Human Molecular Genetics Advance Access originally published online on September 16, 2009
Human Molecular Genetics 2009 18(24):4781-4790; doi:10.1093/hmg/ddp441
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Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease
1 Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA, 2 National Genotyping Center and 3 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, 4 Glycogen Storage Disease Program, University of Florida College of Medicine, Gainesville, FL 32610, USA and 5 Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK
* To whom correspondence should be addressed at: Institute of Biomedical Sciences, Academia Sinica, 128, Sec.2, Academia Rd., Taipei 115, Taiwan. Tel: +886 227899078; Fax: +886 227824066; Email: lli{at}ibms.sinica.edu.tw
Received July 30, 2009; Accepted September 14, 2009
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.