title: Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease.
abstract: Hepatocellular adenoma (HCA) is a frequent long-term complication of glycogen storage disease type I (GSD I) and malignant transformation to hepatocellular carcinoma (HCC) is known to occur in some cases. However, the molecular pathogenesis of tumor development in GSD I is unclear. This study was conducted to systematically investigate chromosomal and genetic alterations in HCA associated with GSD I. Genome-wide SNP analysis and mutation detection of target genes was performed in ten GSD Ia-associated HCA and seven general population HCA cases for comparison. Chromosomal aberrations were detected in 60% of the GSD Ia HCA and 57% of general population HCA. Intriguingly, simultaneous gain of chromosome 6p and loss of 6q were only seen in GSD Ia HCA (three cases) with one additional GSD I patient showing submicroscopic 6q14.1 deletion. The sizes of GSD Ia adenomas with chromosome 6 aberrations were larger than the sizes of adenomas without the changes (P = 0.012). Expression of IGF2R and LATS1 candidate tumor suppressor genes at 6q was reduced in more than 50% of GSD Ia HCA that were examined (n = 7). None of the GSD Ia HCA had biallelic mutations in the HNF1A gene. These findings give the first insight into the distinct genomic and genetic characteristics of HCA associated with GSD Ia. These results strongly suggest that chromosome 6 alterations could be an early event in the liver tumorigenesis in GSD I, and may be in general population. These results also suggest an interesting relationship between GSD Ia HCA and steps to HCC transformation.
authors.affiliation: Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Priya S
authors.initials: PS
authors.lastname: Kishnani
authors.forename: Tzu-Po
authors.initials: TP
authors.lastname: Chuang
authors.forename: Deeksha
authors.initials: D
authors.lastname: Bali
authors.forename: Dwight
authors.initials: D
authors.lastname: Koeberl
authors.forename: Stephanie
authors.initials: S
authors.lastname: Austin
authors.forename: David A
authors.initials: DA
authors.lastname: Weinstein
authors.forename: Elaine
authors.initials: E
authors.lastname: Murphy
authors.forename: Ying-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Keri
authors.initials: K
authors.lastname: Boyette
authors.forename: Chu-Hao
authors.initials: CH
authors.lastname: Liu
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.forename: Ling-Hui
authors.initials: LH
authors.lastname: Li
mesh_terms: D018248:Adenoma, Liver Cell / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002869:Chromosome Aberrations; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D005953:Glycogen Storage Disease Type I / Q000235:genetics*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017527:Receptor, IGF Type 2 / Q000235:genetics; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics
chemical_list: C495270:CTNNB1 protein, human; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D017527:Receptor, IGF Type 2; D051176:beta Catenin; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases