Bilateral germ cell tumor of the testis (TGCT): Implications for a stem cell versus genetic origin of cancers.

5037 Background: Bilateral TGCT provides a unique opportunity to elucidate a stem cell versus genetic origin of cancer. Comparison of the epigenetics and genetics of disparate tumors in either synchronous or metachronous bilateral TGCT from the same patients is feasible and may be informative. Methods: We examined the clinical characteristics and natural history of 38 patients with bilateral TGCT. We performed reduced representation bisulfite sequencing (RRBS) of FFPE DNA and whole exon sequencing (WES) of 9 of those patients whose tumor samples were available for the study. Results: From the database at MDACC, we identified 38 patients with bilateral TGCT, who underwent their first orchiectomy between January 1984 and April 2022 and the second between August 1997 and April 2022. Median follow-up was 134.2 months (IQR 69.5–222.1 months). Seven patients had synchronous, while 31 had metachronous bilateral TGCT. There were 13 bilateral seminomas, 14 bilateral nonseminomas, and 11 bilateral seminoma and nonseminoma. For those patients with metachronous bilateral TGCT, the median time between the two TGCT was 47.7 months (IQR 19.6–108.9). Out of approximately 20,000 genes investigated, 189 (<1%) had a detectable mutation in the 9 paired cases (n=18). A total of 8 genes were mutated in more than 1 sample, including KIT (n=4, 22%) and KRAS (n=6, 33%). Among the 4 bilateral TGCT showing a similar methylation profile in the RRBS analysis, the pattern of single nucleotide variants and type of specific genetic mutations were dissimilar between the right and left TGCT from the same patients in the WES study. Among the 5 bilateral TGCT that did not cluster in the RRBS study, there was differential methylation of the JUP and MAGE-A4 genes between the right and left TGCT from the same patients. Conclusions: The clinical course of our patients with synchronous and metachronous bilateral TGCT and the results of our RRBS and WES reaffirmed that a preponderance of TGCT was curable and suggested that epigenomic findings may supplement, if not complement, genomic data to elucidate a stem-cell versus genetic origin and nature of GCT and cancers in general.