Abstract
Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15 and 40. Although most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal nonseminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggest a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date, however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals have not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of 15 patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced p53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor that gives rise to the parallel evolution of GCTs and blood cancers in these patients.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6668-6676 |
| Number of pages | 9 |
| Journal | Journal of Clinical Investigation |
| Volume | 130 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2020 |
Funding
We thank the patients, their families, and Barbara Solit for tireless help with patient recruitment through Cycle for Survival and the Memorial Sloan Kettering Cancer Center’s Make-An-IMPACT program. JT is supported by the Conquer Cancer Foundation of the American Society of Clinical Oncology, the American Association for Cancer Research, the American Society of Hematology, the Robert Wood Johnson Foundation, and the NIH/NCI (1K08CA230319-01). This work was also funded by Cycle for Survival grants to BST, DBS, DRF, and OAW, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology and the NIH/NCI Cancer Center Support Grant P30 CA008748. Authorship note: JT, MTAD, DRF, and OAW contributed equally to this work. Conflict of interest: SAF has received research support from AstraZeneca and Genen-tech/Roche, has served in a consulting or advisory role for Decibel, AstraZeneca, and Immunai, and has stock or other ownership interests in Urogen, Allogene Therapeutics, Neogene Therapeutics, Vaxigene, Kronos Bio, and Vida Ventures. RKR has received consulting fees from Constellation, Incyte, Celgene, Promedior, CTI, Jazz Pharmaceuticals, Blueprint, and Stemline, and research funding from Incyte, Constellation, and Stemline. DBS has served as a consultant for Pfizer, Loxo Oncology, Lilly Oncology, Q.E.D. Therapeutics, and Illumina. BST reports honoraria and research funding from Genentech and advisory board activities for Boehringer Ingelheim and Loxo Oncology, a wholly owned subsidiary of Eli Lilly. OAW has served as a consultant for H3B Biomedicine, Foundation Medicine Inc, Merck, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc; OAW has received prior research funding from H3B Biomedicine. Copyright: © 2020, American Society for Clinical Investigation. Submitted: April 28, 2020; Accepted: September 3, 2020; Published: November 16, 2020. Reference information: J Clin Invest. 2020;130(12):6668–6676. https://doi.org/10.1172/JCI139682.
ASJC Scopus subject areas
- General Medicine
