Landscape of cyclin pathway genomic alterations across 7,207 non-prostate genitourinary tumors.
549 Background: Cyclin pathway genomic alterations can be a possible therapeutic target as well as a resistance mechanism for therapy. We describe the landscape of cyclin alterations (alt) in non-prostate genitourinary (GU) cancers. Methods: Consecutive samples were analyzed in a CLIA-certified laboratory using comprehensive genomic profiling (CGP) performed by next-generation tissuesequencing (315 genes, >500X coverage). We describe alterations in activating genes (Table) and co-alterations in resistant genes ( RB1 and CCNE1) (related to cyclin inhibition). Results: Alterations in any cyclin pathway genes were found in 37.9% of bladder/urothelial, 33.8% of testicular, 25.2% of penile and 24.6% of kidney cancers. Most alterations were copy number changes and frequencies varied substantially for each tumor type (Table). The high number of cases permitted identification of interesting patterns of outliers for each histology (examples: testis rhabdomyosarcoma and leydig tumor, 50% and 54.5% CDK4 alt; ureter urothelial, 17% CCND1 amp; bladder squamous, 41% CDKN2A del; kidney malignant rhabdoid, 90% SMARCB1 alt; urethra urothelial, 14.7% CCNE1 alt). Alterations in possible resistance genes RB1 and CCNE1 were more frequent in bladder cancers (especially with a neuroendocrine component). Co-occurrence analysis demonstrated a lower likelihood of concomitant vs. isolated alt in cyclin activating and resistance genes (odds ratio for bladder 0.17, p<0.001; OR testis 0.49, p<0.001 and OR kidney 0.45, p<0.001). Conclusions: Cyclin pathway activating and resistance genomic alt are variable in non-prostate GU tumors. Activating alt often occur without simultaneous resistance alt. Our data may inform opportunities for targeted therapy, especially for rare subtypes.[Table: see text]