHepatocellular adenoma
Liver cell adenoma

Clinics and Pathology

Disease Hepatocellular adenomas (HA) are rare benign liver tumors, most frequently occurring in women using oral contraception. HA are single or more rarely multiple nodules; the presence of more than ten nodules in the liver indicates a specific nosological entity: liver adenomatosis
Etiology In 90% of the cases, adenomas are sporadic and only rare cases are developed in a familial context: ( Familial liver adenomatosis). Patients with an inherited mutation in one allele of TCF1/HNF1a may develop maturity onset diabetes of the young type 3 (MODY3) and familial liver adenomatosis, when the second allele is inactivated in hepatocytes by somatic mutation or chromosome deletion.
Epidemiology Hepatocellular adenomas are usually related to oral contraceptive use. The other risk factors are : glycogen storage diseases and the androgen therapy. HA are rare tumours: their estimated incidence in France is approximately one case per 100,000 women. Over the past fifteen years, their incidence has seen a sustained decline in industrialised countries; this trend is probably linked to the reduction in ethinylestradiol doses in oral contraceptives.
Pathology These tumours result from a benign proliferation of hepatocytes which destroy the normal architecture of the liver. They are usually hyper-vascularised and typical adenoma corresponds to a proliferation of benign hepatocytes, intermingled with numerous thin-walled vessels, without portal tracts.
Treatment Surgery is usually proposed for lesion of more than 3 cm
Evolution Hepatocellular adenoma may bleed, or rarely, undergo malignant transformation.
Prognosis The molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with beta-catenin activation have a higher risk of malignant transformation.

Genetics

Note Germline TCF1/HNF1A mutation can predispose to familial liver adenomatosis

Genes involved and Proteins

Note Half of the adenoma cases are mutated for TCF1 gene encoding HNF1a. These mutations are inactivating and both allele are mutated in tumors. Patients with an inherited mutation in one allele of HNF1a may develop maturity onset diabetes of the young type 3 (MODY3) and familial liver adenomatosis, when the second allele is inactivated in hepatocytes by somatic mutation or chromosome deletion. Mutations of CTNNB1 activating the beta-catenin was also found in 15% of the HA cases. The molecular and pathological classification of hepatocellular adenomas permited the identification of strong genotype-phenotype correlations and suggested that adenomas with beta-catenin activation have a higher risk of malignant transformation.
Gene NameHNF1A (HNF1 homeobox A)
Location 12q24.31
Note Alias: HNF1A, hepatocyte nuclear factor 1 alpha, HNF1, LFB1, M57732, MODY3
More than 50 different HNF1a mutations have been identified in HA. These mutations are distributed mainly from exon 1 to 6. Point mutations, small deletions and insertions were identified. Gene deletions are less frequent.

Gene NameCTNNB1 (Catenin, beta-1)
Location 3p22.1
Note Description: catenin (cadherin-associated protein), beta 1
Activating mutations are amino-acid substitution in exon 3 or in-frame deletion including part or all exon 3.
Protein Beta-catenin is an adherens junction protein. Adherens junctions are critical for the establishment and maintenance of epithelial layers, cells adhesion, signal communication, anchorage of the actin cytoskeleton. CTNNB1 has important functions in the E-cadherin-mediated cell-cell adhesion system and also as a dowstream signaling molecule in the Wnt pathway. Cytoplasmic accumulation of b catenin allows it to translocate to the nucleus to form complexes with transcription factors of the T cell factor-lymphoid enhancer factor (Tcf-Lef) family. b-catenin is assumed to transactivate mostly unknown target genes, which may stimulate cell proliferation (acts as an oncogene) or inhibit apoptosis. The b-catenin level in the cell is regulated by its association with the adenomatous polyposis coli ( APC) tumor suppressor protein, axin and GSK-3b. Phosphorylation of b-catenin by the APC-axin-GSK-3b complex leads to its degradation by the ubiquitin-proteasome system.

Bibliography

Familial liver adenomatosis associated with hepatocyte nuclear factor 1alpha inactivation.
Bacq Y, Jacquemin E, Balabaud C, Jeannot E, Scotto B, Branchereau S, Laurent C, Bourlier P, Pariente D, de Muret A, Fabre M, Bioulac-Sage P, Zucman-Rossi J
Gastroenterology. 2003 ; 125 (5) : 1470-1475.
PMID 14598263
 
Bi-allelic inactivation of TCF1 in hepatic adenomas.
Bluteau O, Jeannot E, Bioulac-Sage P, Marqués JM, Blanc JF, Bui H, Beaudoin JC, Franco D, Balabaud C, Laurent-Puig P, Zucman-Rossi J
Nature genetics. 2002 ; 32 (2) : 312-315.
PMID 12355088
 
P53 gene and Wnt signaling in benign neoplasms: beta-catenin mutations in hepatic adenoma but not in focal nodular hyperplasia.
Chen YW, Jeng YM, Yeh SH, Chen PJ
Hepatology (Baltimore, Md.). 2002 ; 36 (4 Pt 1) : 927-935.
PMID 12297840
 
Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature.
Chiche L, Dao T, Salamé E, Galais MP, Bouvard N, Schmutz G, Rousselot P, Bioulac-Sage P, Ségol P, Gignoux M
Annals of surgery. 2000 ; 231 (1) : 74-81.
PMID 10636105
 
Liver-cell adenomas associated with use of oral contraceptives.
Edmondson HA, Henderson B, Benton B
The New England journal of medicine. 1976 ; 294 (9) : 470-472.
PMID 173996
 
Liver adenomatosis. An entity distinct from liver adenoma?
Flejou JF, Barge J, Menu Y, Degott C, Bismuth H, Potet F, Benhamou JP
Gastroenterology. 1985 ; 89 (5) : 1132-1138.
PMID 2412930
 
Familial liver-cell adenomas and diabetes mellitus.
Foster JH, Donohue TA, Berman MM
The New England journal of medicine. 1978 ; 299 (5) : 239-241.
PMID 207987
 
Hepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY)3 families.
Reznik Y, Dao T, Coutant R, Chiche L, Jeannot E, Clauin S, Rousselot P, Fabre M, Oberti F, Fatome A, Zucman-Rossi J, Bellanne-Chantelot C
The Journal of clinical endocrinology and metabolism. 2004 ; 89 (3) : 1476-1480.
PMID 15001650
 
Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3)
Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox RD, Lathrop GM, Boriraj VV, Chen X, Cox NJ, Oda Y, Yano H, Le Beau MM, Yamada S, Nishigori H, Takeda J, Fajans SS, Hattersley AT, Iwasaki N, Hansen T, Pedersen O, Polonsky KS, Bell GI
Nature. 1996 ; 384 (6608) : 455-458.
PMID 8945470
 
Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC.
Zucman-Rossi J, Jeannot E, Nhieu JT, Scoazec JY, Guettier C, Rebouissou S, Bacq Y, Leteurtre E, Paradis V, Michalak S, Wendum D, Chiche L, Fabre M, Mellottee L, Laurent C, Partensky C, Castaing D, Zafrani ES, Laurent-Puig P, Balabaud C, Bioulac-Sage P
Hepatology (Baltimore, Md.). 2006 ; 43 (3) : 515-524.
PMID 16496320
 

Citation

This paper should be referenced as such :
Zucman-Rossi, J
Liver adenoma
Atlas Genet Cytogenet Oncol Haematol. 2006;10(3):201-202.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/LiverAdenomID5420.html


Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes ASPM MIR10B

External links

arrayMap Topo ( C22) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
Disease databaseLiver: Adenoma
REVIEW articlesautomatic search in PubMed
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