title: A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia.
abstract: We report the findings from a patient who presented with a concurrent mediastinal germ cell tumor (GCT) and acute myeloid leukemia (AML). Bone marrow pathology was consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7), and biopsy of an anterior mediastinal mass was consistent with a nonseminomatous GCT. Prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous GCTs, and it was recently suggested that a common founding clone initiated both cancers. We performed enhanced exome sequencing on the GCT and the AML M7 from our patient to define the clonal relationship between the two cancers. We found that both samples contained somatic mutations in PTEN (C136R missense) and TP53 (R213 frameshift). The mutations in PTEN and TP53 were present at ∼100% variant allele frequency (VAF) in both tumors. In addition, we detected and validated five other shared somatic mutations. The copy-number analysis of the AML exome data revealed an amplification of Chromosome 12p. We also identified a heterozygous germline variant in FANCA (S858R), which is known to be associated with Fanconi anemia but is of uncertain significance here. In summary, our data not only support a common founding clone for these cancers but also suggest that a specific set of distinct genomic alterations (in PTEN and TP53) underlies the rare association between GCT and AML. This association is likely linked to the treatment resistance and extremely poor outcome of these patients. We cannot resolve the clonal evolution of these tumors given limitations of our data.
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Peter
authors.initials: P
authors.lastname: Riedell
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA;; Division of Genomics and Bioinformatics, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Hagemann
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Peter
authors.initials: P
authors.lastname: Westervelt
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Ozenberger
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Michelle
authors.initials: M
authors.lastname: O'Laughlin
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Vincent
authors.initials: V
authors.lastname: Magrini
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Demeter
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Duncavage
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Malachi
authors.initials: M
authors.lastname: Griffith
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA;; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Obi L
authors.initials: OL
authors.lastname: Griffith
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA;; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
authors.forename: Lukas D
authors.initials: LD
authors.lastname: Wartman
keywords: hematological neoplasm; neoplasm of the genitourinary tract