Genomic Landscape of Young-Onset Bladder Cancer and Its Prognostic Implications on Adult Bladder Cancer

Abstract

Due to the rare occurrence of young-onset bladder cancer (YBC), its genomic characteristics remain largely unknown. Twenty-nine biopsy-proven YBC cases were collected using a nation-wide search for bladder cancer diagnosed at 20 years or younger. Whole exome sequencing and RNA sequencing were carried out in 21 and 11 cases, respectively, and compared with those of adult bladder cancer (ABC) cases obtained from public databases. Almost all YBCs were low grade, non-invasive papillary tumors. YBC had a low mutation burden and less complex copy number alterations. All cases harbored putative driver mutations. Mutations were most commonly found in HRAS (10 cases), with a preference for exon 5. FGFR3 gene fusions were noted with various partner genes (7 cases). The alterations on HRAS and FGFR3 occurred in a mutually exclusive manner. Others included KRAS mutations (2 cases), chromosomes 4p and 10q arm-level deletions (1 case), and ERCC2 mutation (1 case). There were no point mutations in TP53 and FGFR3. The gene expression profiles of YBC were similar to those of the ABC group with good prognosis. None of the YBCs and ABCs with YBC-like mutations showed progression to muscle-invasive tumors. Our results suggest that bladder cancer with YBC-like mutations represents an indolent bladder tumor, regardless of age.

Keywords: FGFR3; HRAS; next generation sequencing; prognosis; young-onset bladder cancer.

Figure 1

Characteristics of young-onset bladder cancer. (A) Summary of genetic alterations and correlations to clinicopathological features. (B) Representative images of different tumor grades (papillary urothelial neoplasm of low malignant potential (PUNLMP), low grade, and high grade) and histologic features of young-onset bladder cancer.

Figure 2

Genetic alterations of FGFR3 and HRAS and their impact on gene expression. (A) Schematic description of genomic and transcriptomic fusion constructs of FGFR3. Small (B) or large (C) genomic deletion of exon 5 generated HRAS transcripts including exon 6. (A–C) E and I refer to exon and intron, respectively. (D) Gene expression of HRAS in 5 cases with HRAS mutations in young-onset bladder cancer.

Figure 2

Genetic alterations of FGFR3 and HRAS and their impact on gene expression. (A) Schematic description of genomic and transcriptomic fusion constructs of FGFR3. Small (B) or large (C) genomic deletion of exon 5 generated HRAS transcripts including exon 6. (A–C) E and I refer to exon and intron, respectively. (D) Gene expression of HRAS in 5 cases with HRAS mutations in young-onset bladder cancer.

Figure 3

Transcriptomic characteristics of young-onset bladder cancer (YBC) compared to adult non-muscle-invasive bladder cancer (NMIBC) (UROMOL). Heatmap of 117 classifiers (A), early-cell cycle (C), late-cell cycle (D), and keratin (E) genes are presented in each panel. (B) Molecular distances between YBC and the three classes of UROMOL data based on 117 classifier genes are presented as Pearson correlation coefficients.

Figure 4

Comparison of young-onset bladder cancer (YBC) with adult bladder cancer (ABC). (A) The frequencies of FGFR3 fusion and HRAS mutations in YBC were higher than in adult NMIBC (UROMOL) and muscularis propria-invasive bladder cancer (MIBC) (The Cancer Genome Atlas (TCGA)). (B) Synergic effect of HRAS G12/G13/Q61 and exon 5 mutations on gene expression observed in adult NMIBC (UROMOL) and MIBC (TCGA). (C) We compared the frequencies of somatic point mutations of YBC and two adult genomic studies on NIBC tumors (Pietzak et al. [22] and Hurst et al. [23]), where YBC tumors with paired normal samples (n = 12) and ABC tumors with Ta stage were included (n = 82 in Hurst et al.; n = 55 in Pietzak et al. [22]). Somatic point mutations found in more than 20% of cases in each study are shown. The diagonal pattern of the HRAS bar in YBC indicates the exon 5 large deletion.

Figure 5

Clinical outcomes of bladder cancer according to genetic alterations. (A) All YBCs were non-invasive papillary tumors (Ta stage), but ABC data included various tumor stages. (B) All YBCs and ABCs with YBC-like genetic alterations showed no progression to muscle-invasive tumors and better progression-free survival than ABCs with other genetic alterations. (C) Progression-free survival based on tumor grade.