Clinicopathologic and Genomic Evaluation of Translocation Renal Cell Carcinoma
Translocation renal cell carcinomas (tRCC) represent 1-5% of all RCCs and are associated with aggressive disease and poor outcomes. tRCCs uniformly contain gene fusions of either transcription factor E3 (TFE3) or transcription factor EB (TFEB) with various partners, or rarely, TFEB amplification. However, given the rarity of these tumors, much remains unknown about other important genomic drivers of this disease.
From 2004 to 2017, 34 patients with tRCC were retrospectively identified at MSKCC. tRCC was diagnosed using a combination of immunohistochemistry (IHC), fluorescence-in-situ hybridization (FISH) and/or targeted exon sequencing using MSK IMPACT. Genomic alterations were assessed in 21 (61.7%) patients who underwent IMPACT testing utilizing either primary (62%) or metastatic (38%) tumor specimens.
The median follow-up for the cohort was 28.7 months (range 1.6-244.9) with a median age at diagnosis of 48 (range 6-78). Four patients (11.8%) were less than 18 years of age at diagnosis and 19 (55.9%) were women. Surgery was performed in 30 (88.2%) patients, with 19 (63.3%) undergoing radical nephrectomy and 11 (36.6%) partial nephrectomy. The majority of patients had pathologic stage III-IV disease (59%). Notably, 7 (23.3%) of surgical patients had positive nodal disease on pathology. Overall, 7 (20.6%) died of disease with a median overall survival of 27.5 months (IQR 26.8-82.1) with 4 (11.7%) patients lost to follow-up. A TFE3 fusion was identified in 31 patients (91.2%) and 3 (8.8%) had a TFEB fusion. The TFE3 fusion partner was identified in 13 patients (38.2%). Out of six distinct fusion partners identified, the most common TFE3 fusion partner was ASPSCR1 (28.6%). We additionally identified somatic mutations in the TERT promoter (14%), chromatin remodeling (14%) and DNA damage repair (DDR) (14%) genes and these were enriched in metastatic lesions.
tRCC is a rare subtype of RCC presenting in younger patients and more frequent in women compared to clear cell RCC. Furthermore, the majority of these tumors present at advanced stages and with a high rate of nodal disease and recurrence. We demonstrate, for the first time, additional somatic mutations in the TERT promoter, chromatin remodeling, and DDR pathways. These findings may have important implications for understanding the biology of this disease and development of novel therapeutic targets.