Genetic mutation in hepatic adenoma: Seeing is believing

Abstract

Hepatic adenoma is one of the most common benigntumors in the liver, usually occurring in young femaleswith continuous use of oral contraceptives [1]. Hepaticadenoma is sometimes accidentally detected during aphysical examination or through medical imaging ofthe abdomen for other purposes. Some (about 10%)emergency cases presented with sudden and severeabdominal pain due to bleeding and the rupture of alarge, superficial hepatic adenoma. Treatment for symp-tomatic cases requires complete surgical resection. Forasymptomatic hepatic adenoma, regular follow-up andobservation is sufficient, as tumors usually do not growor even regress in rare cases. However, one major andunsettled problem regarding this wait-and-see policyhas been the low, but true, risk of malignant transforma-tion from hepatic adenoma to hepatocellular carcinoma(HCC). In addition, the histology characteristics of cer-tain well-differentiated HCC cannot be confidently dif-ferentiated from that of hepatic adenoma. Carefulpathological examination plus advanced imaging bycontrast MRI may help in some cases, but physiciansstill look for more reliable diagnosis criteria for high-risk adenoma. Fortunately, new and promising geneticcriteria are emerging from recent molecular genetic stud-ies of hepatic adenoma.Genetic mutations leading to hepatic adenoma for-mation can be approached from two directions. The firstone is the candidate gene approach, which is drawn bythe known genes involved in two other common livercancers, HCC and hepatoblastoma [2,3]. One well-known example is the b-catenin gene (CTNNB1), whichis a key molecule in the Wnt signaling pathway. Whenmigrating into the nucleus, b-catenin can activate thetranscription of a variety genes and lead to aberrant cellproliferation. In normal hepatocytes, b-catenin is usual-ly rapidly degraded after phosphorylation by the GSK-3b kinase on its so-called ‘‘degradation domain’’, whichmakes its activation transient andAE strictly regulated.However, because of somatic deletions or mutations inthe ‘‘degradation domains’’, mutant b-catenin resistsdegradation. The nucleus accumulation and continuousactivation of mutant b-catenin may render hepatocytesto grow autonomously and even accelerate the tumorformation [2]. Mutation of b-catenin and its aberrantactivation was reported to be common both in HCCand hepatoblastoma. Taking this precedent, we and oth-ers have found that about 30% of hepatic adeomas actu-ally harbored mutations in the degradation domains ofb-catenin [4]. However, other genes in the Wnt path-ways, such as adenomatous polyposis coli (APC)orAxin family genes, did not show any mutations in thesporadic adenomas [4].The second approach is a genome-wide search formutated genes in the hepatic adenoma [5]. Bluteauet al. conducted a comprehensive screening for chromo-somal deletions in hepatic adenomas. They succeeded inidentifying a homozygous deletion locus in the chromo-some 12 and finally discovered a gene within this region,the hepatocyte nuclear factor (HNF)-1a (TCF1) gene, tobe mutated in about 50% of their collected hepatic ade-nomas. Two alleles of HNF-1a gene were inactivatedeither by frame-shift or by mis-sense somatic mutations[6]. This has been hailed as a major new understandingfor hepatic adenoma. Interestingly, in their initial seriesof samples they did not find any cases with b-cateninmutations and thus suggested the mutations at HNF-1a and b-catenin genes appeared to be mutually exclu-sive [7].To address the clinical significance of the mutation ofb-catenin versus that of HNF-1a, Zucman-Rossi et al.further performed a large series of genetic-clinical asso-ciation studies in France [8]. They studied 96 hepaticadenomas for mutations of HNF-1a and b-catenin