Abstract
Small, macroscopically visible cysts on the surface of the kidneys were observed in eight 6–8-week-old puppies diagnosed with renal cystadenocarcinoma and nodular dermatofibrosis (RCND). Histologic examination of the renal cortices in these puppies reveals numerous small cystic tubular changes. Hyperplastic change of the epithelial lining of cysts is frequently observed. By laser-capture microdissection we have sampled epithelial cells from such early renal cystic lesions in eight paternal half-sibs diagnosed with RCND. DNA was obtained from the laser-captured material, and all coding exons of the germline-mutated FLCN gene were sequenced to detect putative second hits. Samples from 31 independent hyperplastic epithelial cell sections of tubular microcysts of the RCND siblings were examined as well as normal control samples of the tissue sections. Loss of heterozygosity was detected in 35% of the transformed samples. The frequently observed loss of heterozygosity at the FLCN locus in atypical epithelial cells lining the cysts suggests that loss of heterozygosity/function of the FLCN gene may contribute to neoplastic transformation of renal epithelial cells at a very early age of RCND-affected dogs. The transformed renal epithelial cells seem to grow slowly in young puppies, which indicates that other mutational events are required for the development of tumors in adult dogs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Birt AR, Hogg GR, Dube WJ (1977) Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 113:1674–1677
Bønsdorff TB, Jansen JH, Lingaas F (2008) Second hits in the FLCN gene in a hereditary renal cancer syndrome in dogs. Mamm Genome 19:121–126
Kouchi M, Okimoto K, Matsumoto I, Tanaka K, Yasuba M, Hino O (2006) Natural history of the Nihon (Bhd gene mutant) rat, a novel model for human Birt-Hogg-Dube syndrome. Virchows Arch 448:463–471
Lingaas F, Comstock KE, Kirkness EF, Sorensen A, Aarskaug T, Hitte C, Nickerson ML, Moe L, Schmidt LS, Thomas R, Breen M, Galibert F, Zbar B, Ostrander EA (2003) A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. Hum Mol Genet 12:3043–3053
Lium B, Moe L (1985) Hereditary multifocal renal cystadenocarcinomas and nodular dermatofibrosis in the German shepherd dog: macroscopic and histopathologic changes. Vet Pathol 22:447–455
Moe L, Lium B (1997) Computed tomography of hereditary multifocal renal cystadenocarcinomas in German shepherd dogs. Vet Radiol Ultrasound 38:335–343
Moe L, Gamlem H, Jonasdottir TJ, Lingaas F (2000) Renal microcystic tubular lesions in two 1-year-old dogs—an early sign of hereditary renal cystadenocarcinoma? J Comp Pathol 123:218–221
Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS (2002) Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2:157–164
Okimoto K, Kouchi M, Matsumoto I, Sakurai J, Kobayashi T, Hino O (2004a) Natural history of the Nihon rat model of BHD. Curr Mol Med 4:887–893
Okimoto K, Sakurai J, Kobayashi T, Mitani H, Hirayama Y, Nickerson ML, Warren MB, Zbar B, Schmidt LS, Hino O (2004b) A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer. Proc Natl Acad Sci USA 101:2023–2027
Payne SR, Kemp CJ (2005) Tumor suppressor genetics. Carcinogenesis 26:2031–2045
van Steensel MAM, Verstraeten VLRM, Frank J, Kelleners-Smeets NWJ, Poblete-Gutierrez P, Marcus-Soekarman D, Bladergroen RS, Steijlen PM, van Geel M (2007) Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dube patients. J Invest Derm 127:588–593
Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, Merino MJ, Walther MM, Zbar B, Linehan WM (2005) High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dube-associated renal tumors. J Natl Cancer Inst 97:931–935
Acknowledgments
The authors thank Ingvild Østengen, Department of Basic Sciences and Aquatic Medicine, Norwegian School of Veterinary Sciences, for technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bønsdorff, T.B., Jansen, J.H., Thomassen, R.F. et al. Loss of heterozygosity at the FLCN locus in early renal cystic lesions in dogs with renal cystadenocarcinoma and nodular dermatofibrosis. Mamm Genome 20, 315–320 (2009). https://doi.org/10.1007/s00335-009-9183-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00335-009-9183-8