Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study.

Abstract

Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials. Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc). The most frequent GA in both U and NU cohorts included <i>TP53</i> (86.5% <i>v</i> 81.1%) and <i>KRAS</i> (34.6% <i>v</i> 27.7%). GAs characteristic of colorectal adenoCa, such as <i>SMAD4</i> (<i>P</i> = .069) and <i>GNAS</i> (<i>P</i> = .071), were more common in U versus NU. Conversely, <i>TERT</i> (<i>P</i> < .01) and <i>RB1</i> (<i>P</i> = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in <i>PIK3CA</i> (7.5% <i>v</i> 7.9%) and <i>ERBB2</i> (6.8% <i>v</i> 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature. U and NU adenoCAs revealed differences in GA, with <i>PIK3CA</i> and <i>ERBB2</i> being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.