Hepatocyte nuclear factor 1 beta (HNF1B) is a transcription factor which plays a crucial role in nephronogenesis, and its germline mutations have been associated with kidney developmental disorders. However, the effects of HNF1B somatic exonic mutations and its role in the pathogenesis of kidney tumours has not yet been elucidated. Depending on the type of the tumour HNF1B may act as a tumour suppressor or oncogene, although the exact mechanism by which HNF1B participates in the process of cancerogenesis is unknown. Using an immunohistochemical approach, and methylation and mutation analysis, we have investigated the expression, epigenetic, and genetic changes of HNF1B in 130 cases of renal tumours (121 renal cell carcinomas, 9 oncocytomas). In the subset of clear cell renal cell carcinoma (ccRCC), decreased HNF1B expression was associated with a higher tumour grade and higher T stage. The mutation analysis revealed no mutations in the analysed samples. Promoter methylation was detected in two ccRCCs and one oncocytoma. The results of our work on a limited sample set suggest that while in papillary renal cell carcinoma HNF1B functions as an oncogene, in ccRCC and chRCC it may act in a tumour suppressive fashion.

Department of Urology General University Hospital Prague 12808 Prague Czech Republic

Institute of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Studnickova 2 12800 Prague 2 Czech Republic

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Barbacci E, et al. HNF1beta/TCF2 mutations impair transactivation potential through altered co-regulator recruitment. Hum. Mol. Genet. 2004;13:3139–3149. doi: 10.1093/hmg/ddh338. PubMed DOI

Kettunen JLT, et al. Biliary anomalies in patients with HNF1B diabetes. J. Clin. Endocrinol. Metab. 2017;102:2075–2082. doi: 10.1210/jc.2017-00061. PubMed DOI

Banyai D, Sarlos DP, Nagy A, Kovacs G. Recalling Cohnheim's theory: papillary renal cell tumor as a model of tumorigenesis from impaired embryonal differentiation to malignant tumors in adults. Int. J. Biol. Sci. 2018;14:784–790. doi: 10.7150/ijbs.22489. PubMed DOI PMC

Clissold RL, et al. Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1beta-associated renal disease and can be symptomatic. Clin. Kidney J. 2018;11:453–458. doi: 10.1093/ckj/sfx150. PubMed DOI PMC

Clissold RL, Hamilton AJ, Hattersley AT, Ellard S, Bingham C. HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum. Nat. Rev. Nephrol. 2015;11:102–112. doi: 10.1038/nrneph.2014.232. PubMed DOI

Okorn C, et al. HNF1B nephropathy has a slow-progressive phenotype in childhood-with the exception of very early onset cases: results of the German Multicenter HNF1B Childhood Registry. Pediatr. Nephrol. 2019;34:1065–1075. doi: 10.1007/s00467-018-4188-8. PubMed DOI

Omura Y, et al. Clinical manifestations of a sporadic maturity-onset diabetes of the young (MODY) 5 with a whole deletion of HNF1B based on 17q12 microdeletion. Endocr. J. 2019;66:1113–1116. doi: 10.1507/endocrj.EJ19-0020. PubMed DOI

Alvelos MI, et al. A novel mutation of the HNF1B gene associated with hypoplastic glomerulocystic kidney disease and neonatal renal failure: a case report and mutation update. Medicine. 2015;94:e469. doi: 10.1097/MD.0000000000000469. PubMed DOI PMC

Kato N, Motoyama T. Hepatocyte nuclear factor-1beta(HNF-1beta) in human urogenital organs: its expression and role in embryogenesis and tumorigenesis. Histol. Histopathol. 2009;24:1479–1486. doi: 10.14670/HH-24.1479. PubMed DOI

Madariaga L, et al. Variable phenotype in HNF1B mutations: extrarenal manifestations distinguish affected individuals from the population with congenital anomalies of the kidney and urinary tract. Clin. Kidney J. 2019;12:373–379. doi: 10.1093/ckj/sfy102. PubMed DOI PMC

Roehlen N, et al. 17q12 deletion syndrome as a rare cause for diabetes mellitus type MODY5. J. Clin. Endocrinol. Metab. 2018;103:3601–3610. doi: 10.1210/jc.2018-00955. PubMed DOI

Dubois-Laforgue D, et al. Diabetes, associated clinical spectrum, long-term prognosis, and genotype/phenotype correlations in 201 adult patients with hepatocyte nuclear factor 1B (HNF1B) molecular defects. Diabetes Care. 2017;40:1436–1443. doi: 10.2337/dc16-2462. PubMed DOI

Stiles CE, et al. De novo HNF1 homeobox B mutation as a cause for chronic, treatment-resistant hypomagnesaemia. Endocrinol. Diabetes Metab. Case Rep. 2018;1:5. doi: 10.1530/EDM-17-0120. PubMed DOI PMC

Berndt SI, et al. Large-scale fine mapping of the HNF1B locus and prostate cancer risk. Hum. Mol. Genet. 2011;20:3322–3329. doi: 10.1093/hmg/ddr213. PubMed DOI PMC

Ross-Adams H, et al. HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer. Oncotarget. 2016;7:74734–74746. doi: 10.18632/oncotarget.12543. PubMed DOI PMC

Painter JN, et al. Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk. Hum. Mol. Genet. 2015;24:1478–1492. doi: 10.1093/hmg/ddu552. PubMed DOI PMC

Setiawan VW, et al. HNF1B and endometrial cancer risk: results from the PAGE study. PLoS ONE. 2012;7:e30390. doi: 10.1371/journal.pone.0030390. PubMed DOI PMC

Rebouissou S, et al. Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas. Hum. Mol. Genet. 2005;14:603–614. doi: 10.1093/hmg/ddi057. PubMed DOI

Bartu M, et al. The role of HNF1B in tumorigenesis of solid tumours: a review of current knowledge. Folia Biol. (Praha) 2018;64:71–83. PubMed

Matsui A, et al. Hepatocyte nuclear factor 1 beta induces transformation and epithelial-to-mesenchymal transition. FEBS Lett. 2016;590:1211–1221. doi: 10.1002/1873-3468.12147. PubMed DOI

Buchner A, et al. Downregulation of HNF-1B in renal cell carcinoma is associated with tumor progression and poor prognosis. Urology. 2010;76(507):e506–511. doi: 10.1016/j.urology.2010.03.042. PubMed DOI

Sun M, et al. HNF1B loss exacerbates the development of chromophobe renal cell carcinomas. Cancer Res. 2017;77:5313–5326. doi: 10.1158/0008-5472.CAN-17-0986. PubMed DOI PMC

Szponar A, Yusenko MV, Kuiper R, van Kessel AG, Kovacs G. Genomic profiling of papillary renal cell tumours identifies small regions of DNA alterations: a possible role of HNF1B in tumour development. Histopathology. 2011;58:934–943. doi: 10.1111/j.1365-2559.2011.03795.x. PubMed DOI

Escudier B, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-updagger. Ann. Oncol. 2019;30:706–720. doi: 10.1093/annonc/mdz056. PubMed DOI

Turajlic S, Swanton C, Boshoff C. Kidney cancer: The next decade. J. Exp. Med. 2018;215:2477–2479. doi: 10.1084/jem.20181617. PubMed DOI PMC

Courthod G, Tucci M, Di Maio M, Scagliotti GV. Papillary renal cell carcinoma: a review of the current therapeutic landscape. Crit. Rev. Oncol. Hematol. 2015;96:100–112. doi: 10.1016/j.critrevonc.2015.05.008. PubMed DOI

Gallardo E, et al. SEOM clinical guideline for treatment of kidney cancer (2017) Clin. Transl. Oncol. 2018;20:47–56. doi: 10.1007/s12094-017-1765-4. PubMed DOI PMC

Bartu M, et al. Expression, epigenetic, and genetic changes of HNF1B in colorectal lesions: an analysis of 145 cases. Pathol. Oncol. Res. 2020 doi: 10.1007/s12253-020-00830-2. PubMed DOI

Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO Classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours. Eur. Urol. 2016;70:93–105. doi: 10.1016/j.eururo.2016.02.029. PubMed DOI

Hirsch FR, et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J. Clin. Oncol. 2003;21:3798–3807. doi: 10.1200/JCO.2003.11.069. PubMed DOI

Gregova M, et al. Leiomyoma with bizarre nuclei: a study of 108 cases focusing on clinicopathological features, morphology, and fumarate hydratase alterations. Pathol. Oncol. Res. 2019 doi: 10.1007/s12253-019-00739-5. PubMed DOI

Ticha I, et al. A comprehensive evaluation of pathogenic mutations in primary cutaneous melanomas, including the identification of novel loss-of-function variants. Sci. Rep. 2019;9:17050. doi: 10.1038/s41598-019-53636-x. PubMed DOI PMC

Shen H, et al. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nat. Commun. 2013;4:1628. doi: 10.1038/ncomms2629. PubMed DOI PMC

Wojdacz TK, Dobrovic A, Hansen LL. Methylation-sensitive high-resolution melting. Nat. Protoc. 2008;3:1903–1908. doi: 10.1038/nprot.2008.191. PubMed DOI

Bockenhauer D, Jaureguiberry G. HNF1B-associated clinical phenotypes: the kidney and beyond. Pediatr. Nephrol. 2016;31:707–714. doi: 10.1007/s00467-015-3142-2. PubMed DOI

Sun J, et al. Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12. Nat. Genet. 2008;40:1153–1155. doi: 10.1038/ng.214. PubMed DOI PMC

Kobel M, et al. A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary. Am. J. Surg. Pathol. 2009;33:14–21. doi: 10.1097/PAS.0b013e3181788546. PubMed DOI

Amano Y, et al. Metabolic alterations caused by HNF1beta expression in ovarian clear cell carcinoma contribute to cell survival. Oncotarget. 2015;6:26002–26017. doi: 10.18632/oncotarget.4692. PubMed DOI PMC

Cuff J, et al. Integrative bioinformatics links HNF1B with clear cell carcinoma and tumor-associated thrombosis. PLoS ONE. 2013;8:e74562. doi: 10.1371/journal.pone.0074562. PubMed DOI PMC

Nemejcova K, et al. Expression, epigenetic and genetic changes of HNF1B in endometrial lesions. Pathol. Oncol. Res. 2016;22:523–530. doi: 10.1007/s12253-015-0037-2. PubMed DOI

Lebrun G, et al. Cystic kidney disease, chromophobe renal cell carcinoma and TCF2 (HNF1 beta) mutations. Nat. Clin. Pract. Nephrol. 2005;1:115–119. doi: 10.1038/ncpneph0054. PubMed DOI

Bubancova I, et al. Next-generation sequencing approach in methylation analysis of HNF1B and GATA4 genes: searching for biomarkers in ovarian cancer. Int. J. Mol. Sci. 2017;18:1. doi: 10.3390/ijms18020474. PubMed DOI PMC

Cancer Genome Atlas Research N The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–1025. doi: 10.1016/j.cell.2015.10.025. PubMed DOI PMC

Wang CC, Mao TL, Yang WC, Jeng YM. Underexpression of hepatocyte nuclear factor-1beta in chromophobe renal cell carcinoma. Histopathology. 2013;62:589–594. doi: 10.1111/his.12026. PubMed DOI

Yu DD, Guo SW, Jing YY, Dong YL, Wei LX. A review on hepatocyte nuclear factor-1beta and tumor. Cell Biosci. 2015;5:58. doi: 10.1186/s13578-015-0049-3. PubMed DOI PMC

Tsuchiya A, et al. Expression profiling in ovarian clear cell carcinoma: identification of hepatocyte nuclear factor-1 beta as a molecular marker and a possible molecular target for therapy of ovarian clear cell carcinoma. Am. J. Pathol. 2003;163:2503–2512. doi: 10.1016/S0002-9440(10)63605-X. PubMed DOI PMC

Akin IB, et al. Discrimination of oncocytoma and chromophobe renal cell carcinoma using MRI. Diagn. Interv. Radiol. 2019;25:5–13. doi: 10.5152/dir.2018.18013. PubMed DOI PMC

von Brandenstein M, et al. MicroRNAs as urinary biomarker for oncocytoma. Dis Markers. 2018;1:6979073. doi: 10.1155/2018/6979073. PubMed DOI PMC

Conner JR, Hirsch MS, Jo VY. HNF1beta and S100A1 are useful biomarkers for distinguishing renal oncocytoma and chromophobe renal cell carcinoma in FNA and core needle biopsies. Cancer Cytopathol. 2015;123:298–305. doi: 10.1002/cncy.21530. PubMed DOI

Comprehensive quantitative analysis of alternative splicing variants reveals the HNF1B mRNA splicing pattern in various tumour and non-tumour tissues