Abstract
Autosomal dominant polycystic liver disease (ADPLD) is caused by variants in PRKCSH, SEC63, and LRP5, whereas autosomal dominant polycystic kidney disease is caused by variants in PKD1 and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild-type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel PLD genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0 Mb) and large CNVs (>1.0 Mb). We found frequent LOH in PRKCSH (22/29) and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy-number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD.
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References
Bae KT, Zhu F, Chapman AB et al: Magnetic resonance imaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Clin J Am Soc Nephrol 2006; 1: 64–69.
Pirson Y : Extrarenal manifestations of autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis 2010; 17: 173–180.
Waanders E, te Morsche RH, de Man RA, Jansen JB, Drenth JP : Extensive variantal analysis of PRKCSH and SEC63 broadens the spectrum of polycystic liver disease. Hum Mutat 2006; 27: 830.
Cnossen WR, te Morsche RH, Hoischen A et al: Whole-exome sequencing reveals LRP5 variants and canonical Wnt signaling associated with hepatic cystogenesis. Proc Natl Acad Sci USA 2014; 111: 5343–5348.
Harris PC, Torres VE : Polycystic kidney disease. Annu Rev Med 2009; 60: 321–337.
Wills ES, Roepman R, Drenth JP : Polycystic liver disease: ductal plate malformation and the primary cilium. Trends Mol Med 2014; 20: 261–270.
Fedeles SV, Gallagher AR, Somlo S : Polycystin-1: a master regulator of intersecting cystic pathways. Trends Mol Med 2014; 20: 251–260.
Fedeles SV, Tian X, Gallagher AR et al: A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat Genet 2011; 43: 639–647.
Ma M, Tian X, Igarashi P, Pazour GJ, Somlo S : Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat Genet 2013; 45: 1004–1012.
Janssen MJ, Salomon J, Te Morsche RH, Drenth JP : Loss of heterozygosity is present in SEC63 germline carriers with polycystic liver disease. PLoS One 2012; 7: e50324.
Janssen MJ, Waanders E, Te Morsche RH et al: Secondary, somatic variants might promote cyst formation in patients with autosomal dominant polycystic liver disease. Gastroenterology 2011; 141: e2052.
Pei Y : A "two-hit" model of cystogenesis in autosomal dominant polycystic kidney disease? Trends Mol Med 2001; 7: 151–156.
Pei Y, Watnick T, He N et al: Somatic PKD2 variants in individual kidney and liver cysts support a "two-hit" model of cystogenesis in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1999; 10: 1524–1529.
Watnick T, He N, Wang K et al: Variants of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous variants. Nat Genet 2000; 25: 143–144.
Wu G, Tian X, Nishimura S et al: Trans-heterozygous Pkd1 and Pkd2 variants modify expression of polycystic kidney disease. Hum Mol Genet 2002; 11: 1845–1854.
Li M, Qin S, Wang L, Zhou J : Genomic instability in patients with autosomal-dominant polycystic kidney disease. J Int Med Res 2013; 41: 169–175.
Gogusev J, Murakami I, Doussau M et al: Molecular cytogenetic aberrations in autosomal dominant polycystic kidney disease tissue. J Am Soc Nephrol 2003; 14: 359–366.
Janssen MJ, Salomon J, Cnossen WR, Bergmann C, Pfundt R, Drenth JP : Somatic loss of polycystic disease genes contributes to the formation of isolated and polycystic liver cysts. Gut 2014; 64: 688–690.
Huch M, Gehart H, van Boxtel R et al: Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 2014; 160: 299–312.
Tan YC, Michaeel A, Blumenfeld J et al: A novel long-range PCR sequencing method for genetic analysis of the entire PKD1 gene. J Mol Diagn 2012; 14: 305–313.
Reynolds DM, Falk CT, Li A et al: Identification of a locus for autosomal dominant polycystic liver disease, on chromosome 19p13.2-13.1. Am J Hum Genet 2000; 67: 1598–1604.
Pei Y, Obaji J, Dupuis A et al: Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol 2009; 20: 205–212.
Baker DJ, Jin F, Jeganathan KB, van Deursen JM : Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer Cell 2009; 16: 475–486.
Lindhurst MJ, Sapp JC, Teer JK et al: A mosaic activating variant in AKT1 associated with the Proteus syndrome. N Engl J Med 2011; 365: 611–619.
Dunn JM, Phillips RA, Becker AJ, Gallie BL : Identification of germline and somatic variants affecting the retinoblastoma gene. Science 1988; 241: 1797–1800.
de Voer RM, Geurts van Kessel A, Weren RD et al: Germline variants in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer. Gastroenterology 2013; 145: 544–547.
Yu HE, Hawash K, Picker J et al: A recurrent 1.71 Mb genomic imbalance at 2q13 increases the risk of developmental delay and dysmorphism. Clin Genet 2012; 81: 257–264.
Decaens T, Godard C, de Reynies A et al: Stabilization of beta-catenin affects mouse embryonic liver growth and hepatoblast fate. Hepatology 2008; 47: 247–258.
Saadi-Kheddouci S, Berrebi D, Romagnolo B et al: Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene. Oncogene 2001; 20: 5972–5981.
Blaker H, Hofmann WJ, Rieker RJ, Penzel R, Graf M, Otto HF : Beta-catenin accumulation and variant of the CTNNB1 gene in hepatoblastoma. Genes Chromosomes Cancer 1999; 25: 399–402.
Giardiello FM, Petersen GM, Brensinger JD et al: Hepatoblastoma and APC gene variant in familial adenomatous polyposis. Gut 1996; 39: 867–869.
Lal M, Song X, Pluznick JL et al: Polycystin-1 C-terminal tail associates with beta-catenin and inhibits canonical Wnt signaling. Hum Mol Genet 2008; 17: 3105–3117.
Geng M, Cao YC, Chen YJ, Jiang H, Bi LQ, Liu XH : Loss of Wnt5a and Ror2 protein in hepatocellular carcinoma associated with poor prognosis. World J Gastroenterol 2012; 18: 1328–1338.
Gevers TJ, Drenth JP : Diagnosis and management of polycystic liver disease. Nat Rev Gastroenterol Hepatol 2013; 10: 101–108.
Sherstha R, McKinley C, Russ P et al: Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease. Hepatology 1997; 26: 1282–1286.
Chapman AB : Cystic disease in women: clinical characteristics and medical management. Adv Ren Replace Ther 2003; 10: 24–30.
Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L : A review of trisomy X (47,XXX). Orphanet J Rare Dis 2010; 5: 8.
Caroli A, Perico N, Perna A et al: Effect of longacting somatostatin analogue on kidney and cyst growth in autosomal dominant polycystic kidney disease (ALADIN): a randomised, placebo-controlled, multicentre trial. Lancet 2013; 382: 1485–1495.
Hogan MC, Masyuk TV, Page LJ et al: Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol 2010; 21: 1052–1061.
Caroli A, Antiga L, Cafaro M et al: Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide. Clin J Am Soc Nephrol 2010; 5: 783–789.
Gevers TJ, Drenth JP : Somatostatin analogues for treatment of polycystic liver disease. Curr Opinion Gastroenterol 2011; 27: 294–300.
Hesson LB, Cooper WN, Latif F : Evaluation of the 3p21.3 tumour-suppressor gene cluster. Oncogene 2007; 26: 7283–7301.
Tommasi S, Dammann R, Zhang Z et al: Tumor susceptibility of Rassf1a knockout mice. Cancer Res 2005; 65: 92–98.
Tischoff I, Markwarth A, Witzigmann H et al: Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors. Int J Cancer 2005; 115: 684–689.
Thivierge C, Kurbegovic A, Couillard M, Guillaume R, Cote O, Trudel M : Overexpression of PKD1 causes polycystic kidney disease. Mol Cell Biol 2006; 26: 1538–1548.
Acknowledgements
We thank our patients and their families for their participation and providing samples. We appreciate the input of the Genomic Disorders Group and the Molecular Biology of Ciliopathies group from the Department of Human Genetics, Radboud University Medical Center. We thank Dr Erwin van Geffen, Department of Surgery, Jeroen Bosch ziekenhuis for his valuable assistance in obtaining and processing the samples and the data. This work was supported by a grant of the Institute for Genetic and Metabolic Disease (IGMD) of the Radboud University Medical Center and by a grant from the Dutch foundation of digestive diseases WO10-50 (MLDS) (both to ESW and WRC).
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Wills, E., Cnossen, W., Veltman, J. et al. Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes. Eur J Hum Genet 24, 1707–1714 (2016). https://doi.org/10.1038/ejhg.2016.97
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DOI: https://doi.org/10.1038/ejhg.2016.97
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