Origin of Subsequent Malignant Neoplasms in Patients with History of Testicular Germ Cell Tumor

Abstract

Although genetic changes may be pivotal in the origin of cancer, cellular context is paramount. This is particularly relevant in a progenitor germ cell tumor and its differentiated mature teratoma counterpart when it concerns tumor heterogeneity and cancer dormancy in subsequent second malignancies (subsequent malignant neoplasms (SMNs)). From our tumor registry database, we identified 655 testicular germ cell tumor (TGCT) patients who developed SMNs between January 1990 and September 2018. Of the 113 solid organ SMNs, 42 had sufficient tumor tissue available for fluorescence in situ hybridization (FISH) analysis of isochromosome 12p [i(12p)]. We identified seven additional patients for targeted DNA and RNA sequencing of teratomas and adjacent somatic transformation. Finally, we established cell lines from freshly resected post-chemotherapy teratomas and evaluated the cells for stemness expression by flow cytometry and by the formation of teratomas in a xenograft model. In our cohort, SMNs comprising non-germ cell tumors occurred about 18 years after a diagnosis of TGCT. Of the 42 SMNs examined, 5 (12%) contained i(12p) and 16 (38%) had 12p gain. When comparing a teratoma and adjacent somatic transformation, targeted DNA and RNA sequencing demonstrated high concordance. Studies of post-chemotherapy teratoma-derived cell lines revealed cancer-initiating cells expressing multipotency as well as early differentiation markers. For the first time, we demonstrated the prevalence of i(12p) in SMNs and the presence of progenitor cells embedded within mature teratomas after chemotherapy. Our findings suggest a progenitor stem-like cell of origin in SMN and TGCT and highlight the importance of cellular context in this disease.

Curing Cancer: Lessons from a Prototype

“…We revisit seminal experiments of other cancers supporting the idea that cancer is a stem cell disease. We reiterate recent experiments that affirm a close relationship between a primary TGCT and a second subsequent malignant neoplasm (SMN) separated by years, if not decades, and between a mature teratoma and a somatically transformed malignant neoplasm within the same tumor in the same patient [8]. In principle, these experiments validate a universal cancer theory based on pertinent clinical observations.…”

Stem Cell Theory of Cancer: Origin of Tumor Heterogeneity and Plasticity

“…Importantly, TGCT is a preeminently curable cancer (>90% cure rate) even when it is advanced and metastatic, in part because we know how to deal with its genotypes and how to treat its phenotypes [15][16][17]. Hence, in a mixed TGCT containing embryonal carcinoma and teratoma, both have the same genetic marker (i.e., i(12p)) and a similar if not identical genetic makeup due to their common clonal origin.…”

Stem Cell Theory of Cancer: Rude Awakening or Bad Dream from Cancer Dormancy?

“…In many respects, the indolent and dormant nature of yolk sac tumor and teratoma belies their treacherous eventual outcome. Importantly, ensconced within a residual, supposedly innocuous teratoma after chemotherapy are dormant and covert progenitor stem cells that may reawaken and relapse as a yolk sac tumor and/or a somatically transformed tumor [40].…”

“…Umbreit et al [40] found that about half of a variety of subsequent malignant neoplasms (SMN), including lung cancer, colon cancer, and kidney cancer, in 42 patients with a previous history of TGCT contained a common genetic biomarker for TGCT, namely isochromosome 12p [i(12p)] (12%) or 12p gain (38%), by fluorescent in situ hybridization analysis. These SMN comprising non-TGCT occurred about 18 years (range 0.4-53.6 years) after an initial diagnosis of TGCT.…”