Abstract LB-109: Exome sequencing identifies common somatic mutations in an adult patient with a concurrent germ cell tumor (GCT) and acute myeloid leukemia (AML) suggesting a single clonal origin
Authors: Lu Charles , Riedell Peter , Westervelt Peter , Miller Christopher , Hagemann Ian S. , Duncavage Eric J. , Mardis Elaine R. , Wilson Richard K. , Ozenberger Bradley A. , Wartman Lukas D. 
Published: August 2015

The Genomics Tumor Board at Washington University was established to increase knowledge, competence, and performance in the application of genomic testing in cancer care. Here we report the findings from a Tumor Board case of concurrent germ cell tumor and acute myeloid leukemia. A 33-year old male presented with generalized weakness, weight loss, and dyspnea on exertion. Initial workup was notable for a platelet count of 5,000 platelets/μL, hemoglobin of 13.1g/dl, and a white count of 9,200 cells/μL with a normal differential. His AFP was 237 (ULN 8.1 ng/ml), LDH was 6760 U/L (ULN 250 U/L) and β-hCG &lt;5 (normal &lt;5 IU/L). Chest CT scan revealed an anterior mediastinal mass. A bone marrow biopsy and aspirate showed a cellularity of 70%, with the core biopsy showing a fibrotic marrow with a population of larger mononuclear cells. The hemodilute aspirate showed 15% large blasts, and a subset of the larger cells expressed CD61 and weak CD117. These findings were consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7). The patient underwent incisional biopsy of the mediastinal mass with pathology showing necrotic fragments of tissue with scattered foci of moderately to poorly differentiated adenocarcinoma. Immunostaining was consistent with a nonseminomatous germ cell tumor. Multiple prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous germ cell tumors, and a recent study identified a patient with a concurrent AML and GCT that shared several mutations including PTEN, TP53, and chromosome 12 abnormalities, suggesting that a common founding clone initiated both cancers (Oshrine, B. R., et al. Cancer Genet 2014). To investigate the clonal relationship in our samples, we studied the GCT (whole genome amplification was performed on 2 ng of DNA isolated by laser capture microdissection of viable cells from the FFPE tumor specimen) and the M7 AML (cryopreserved cells from the diagnostic bone marrow biopsy were flow-sorted using the above markers) by whole exome sequencing. We found both samples contained somatic mutations in PTEN (C136R missense) and TP53 (R213 frameshift). Both the mutations in PTEN and TP53 were present at ∼100% variant allele frequency (VAF) in both tumors. A copy number comparison between the 2 samples revealed similar amplifications of chromosome 12p. In addition, we detected a heterozygous germline variant in FANCA (R858D), which is known to be associated with Fanconi anemia and is of uncertain significance here. In conclusion, the data not only support a common clonal ancestor for these cancers but also suggest that a specific set of distinct genomic alterations drives the rare association between GCT and AML, and likely underlies the poor outcome of these patients.

Citation Format: Charles Lu, Peter Riedell, Peter Westervelt, Christopher Miller, Ian S. Hagemann, Eric J. Duncavage, Elaine R. Mardis, Richard K. Wilson, Bradley A. Ozenberger, Lukas D. Wartman. Exome sequencing identifies common somatic mutations in an adult patient with a concurrent germ cell tumor (GCT) and acute myeloid leukemia (AML) suggesting a single clonal origin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-109. doi:10.1158/1538-7445.AM2015-LB-109