TP53 structural variants in metastatic prostatic carcinoma

Sequencing data have been instrumental in identifying oncogenic drivers in prostatic carcinoma and highlighting biomarkers that define aggressive disease. A review of a series of 30 primary and metastatic prostatic carcinomas clinically sequenced at our cancer genomics laboratory utilizing a targeted gene panel identified recurrent structural variants in the TP53 gene. These structural variants were found in 27% of all sequenced cases and represented 36% of the cases with metastatic disease. TP53 structural rearrangements have been previously reported in a significant subset of osteosarcomas, where they result in loss of p53 protein expression by immunohistochemistry. Similarly, in our prostate cases with TP53 structural rearrangements for which tissue was available for testing, we find loss of p53 protein expression by immunohistochemistry. In the eight TP53-rearranged cases, concurrent PTEN loss was identified in 4 cases, TMPRSS2-ERG fusion in 5 cases, and AR and FOXA1 amplification in 1 case each. Our results from this small case series suggest that TP53 rearrangements with loss of expression represent a frequent alternative mechanism of inactivation of this key tumor suppressor gene with potential utility as a marker of aggressive disease. Recognition of this TP53 rearrangement pathway is essential to accurately identify prostatic carcinomas with loss of TP53 function.