Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas

Area of Science:

• Oncology
• Genomics
• Cancer Biology

Background:

• Urachal cancer (UrC) is a rare, aggressive malignancy often diagnosed at advanced stages.
• Current systemic treatments, including chemotherapy, have limited effectiveness.
• Targeted therapies and immunotherapies offer potential alternative treatment strategies for UrC.

Purpose of the Study:

• To investigate the molecular profile of urachal adenocarcinomas.
• To identify potential therapeutic targets and biomarkers for UrC treatment.
• To compare the genomic landscape of UrC with other cancer types.

Main Methods:

• Targeted next-generation sequencing of 70 urachal adenocarcinomas.
• In situ and immunohistochemical analyses, including PD-L1 and DNA mismatch repair (MMR) protein expression.
• Microsatellite instability (MSI) status evaluation and correlation with clinical data.

Main Results:

• TP53 mutations were frequent (66%), followed by KRAS (21%).
• Actionable alterations in RAS/RAF/PI3K pathways were found in 31% of cases, with potential for anti-EGFR therapy.
• No evidence of MMR-deficiency/MSI-high was detected; 16% expressed PD-L1, suggesting immunotherapy potential.
• Genomic profile suggests UrC is distinct, resembling colorectal more than bladder cancer.

Conclusions:

• Urachal cancer exhibits a distinct molecular profile with actionable mutations.
• Targeted therapies (e.g., anti-EGFR) and immunotherapies (anti-PD-1/PD-L1) show promise for UrC treatment.
• Further research into UrC's unique genomic characteristics is warranted.