Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas

Abstract

Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy based on a biological rationale may provide an alternative strategy. We therefore subjected 70 urachal adenocarcinomas to targeted next-generation sequencing, conducted in situ and immunohistochemical analyses (including PD-L1 and DNA mismatch repair proteins [MMR]) and evaluated the microsatellite instability (MSI) status. The analytical findings were correlated with clinicopathological and outcome data and Kaplan-Meier and univariable/multivariable Cox regression analyses were performed. The patients had a mean age of 50 years, 66% were male and a 5-year overall survival (OS) of 58% and recurrence-free survival (RFS) of 45% was detected. Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%). Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%). We detected no evidence of MMR-deficiency (MMR-d)/MSI-high (MSI-h), whereas 10 of 63 cases (16%) expressed PD-L1. Therefore, anti-PD-1/PD-L1 immunotherapy approaches might be tested in UrC. Importantly, we found aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31% of UrCs with potential implications for anti-EGFR therapy. Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA. The molecular profile strengthens the notion that UrC is a distinct entity on the genomic level with closer resemblance to colorectal than to bladder cancer.

Comparative genomic profiling of glandular bladder tumours

“…For UAC, several studies have been published which mainly focus on current therapeutic targets [11][12][13][14][15][16]. Reis et al identified, for instance, various druggable alterations (e.g.…”

“…So far, the pathogenesis of BAC remains poorly understood, and morphological resemblance to colorectal adenocarcinomas (CORAD) suggests potential analogies. Nextgeneration sequencing (NGS) data have improved our knowledge of genetic driver alterations in urothelial carcinomas [7] and CORAD [8], and first NGS data are now available for rare BAC [9,10] and UAC [11][12][13][14][15][16]. Additionally, a few single gene sequencing reports for BAC and UAC (e.g.…”

Urachal Cancer in Germany and the USA: An RKI/SEER Population-Based Comparison Study

“…Therapeutic options include (partial) cystectomy with en bloc resection of the median umbilical ligament and umbilicus in local disease and mostly 5-fluorouracil-based chemotherapy regimes in advanced cases [5][6][7]. Recently, molecular studies have allowed more insights in the genetic background of UrC, which seems to be a distinct molecular entity [8][9][10][11][12][13][14][15][16][17].…”

Histologic Variants of Urothelial Carcinoma: Morphology, Molecular Features and Clinical Implications

“…Next-generation sequencing was performed on 70 urachal carcinomas and showed mutations in TP53, KRAS, BRAF and PIK3CA, which are commonly mutated in colon cancer [107]. In a series of 12 urachal adenocarcinomas analyzed by targeted exon sequencing and transcriptome profiling, investigators found that urachal adenocarcinoma closely resembles colorectal cancer with a subset of cases showing a microsatellite unstable phenotype.…”

“…In a series of 12 urachal adenocarcinomas analyzed by targeted exon sequencing and transcriptome profiling, investigators found that urachal adenocarcinoma closely resembles colorectal cancer with a subset of cases showing a microsatellite unstable phenotype. A single patient in this series underwent treatment with immune checkpoint blockade, resulting in stabilization of their metastatic disease [107][108][109].…”