PMID- 33327406 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210421 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 12 IP - 12 DP - 2020 Dec 14 TI - Origin of Subsequent Malignant Neoplasms in Patients with History of Testicular Germ Cell Tumor. LID - 10.3390/cancers12123755 [doi] LID - 3755 AB - 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. FAU - Umbreit, Eric C AU - Umbreit EC AD - Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Siddiqui, Bilal A AU - Siddiqui BA AUID- ORCID: 0000-0002-6806-1294 AD - Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Hwang, Michael J AU - Hwang MJ AD - Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Joon, Aron Y AU - Joon AY AD - Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Maity, Tapati AU - Maity T AD - Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Westerman, Mary E AU - Westerman ME AD - Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Merriman, Kelly W AU - Merriman KW AD - Department of Tumor Registry, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Alhasson, Hussam AU - Alhasson H AD - Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Uthup, Joma AU - Uthup J AD - Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Guo, Tao AU - Guo T AD - Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Moore, Joseph A AU - Moore JA AD - Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Ward, John F AU - Ward JF AD - Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Karam, Jose A AU - Karam JA AD - Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Wood, Christopher G AU - Wood CG AD - Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Pisters, Louis L AU - Pisters LL AD - Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Zhang, Miao AU - Zhang M AD - Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Tu, Shi-Ming AU - Tu SM AD - Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - CA016672/University of Texas MD Anderson Cancer Center/ PT - Journal Article DEP - 20201214 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC7764868 OTO - NOTNLM OT - cancer stem cell OT - isochromosome 12p OT - second malignancy OT - somatic transformation OT - teratoma OT - testicular cancer COIS- The authors declare no conflict of interest. EDAT- 2020/12/18 06:00 MHDA- 2020/12/18 06:01 PMCR- 2020/12/14 CRDT- 2020/12/17 01:02 PHST- 2020/10/06 00:00 [received] PHST- 2020/12/05 00:00 [revised] PHST- 2020/12/10 00:00 [accepted] PHST- 2020/12/17 01:02 [entrez] PHST- 2020/12/18 06:00 [pubmed] PHST- 2020/12/18 06:01 [medline] PHST- 2020/12/14 00:00 [pmc-release] AID - cancers12123755 [pii] AID - cancers-12-03755 [pii] AID - 10.3390/cancers12123755 [doi] PST - epublish SO - Cancers (Basel). 2020 Dec 14;12(12):3755. doi: 10.3390/cancers12123755.