Comprehensive Genomic Sequencing of Urothelial Tumors Identifies Rare SMARCB1 (INI-1)-Deficient Carcinomas of the Urinary System.

Purpose: Tumor genomic profiling helps direct therapy for advanced urothelial carcinoma (UC). In the course of clinical care, we encountered a patient with a complete loss of SMARCB1 (switch/sucrose nonfermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), which encodes INI-1 (integrase interactor 1), as the sole detected driver of their urinary tract tumor. Our objective was the identification and genomic characterization of urinary tract neoplasia with complete SMARCB1 loss.

Patients And Methods: Tissue from 1287 patients with UC was assayed by hybrid capture-based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA), such as, base substitutions, insertions/deletions, amplifications, copy number alterations, fusions/rearrangements, and targeted therapy opportunities. A total of 315 genes frequently altered in cancer were assayed.

Results: CGP identified 10 patients with SMARCB1 alterations. Of the 10 patients, 4 (1 each with renal pelvis, ureter, bladder, and unknown primary cancer) had complete loss of SMARCB1, and 6 had loss of heterozygosity with an unknown effect on function or heterozygous loss. Patients with complete SMARCB1 loss had few or no additional alterations. Compared with conventional UC, the tumor mutational burden was significantly lower (P = .004). All 4 patients with complete SMARCB1-loss tumors were < 56 years old and 3 were female.

Conclusion: The genomic profiles of the tumors from patients with UC revealed a population of tumors driven by complete loss of SMARCB1. This previously uncharacterized subset of INI-1-deficient urinary tract tumors might constitute a new tumor category that could be sensitive to targeted therapy, including EZH2 (enhancer of zeste homolog 2) inhibition. Clinical trial testing could be challenging owing to the rarity of the disease.