Genomic analysis of translocation renal cell carcinoma: Association of frequent 3p loss and poor outcome.

Abstract

360 Background: Translocation renal cell carcinoma (RCC) is a rare subtype of kidney cancer that is characterized by translocations involving TFEB or TFE3 genes. We recently reported that adults with translocation RCC have worse prognosis than pediatric and adolescent patients (Malouf et al, J Urol, 2011), however little is known about the genetic and epigenetic differences between these groups. Methods: Cytogenomic analysis was performed with 250K SNP microarrays (Affymetrix) on 19 tumor specimens of translocation RCC (Age <18 (n=6); Age >=18 (n=13) and 2 established cell lines (UOK109, UOK146). Changes in global DNA methylation levels were measured by using pyrosequencing of highly repetitive LINE-1 sequences on 27 tumor samples. Results were correlated with the patients’ clinical data. Results: 3p loss was observed in 8 patients (42%) and was associated with other chromosomal alterations frequently seen in clear-cell RCC such as 9p loss. Patients with 3p loss showed poor overall survival (OS) as compared to patients without 3p loss (Median OS 12.7 month vs. not reached) [p=0.03]. There was no association found between 3p loss and clinico-pathological variables such as AJCC stage, age and gender. The UOK146 cell line also showed 3p and 9p loss. Young patients (<18 years) displayed fewer number of genetic abnormalities as compared to older patients (p=0.02). Moreover, Line-1 methylation was found to be lower in adult as compared to young patients (76.7% vs. 71.1%, p=0.02). Conclusions: Our results show that a subset of translocation RCC is characterized by a genetic profile similar to that of clear-cell RCC and these tumors seem to behave aggressively. Studies to determine the presence of VHL mutation in these tumors are underway. Adult patients display higher genetic abnormalities and lower Line-1 methylation as compared to young patients. These results might explain the different behavior of pediatric and adult translocation RCC.