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

Authors

Eric C. Umbreit, University of Texas MD Anderson Cancer Center
Bilal A. Siddiqui, University of Texas MD Anderson Cancer Center
Michael J. Hwang, University of Texas MD Anderson Cancer Center
Aron Y. Joon, University of Texas MD Anderson Cancer Center
Tapati Maity, University of Texas MD Anderson Cancer Center
Mary E. Westerman, University of Texas MD Anderson Cancer Center
Kelly W. Merriman, University of Texas MD Anderson Cancer Center
Hussam Alhasson, University of Texas MD Anderson Cancer Center
Joma Uthup, University of Texas MD Anderson Cancer Center
Tao Guo, University of Texas MD Anderson Cancer Center
Joseph A. Moore, University of Texas MD Anderson Cancer Center
John F. Ward, University of Texas MD Anderson Cancer Center
Jose A. Karam, University of Texas MD Anderson Cancer Center
Christopher G. Wood, University of Texas MD Anderson Cancer Center
Louis L. Pisters, University of Texas MD Anderson Cancer Center
Miao Zhang, University of Texas MD Anderson Cancer Center
Shi-Ming Tu, University of Texas MD Anderson Cancer Center

Document Type

Article

Publication Date

12-14-2020

Publication Title

Cancers

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.

DOI

10.3390/cancers12123755

Recommended Citation

Umbreit, Eric C.; Siddiqui, Bilal A.; Hwang, Michael J.; Joon, Aron Y.; Maity, Tapati; Westerman, Mary E.; Merriman, Kelly W.; Alhasson, Hussam; Uthup, Joma; Guo, Tao; Moore, Joseph A.; Ward, John F.; Karam, Jose A.; Wood, Christopher G.; Pisters, Louis L.; Zhang, Miao; and Tu, Shi-Ming, "Origin of Subsequent Malignant Neoplasms in Patients with History of Testicular Germ Cell Tumor" (2020). LSU-LCMC Cancer Center Faculty Publications. 17.
https://digitalscholar.lsuhsc.edu/llcc_facpubs/17
10.3390/cancers12123755