Comparative genomic profiling of glandular bladder tumours

Abstract

Primary glandular bladder tumours (bladder adenocarcinoma [BAC], urachal adenocarcinoma [UAC], urothelial carcinoma with glandular differentiation [UCg]) are rare malignancies with histological resemblance to colorectal adenocarcinoma (CORAD) in the majority of this subgroup. Definite case numbers are very low, molecular data are limited and the pathogenesis remains poorly understood. Therefore, this study was designed to complement current knowledge by in depth analysis of BAC (n = 12), UAC (n = 13), UCg (n = 11) and non-invasive glandular lesions (n = 19). In BAC, in addition to known alterations in TP53, Wnt, MAP kinase and MTOR pathway, mutations in SMAD4, ARID1A and BRAF were identified. Compared to published data on muscle invasive bladder cancer (BLCA) and CORAD, UCg exhibited frequent "urothelial" like alterations while BAC and UAC were characterised by a more "colorectal" like mutational pattern. Immunohistochemically, there was no evidence of DNA mismatch repair deficiency or PD-L1 tumour cell positivity in any sample. Depending on the used antibody 0-45% of BAC, 0-30% of UCg and 0% UAC cases exhibited PD-L1 expressing tumour associated immune cells. A single BAC (9%, 1/11) showed evidence of ARID1A protein loss, and two cases of UCg (20%, 2/10) showed loss of SMARCA1 and PBRM1, respectively. Taken together, our data suggest at least in part involvement of similar pathways driving tumourigenesis of adenocarcinomas like BAC, UAC and CORAD independent of their tissue origin. Alterations of TERT and FBXW7 in single cases of intestinal metaplasia further point towards a possible precancerous character in line with previous reports.

Molecular Characterization of Muellerian Tumors of the Urinary Tract

“…However, our findings may help in diagnostically very difficult MTUT cases, since a wild type TERT promoter mutation analysis could serve as an additional tool to guide pathologists as well as clinicians in diagnosis and management. Comparing the data with our previous characterization of genetic alterations of intestinal type adenocarcinomas of the bladder, it parallels with clear cell adenocarcinomas, since genes such as ARID1A (intestinal type: 30.6%), CTNNB1 (intestinal type: 11.1%), and MSH6 (intestinal type: 8.3%) showed similar mutational frequencies between both carcinomas [22]. In contrast, TP53 mutations seem to be much more predominant in intestinal type adenocarcinomas of the bladder (31 out of 36) than in clear cell adenocarcinomas of the bladder/urethra (1 out of 11).…”

A new technological approach in diagnostic pathology: mass spectrometry imaging-based metabolomics for biomarker detection in urachal cancer

“…The histopathological differential diagnostic process of UrC is of major therapeutic importance. However, as supportive diagnostic technologies were shown to be helpful only in a subset of cases or specific settings [ 4 , 28 , 29 ], diagnostic biomarkers are urgently needed.…”

A phase II trial of durvalumab and tremelimumab in metastatic, non‐urothelial carcinoma of the urinary tract

“…As observed in other neuroendocrine cohorts, 4,29 TP53 and RB1 were co‐altered in all four NE histology tumors, but other neuronal genes previously described in neuroendocrine‐like bladder tumors 37,38 were not present. Additionally, a KRAS activating mutation was seen in one urachal ADC and a SMAD4 truncating mutation in a second, both of which have been reported in cohorts of urinary tract ADC 39,40 . Notably, the one patient who derived clinical benefit on study had a NE carcinoma that exhibited a high TMB, which has been associated with sensitivity to checkpoint blockade in UC 28 …”

“…Additionally, a KRAS activating mutation was seen in one urachal ADC and a SMAD4 truncating mutation in a second, both of which have been reported in cohorts of urinary tract ADC. 39,40 Notably, the one patient who derived clinical benefit on study had a NE carcinoma that exhibited a high TMB, which has been associated with sensitivity to checkpoint blockade in UC 28 Given the published data indicating a correlation between DDR gene alterations and response to checkpoint blockade in UC, 41 we also looked for a similar correlation within our non-UC cohort. One patient with NE had an ERCC2 S44L mutation.…”