34. De novo constitutional PATRR-mediated t(3;8) balanced translocation associated with clear cell renal cell carcinoma

      Our study describes a 33-year old male diagnosed with bilateral clear cell renal cell carcinoma (ccRCC) (8 primary tumors) who harbors a de novo constitutional Palindromic Adenine and Thymine Rich Repeat (PATRR)- mediated t(3;8) balanced translocation validated by spectral karyotyping. No germline or somatic pathogenic alterations were detected in VHL gene suggesting that his phenotype is not associated with Von Hippel-Lindau syndrome. Of note, there is no history of cancer in the family. We determined the chromosome 3 breakpoint to be located in an AT-rich palindromic sequence in the third intron of FHIT gene, member of the fragile histidine triad family, and the chromosome 8 breakpoint in the first intron of TRC8 gene, a E3 ubiquitin ligase which regulates cholesterol and lipid biosynthesis. This translocation results in the expression of a fusion transcript and disrupts the TRC8 gene within its sterol sensing domain. During the proband's latest partial nephrectomy we isolated his newly developed tumor and generated an immortalized ccRCC cell line which harbors the t(3;8). This case illustrates the importance of considering karyotype analysis in individuals with early-onset ccRCC, when VHL gene testing is normal. It would be ideal to create a practice guideline to include translocations on the differential for such families when appropriate. Employing genomic and transcriptomic techniques and possibly future functional experimental approaches this study elucidates the pathobiology of a de novo constitutional PATRR-mediated t(3;8) balanced translocation associated with ccRCC and might pave the way for novel therapeutic strategies in the field of Personalized Cancer Genomics.
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