Subsequent malignant neoplasms (SMN) in patients with germ cell tumor of the testis (TGCT): Implications on a genetic vs stem cell origin of cancers

BackgroundAbout 10% of patients with TGCT develop SMN over a 25-year period following treatment [Groot, 2018]. Previously, we reported that up to 50% of those SMN comprising non-germ cell tumors harbored i(12p)/12p gain [Umbreit, 2020].MethodsWe identified 4 patients, 2 of whom had 2 separate SMN, and 1 had a SMN and a SBN (subsequent benign neoplasia), whose SMN/SBN showed i(12p)/12p gain on Fluorescent in Situ Hybridization (FISH). We performed reduced representation bisulfite sequencing (RRBS) of FFPE DNA and whole exon sequencing (WES) of their paired SMN/SBN/primary TGCT tumor samples.ResultsWe examined the epigenomic and genomic profiles of 6 paired SMN, 1 SBN (tubule-villous adenoma), and 1 primary TGCT from 4 patients. The median age at the time of diagnosis of primary TGCT was 45 years (range: 20-58). The median age at the time of diagnosis of SMN was 61 years (range: 51-76). The median time to diagnosis of SMN from diagnosis of primary TGCT was 18 years (range: 6.5-48). The table lists the clinicopathologic features and FISH results. Methylation profiling revealed a continuum for the various tumor phenotypes. Exome sequencing results are pending and may or may not show a concordance between the paired samples, according to a genetic vs stem cell origin of TGCT, respectively. Table: 705P Case No. Primary Testicular Tumor Age at Initial Diagnosis Primary treatment after orch Age at SMN Time to SMN (yrs) SMN Histology Metastatic Tumor % i(12p)*/ Extra Copies Chromosome 12 15A Seminoma 51 BEP RPLND 57 6.5 Unclass sarcoma RP 56%* 15C 6.5 Adenoca Right colon 76% 12C Seminoma 58 XRT 71 13.3 Adenoca Right colon 36% 12A 76 18.0 Angiosarc Right cheek 96% PT Nonseminoma 45 CEB 61 16.0 Adenoca Left colon 83%* PTT NA SP1C TGCT 20 None 68 48.0 Carcinoma Kidney 86% SP1A 48.0 Villous adenoma Right colon 34% ConclusionsOur data suggest that even though the genetic makeup of cancer is pivotal, its cellular context is paramount. Concordance in the molecular (epigenomic and genomic) signatures of a primary TGCT and its corresponding SMN as well as between SMN (and SBN) in the same patients supports a common clonal origin of disparate tumors in time, space, and trait. Groot HJ, et al. Risk of solid cancer after treatment of testicular germ cell cancer in the platinum era. J Clin Oncol 2018;36:2504-13. Umbreit EC, et al. Origin of subsequent malignant neoplasms in patients with history of testicular germ cell tumor. Cancers 2020;12:3755.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureAll authors have declared no conflicts of interest.