Cytogenomic Analysis of Translocation Renal Cell Carcinomas Reveals Distinct Molecular Subtypes with Similarities to Other Renal Cell Tumors
Federico A Monzon, Gabriel Malouf, Jerome Couturier, Vincent Molinie, Philippe Escudier, Pheroze Tamboli, Dolores Lopez-Terrada, Maria Picken, Marileila Garcia, Nizar Tannir. The Methodist Hospital, Houston, TX; MD Anderson Cancer Center, Houston, TX; Institut Curie, Paris, France; Hopital Saint Joseph, Paris, France; Institut Gustave Roussy, Villejuif, France; Texas Children's Hospital, Houston, TX; Loyola University Medical Center, Chicago, IL; University of Colorado, Aurora, CO
Background: Translocation renal cell carcinoma (RCC) is a subtype of kidney cancer characterized by translocations involving TFEB or TFE3 genes. Little is known about the whole genome and epigenetic characteristics of these tumors. Translocation RCC shows heterogeneity in clinical behavior with some patients having highly aggressive tumors. We performed genomic characterization of a cohort of translocation RCCs to investigate if molecular subtypes of these tumors exist.
Design: Cytogenomic analysis was performed with 250K Nsp 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 level were measured by using pyrosequencing of highly repetitive LINE-1 sequences on 27 tumor samples. Results were correlated with clinical and demographic information.
Results: Three distinct molecular subtypes were identified. Eight patients and one cell line (42%) showed 3p loss in a background of chromosomal imbalances commonly seen in clear-cell RCC. Three patients and the other cell line (19%) showed profiles similar to papillary RCC with gains of 7 and/or 17. The remaining 8 patients showed either a diploid genome or unique cytogenomic profiles. Three cases showed uniparental disomy lesions (UPD). Patients with 3p loss showed poor overall survival (OS) (Median OS: 12.7 month vs not reached) (p=0.03). There was no association between 3p loss and other clinico-pathological variables. Young patients (<18 years) displayed fewer numbers of genetic abnormalities as compared to older patients (p=0.02). Line-1 methylation was found to be lower in adult patients (71.1% vs 76.7%, p=0.02).
Conclusions: Our results show that subsets of translocation RCC are characterized by genetic profiles similar to those of clear-cell and papillary RCC. Evaluation of VHL mutation in tumors with 3p loss is underway. Tumors with 3p loss appear to show more aggressive behavior. We also identified Line-1 hypomethylation in adult tumors. These findings could explain the clinical heterogeneity observed in translocation RCC patients and could potentially be used to determine treatment strategies.
Category: Genitourinary (including renal tumors)
Monday, March 19, 2012 11:00 AM
Platform Session: Section A, Monday Morning