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.

TP53 and PTEN Mutations Were Shared in Concurrent Germ Cell Tumor and Acute Megakaryoblastic Leukemia

“…In the present case, the common cytogenetic Two cases harboring concurrent mutations of TP53 and PTEN in both mGCTs and AMKL have been reported [9,10], and our case is the third. As for the TP53 mutation, a nonsynonymous mutation (exon2:c.389T>C:p.L130P) and a frameshift mutation (exon10:c.7578213A>del:p.R213fs_del) in the DNA binding domain was reported in each case, which both lead to the loss of its transcription activity [9,10,12,13]. In our case, similar to the previous two cases, the TP53 mutation occurred in the DNA binding domain (exon8:c.G836A:p.G279E), and might cause the impairment of TP53 function ( Figure 6A).…”

“…The datasets generated and/or analyzed during the current study are available in the Japanese Location of TP53 mutations (A) and PTEN mutations (B) in three cases including our case. * our case; ‡ Oshrine et al [9]; † Lu et al [10].…”

“…In our case, similar to the previous two cases, the TP53 mutation occurred in the DNA binding domain (exon8:c.G836A:p.G279E), and might cause the impairment of TP53 function ( Figure 6A). In case of the PTEN mutation, nonsynonymous mutations in phosphatase domain and C2 domain (exon6:c.725G>T:p.G251V; exon10:c.89692922T.C:p.C136R) were reported in each case [9,10], which might lead to the reduction of PTEN's membrane affinity, and subsequent loss of suppression of cell growth [14,15]. In our case, the PTEN mutation occurred in the splicing donor site of intron 5 (exon5:c.492+1G>A), resulting in a PTEN splicing mutant ( Figure 6B) [16].…”

“…Previous research demonstrating isochromosome 12p in both GCTs and HMs suggested that these malignancies had a common progenitor, and the identification of the same gene mutations, including of TP53 and PTEN, in both mGCTs and AML samples in two cases established the idea that the mGCT and AML share a founding clone [6,9,10]. In the present case, the common cytogenetic Two cases harboring concurrent mutations of TP53 and PTEN in both mGCTs and AMKL have been reported [9,10], and our case is the third.…”

“…Previous research demonstrating isochromosome 12p in both GCTs and HMs suggested that these malignancies had a common progenitor, and the identification of the same gene mutations, including of TP53 and PTEN, in both mGCTs and AML samples in two cases established the idea that the mGCT and AML share a founding clone [6,9,10]. In the present case, the common cytogenetic Two cases harboring concurrent mutations of TP53 and PTEN in both mGCTs and AMKL have been reported [9,10], and our case is the third. As for the TP53 mutation, a nonsynonymous mutation (exon2:c.389T>C:p.L130P) and a frameshift mutation (exon10:c.7578213A>del:p.R213fs_del) in the DNA binding domain was reported in each case, which both lead to the loss of its transcription activity [9,10,12,13].…”