Lu Charles, Riedell Peter, Miller Christopher A, Hagemann Ian S, Westervelt Peter, Ozenberger Bradley A, O'Laughlin Michelle, Magrini Vincent, Demeter Ryan T, Duncavage Eric J, Griffith Malachi, Griffith Obi L, Wartman Lukas D
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;
Cold Spring Harb Mol Case Stud. 2016 Jan;2(1):a000687. doi: 10.1101/mcs.a000687.
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.
我们报告了一名同时患有纵隔生殖细胞肿瘤（GCT）和急性髓系白血病（AML）患者的研究结果。骨髓病理学检查结果符合急性巨核细胞白血病（AML M7）的诊断，前纵隔肿块活检结果符合非精原细胞瘤性GCT。既往研究描述了血液系统恶性肿瘤之间的关联，包括AML M7和非精原细胞瘤性GCT，最近有人提出一个共同的起始克隆引发了这两种癌症。我们对该患者的GCT和AML M7进行了增强外显子组测序，以确定这两种癌症之间的克隆关系。我们发现两个样本中均存在PTEN（C136R错义突变）和TP53（R213移码突变）的体细胞突变。PTEN和TP53的突变在两个肿瘤中的变异等位基因频率（VAF）均约为100%。此外，我们检测并验证了其他五个共同的体细胞突变。AML外显子组数据的拷贝数分析显示12号染色体短臂扩增。我们还在FANCA基因中鉴定出一个杂合的种系变异（S858R），已知该变异与范可尼贫血相关，但在此处其意义尚不确定。总之，我们的数据不仅支持这些癌症有一个共同的起始克隆，还表明一组特定的独特基因组改变（PTEN和TP53中的改变）是GCT和AML之间罕见关联的基础。这种关联可能与这些患者的治疗抵抗和极差预后有关。鉴于我们数据的局限性，我们无法解析这些肿瘤的克隆进化情况。
