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.