Germ cell tumors and associated hematologic malignancies evolve from a common shared precursor
Justin Taylor, … , Darren R. Feldman, Omar Abdel-Wahab
Justin Taylor, … , Darren R. Feldman, Omar Abdel-Wahab
Published September 8, 2020
Citation Information: J Clin Invest. 2020;130(12):6668-6676. https://doi.org/10.1172/JCI139682.
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Research Article Genetics Hematology

Germ cell tumors and associated hematologic malignancies evolve from a common shared precursor

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.

Authors

Justin Taylor, Mark T.A. Donoghue, Caleb Ho, Kseniya Petrova-Drus, Hikmat A. Al-Ahmadie, Samuel A. Funt, Yanming Zhang, Umut Aypar, Pavitra Rao, Shweta S. Chavan, Michael Haddadin, Roni Tamari, Sergio Giralt, Martin S. Tallman, Raajit K. Rampal, Priscilla Baez, Rajya Kappagantula, Satyajit Kosuri, Ahmet Dogan, Satish K. Tickoo, Victor E. Reuter, George J. Bosl, Christine A. Iacobuzio-Donahue, David B. Solit, Barry S. Taylor, Darren R. Feldman, Omar Abdel-Wahab

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Figure 2

Genetic evolution of germ cell tumors (GCTs) and hematologic malignancies from a common ancestral clone.

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Genetic evolution of germ cell tumors (GCTs) and hematologic malignancie...
Whole-exome sequencing was performed in 5 patients, 3 shown here and 2 shown in Figures 3 and 4. (A) Shown are the somatic mutations (known oncogenic and variants of undetermined significance [VUS]) and their fraction of tumor cells mutated (cancer cell fraction [CCF]), the (B) allelic DNA copy number, and (C) inferred evolutionary relationships of a GCT and associated myelodysplastic syndrome (MDS) in a 24-year-old male with both diagnoses. An ancestral clone with shared isochromosome 12p and a KRAS G12S mutation (among other shared mutations) was detected followed by independent acquisition of numerous distinct mutations. (D–F) Similar CCF (D), allele copy number (E), and evolutionary relationships (F) in a 28-year-old with shared GCT and AML. In this case, both tumors derived from a TP53 R248L–mutant ancestral precursor that underwent copy-neutral loss of heterozygosity (CNLOH). (G–J) In another patient, a KRAS G12D–mutant precursor gave rise to GCT and MDS, each of which later independently acquired TP53 hotspot mutations with CNLOH. (I) Aligned TP53 reads over the regions of mutations, highlighting mutual exclusivity of each mutation across the GCT and MDS samples. AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia.