Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma

Area of Science:

• Uro-oncology
• Genomics
• Cancer Biology

Background:

• Urothelial carcinoma (UC) can arise in the upper urinary tract (UTUC) or bladder (UCB).
• Understanding the genomic landscape and clonal relationship between UTUC and UCB is crucial for diagnosis and treatment.

Purpose of the Study:

• To investigate genomic differences between UTUC and UCB.
• To define the clonal relatedness of temporally distinct UTUC and UCB tumors within individual patients.

Main Methods:

• Prospective sequencing of tumors and matched germline DNA from 195 UTUC and 454 UCB patients.
• Targeted next-generation sequencing was employed.
• Clonal relatedness was assessed in a subgroup of 29 patients with both UTUC and subsequent UCB.

Main Results:

• Significant genomic differences exist between UTUC and UCB, notably in TP53, RB1, ERBB2, FGFR3, and HRAS alterations.
• UTUC progression correlated with fewer RTK/RAS pathway alterations and more TP53/MDM2 alterations.
• 7.2% of UTUC tumors were MSI-high/dMMR. Mutations in FGFR3, KDM6A, CCND1, and TP53 were associated with bladder recurrence risk.
• UCB and UTUC tumors from the same patient demonstrated clonal relatedness.

Conclusions:

• UTUC and UCB exhibit distinct genomic alterations.
• Temporally distinct UTUC and UCB in the same patient are clonally related.
• Genomic analysis of UTUC aids in predicting bladder recurrence and identifying potential Lynch syndrome cases.