Clinical sequencing identifies potential actionable alterations in a high rate of urachal and primary bladder adenocarcinomas

Abstract

Administration of targeted therapies provides a promising treatment strategy for rare cancers such as urachal adenocarcinoma (UrC) or primary bladder adenocarcinoma (PBAC), however, the selection of appropriate drugs remains difficult. Therefore, in the present study, we aimed to establish a routine compatible methodological pipeline for the identification of the most important therapeutic targets and potentially effective drugs for UrC and PBAC. Next-generation sequencing using a 161 cancer driver gene panel was performed on 41 UrC and 13 PBAC samples. Clinically relevant alterations were filtered by four publicly available databases. Therapeutic interpretation has been performed by in silico evaluation of drug-gene interactions using an evidence-based decision support tool. After data processing, 45/54 samples (33 UrC and 12 PBAC) passed the quality control. The sequencing analyses revealed a total of 191 pathogenic SNVs in 68 genes. The most frequent gain-of-function mutations in UrC were found in KRAS (33%), MYC (15%), EGFR (9%) and ERBB2 (9%), while in PBAC KRAS (25%), MYC (25%), FLT3 (17%) and TERT (17%) were recurrently affected. The most frequently affected pathways in both tumour types were related to cell cycle regulation, DNA damage control and the MAPK/RAS pathway. Actionable mutations with at least one available, regulatory agency-approved drug could be identified for 31/33 (94%) of UrC and 8/12 (67%) of PBAC patients. In this study, we used a commercially available assay and developed a data processing pipeline for the detection and therapeutic interpretation of genetic alterations in two rare cancers. Our analyses revealed actionable mutations in a high rate of cases, including EGFR, BRCA, CCND1/2/3, ERBB2, METex14 suggesting a potentially feasible strategy for both UrC and PBAC treatment.

Progress and prospects of targeted therapy and immunotherapy for urachal carcinoma

“…Lee et al (2017) reported EGFR amplification in 23.5% of patients (4/17) by detecting somatic copy number aberrations. More recently, Varadi et al (2023) described EGFR mutations in 9.1% (3/33) of UrC cases by applying next-generation sequencing. These authors detected two samples with amplification and one sample with a missense mutation.…”

“…MET can act as a driver of malignant progression but also as a mediator of drug resistance in various cancers. Varadi et al (2023) used a next-generation sequencing approach and identified MET mutations in 12% (4/3) of UrC cases. In addition, these authors detected two samples with functional mutations; one of these was a dysfunctional mutation while the status of the other mutation remained unknown.…”