Characterisation of renal cell carcinoma-associated constitutional chromosome abnormalities by genome sequencing.

Constitutional translocations, typically involving chromosome 3, have been recognised as a rare cause of inherited predisposition to renal cell carcinoma (RCC) for four decades. However, knowledge of the molecular basis of this association is limited. We have characterised the breakpoints by genome sequencing (GS) of constitutional chromosome abnormalities in five individuals who presented with RCC. In one individual with constitutional t(10;17)(q11.21;p11.2) the translocation breakpoint disrupted two genes: the known renal tumour suppressor gene (TSG) FLCN (and clinical features of Birt-Hogg-Dubé syndrome were detected) and RASGEF1A. In four cases the rearrangement breakpoints did not disrupt known inherited RCC genes. In the second case without chromosome 3 involvement the translocation breakpoint in an individual with a constitutional t(2;17)(q21.1;q11.2) mapped 12 Kb upstream of NLK. Interestingly NLK has been reported to interact indirectly with FBXW7 and a previously reported RCC-associated translocation breakpoint disrupted FBXW7. In two cases of constitutional chromosome 3 translocations, no candidate TSGs were identified in the vicinity of the breakpoints. However, in an individual with a constitutional chromosome 3 inversion, the 3p breakpoint disrupted the FHIT TSG (which has been reported previously to be disrupted in two apparently unrelated families with an RCC-associated t(3;8)(p14.2;q24.1). These findings a) expand the range of constitutional chromosome rearrangements that may be associated with predisposition to RCC, b) confirm that chromosome rearrangements not involving chromosome 3 can predispose to RCC, c) suggest that a variety of molecular mechanisms are involved the pathogenesis of translocation-associated RCC and d) demonstrate the utility of genome sequencing for investigating such cases. This article is protected by copyright. All rights reserved.

Genes, chromosomes & cancer. 2020 Jan 14 [Epub ahead of print]

Philip S Smith, James Whitworth, Hannah West, Jacqueline Cook, Carol Gardiner, Derek Lim, Patrick J Morrison, R Gordon Hislop, Emily Murray, NIHR Rare Disease BioResource , Marc Tischkowitz, Anne Y Warren, Emma R Woodward, Eamonn R Maher

Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, Cambridge Biomedical Campus, Cambridge, UK., Department of Clinical Genetics, Sheffield Children's Hospital, Sheffield, UK., West of Scotland Genetics Services, Queen Elizabeth University Hospital, Glasgow, UK., West Midlands Regional Genetics Service, Birmingham Women's and Children's National Health Service (NHS) Foundation Trust, Birmingham, UK., Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast Health & Social Care Trust, Belfast, UK., Ninewells Hospital, University of Dundee, Dundee, UK., NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, UK., Department of Histopathology, Cambridge University NHS Foundation Trust and Cancer Research UK Cambridge Centre, Cambridge, UK., Manchester Centre for Genomic Medicine and NW Laboratory Genetics Hub, Manchester University Hospitals NHS Foundation Trust, and Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Health Innovation Manchester, Manchester, UK.