Introduction

Upper urinary tract urothelial carcinoma (UTUC) is relatively rare and its molecular biology is poorly understood. To clarify distinct characteristics of UTUC, we comprehensively investigated the genetic alterations of this disease.

Methods

Surgical specimens of UTUC and matched normal samples were obtained from 99 patients with various stages and subjected to whole exome and RNA sequencing. Apparently normal urothelial epithelia and preoperative urine sediments were also analysed in 5 cases.

Results

Genetic alterations were most frequently observed in TERT promoter (51% of cases), followed by KMT2D (48%), FGFR3 (44%), CDKN2A (42%), TP53 (31%), and RAS pathway (HRAS/KRAS/NRAS, 21%). More than 95% of cases harbored either TP53/MDM2, FGFR3, or RAS pathway mutations in an almost mutually exclusive manner, based on which UTUCs are classified into 3 distinct subgroups with unique molecular and clinical features; FGFR3-mutated tumors showed a significantly better prognosis than those with TP53/MDM2 (p<0.001) and RAS pathway (p=0.010) lesions. We also found 4 hypermutated cases which harbored biallelic mutations in mismatch repair genes._x000D_ To further clarify the unique feature of mutations in UTUC, the mutation patterns were compared with those of bladder urothelial carcinoma (BUC) using previously reported datasets. Although altered genes in UTUC were almost same as those of BUC, frequencies were substantially different in some genes such as KMT2D and RB1. In addition, mutation spectrum in UTUC were also different depending on the anatomical location; Most of the RAS pathway mutations were found in renal pelvis (p=0.0013) while KMT2D mutations were observed more frequently in ureter (p<0.0001). _x000D_ In the analysis of normal epithelia, some epithelia and primary tumors harbored shared mutations as well as their private ones, indicating that clonal precancerous area expands in normal epithelia. By contrast, in other epithelia, we also found driver gene mutations that were not shared by primary tumors, suggesting the presence of a mutagenic field effect on urothelial multiple occurence. _x000D_ We also detected mutations in urine sediments identical to primary tumors with similar allele frequencies, suggesting that sequencing urine may be useful for disease monitoring._x000D_

Conclusions

UTUC tumors are classified into 3 molecularly and clinically distinct subtypes based on the status of mutations in TP53/MDM2, FGFR3, and RAS pathway. Depending on their location, urothlial cancers have different genetic backgrounds, where a field effect and clonal expansion might contribute to multifocal occurrence of UTUC.

Funding

none