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Human Molecular Genetics Advance Access published online on March 11, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh111
© 2004 by Oxford University Press
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©2004 Oxford University Press

Article

Cloning of a new familial t(3;8) translocation associated with conventional renal cell carcinoma reveals a 5 Kb microdeletion and no gene involved in the rearrangement

Sandra Rodríguez-Perales 1, Bárbara Meléndez 2, Susan M Gribble 3, Laura Valle 2, Nigel P. Carter 3, Iñigo Santamaría 4, Lucia Conde 5, Miguel Urioste 2, Javier Benítez 2, and Juan C. Cigudosa 6*

1 Cytogenetics Unit, Biotechnology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
2 Department of Human Genetics, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
3 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. Trust Genome Campus, Hinxton, Cambridge, UK
4 Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Oviedo, 33006, Spain
5 Bioinformatics Unit, Biotechnology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
6 Cytogenetics Unit, Biotechnology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro, 3, 28029 Madrid, Spain

* To whom correspondence should be addressed. E-mail: jccigudosa{at}cnio.es.


  Abstract

This study describes the molecular cloning of a familial translocation, t(3;8)(p14.2;q24.2), that segregates with the conventional renal cell carcinoma (conventional-RCC). We had previously reported the family history and, through loss of heterozigosity (LOH) and comparative genomic hybridisation (CGH), detected the loss of the 3p chromosome arm and somatic mutation in the retained VHL gene in some members of the family. With the help of array painting and STS-PCR on flow sorted derivative chromosomes, we have cloned the breakpoints of the translocation. We have studied the junctions on both derivative chromosomes at the genomic and expression levels. The analysis of the sequence revealed a 5 Kb microdeletion at the chromosome 3 breakpoint together with a high density of repetitive motifs (Alu, SINE) and an AT-rich region. Both chromosome 3 and 8 rearranged regions were very poor in gene content. We tested an EST, two predicted genes, one novel gene and LRIG1, a gene located more than 200 Kb apart from the breakpoint on chromosome 3. None of these genes showed expression in any of the tested tissues (including normal adult and foetal kidney, sporadic kidney tumours and tumour samples from the proband's family). Taken together, all these data suggest that, rather than deregulation of specific genes that may be rearranged by the translocation, the proposed three-step model of tumour development (translocation, loss of the 3p chromosome, and mutation in a tumour suppressor gene located within that region) could be the biological mechanism that takes places in this familial form of conventional-RCC.


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