Discussion
Here, we present a case of urogenital ERMS that developed in a teenager with a history of PPB and a germline intronic pathogenic variant inDICER1 . During the PPB diagnosis, the tumor was considered sporadic based on WES findings. However, further analysis performed after the patient developed subsequent cancer revealed a genetic susceptibility to DICER1 -related tumors.
The majority of pathogenic variants in DICER1 syndrome patients is detected by Sanger sequencing, multi-gene panel testing, or WES, with all of these focused on coding regions. However, some patients reportedly develop DICER1 syndrome due to intronic or mosaic pathogenic variants that cannot be detected by conventional sequencing methods or analysis pipelines4,6–12. Along with these findings, our case emphasizes the importance of germline-specific analysis, including cDNA analysis. In our case, the analysis ofDICER1 in tumor samples was also critical for confirming the diagnosis. The detection of the hotspot mutation of p.D1810Y in the initial and recurrent PPB tissues and that of p.E1813D in the subsequent tumor demonstrated that different second hits contributed to the patient’s tumor pathogenesis. That is, the second tumor was considered a new primary tumor, not a recurrence of PPB.
Although ERMS, particularly female cervical ERMS, is recognized as a manifestation of DICER1 syndrome, it is infrequently observed in the male urogenital system13. At least four bladder ERMS cases have been reported in pediatric patients with DICER1syndrome, including three males14,15. Additionally, an autopsy case of adult prostatic ERMS with a DICER1 hotspot mutation with lung and bone metastases and a female case of a bladder tumor with DICER1 mutations (a hotspot mutation and a truncating mutation) were also reported, although the germline status was not confirmed in these cases16,17. Regarding the surveillance protocols for DICER1 syndrome, regular imaging tests for the early detection of male genitourinary tumors would not be recommended due to their low expected frequency18,19. Nevertheless, it is important to consider the possibility of tumors when patients with DICER1 syndrome show atypical or unexplained symptoms20.
In summary, the present case highlights the importance of performing germline-specific testing, including cDNA, for the diagnosis of cancer predisposition disorders, Moreover, our report provides evidence thatDICER1 -related ERMS is not exclusively cervical and can develop in men. Transcriptome analysis may be useful in understanding the etiology by supplementing WES and whole-genome sequencing with which cancer predisposition may be underdiagnosed.