EURURO Vol. 72 No. 4

SH3KBP1 was highly elevated in the patient harboring the

fusion in comparison to the other patients.

Discussion

This is the first comprehensive, integrated genomic analysis

of UTUC. Procurement of sufficient banked samples of this

rare disease required pooling from two different institu-

tions, and harmonization of clinical and genomic data. From

the merged WES data set we identified 2784 mutations,

with

FGFR3

the most commonly mutated gene (74%) in both

low-grade (92%) and high-grade (60%) tumors. The rela-

tively high rate of

FGFR3

mutations in high-grade tumors is

nearly double the rate previously reported

. The

APOBEC mutation signature seen in 45% of patients is part

of the DNA repair pathway and may explain the high

mutation rates in patients with

ERCC2

mutation.

Comparison of mutational profiles for low- and high-

grade tumors revealed a significantly higher occurrence of

mutations in the p53 and related interacting pathways in

high-grade tumors, leading to greater genomic instability,

copy number alterations, and disruption of cell-cycle and

apoptotic pathways corroborated by protein analysis.

Using unsupervised consensus clustering of RNAseq

data, we identified four putative molecular subtypes

correlating with relevant clinical variables. These clusters

bear some similarity to the previously described bladder

subtypes

cluster 1 is similar to the bladder luminal

subtype, cluster 2 is more similar to the basal subtype, and

cluster 4 has a high rate of upregulated immune checkpoint

[(Fig._4)TD$FIG]

Fig. 4 – Novel gene fusion. (A) Schematic of SH3KBP1 and CNTNAP5 protein showing domains and position of the breakpoint (red arrowheads) of the

fusion. The blue arrow shows the resulting fusion product. (B) DNA gel image of the polymerase chain reaction products validating the gene fusions.

Forward primers for 5

genes and reverse primers for 3

genes are indicated by numbers in the schematic, and primer pairs are shown below the gel

image.

E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 6 4 1 – 6 4 9

647