Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
J Clin Invest. 2020 Dec 1;130(12):6238-6241. doi: 10.1172/JCI143884.
Some germ cell tumors (GCTs) in men develop into hematologic malignancies; however, the clonal origins of such malignancies remain unknown. In this issue of the JCI, Taylor, Donoghue, et al. unravel the clonal relationship between primary mediastinal nonseminomas (PMNs) and hematologic somatic-type malignancies (HSTMs). Whole-exome sequencing was used to construct phylogenetic trees of the PMNs and the ensuing HSTM clones. HSTMs were derived from multiple distinct clones not detected within the PMNs. Clones from PMNs and HSTMs shared a common precursor, arguably an embryonal carcinoma cell resulting from a reprogrammed primordial germ cell from the thymus. Mutational and copy number variation analysis of a large cohort of patients with PMNs also demonstrated a high prevalence of TP53 mutations not found in testicular nonseminomas. These data likely explain why patients with PMNs are frequently resistant to platinum-based chemotherapy and provide TP53 mutations as potential targets.
一些男性生殖细胞肿瘤（GCT）会发展为血液系统恶性肿瘤，但这些恶性肿瘤的克隆起源仍不清楚。在本期 JCI 中，Taylor、Donoghue 等人揭示了原发性纵隔非精原细胞瘤（PMN）和血液系统体细胞型恶性肿瘤（HSTM）之间的克隆关系。全外显子组测序用于构建 PMN 和随后的 HSTM 克隆的系统发育树。HSTM 来源于多个在 PMN 中未检测到的不同克隆。PMN 和 HSTM 的克隆共享一个共同的前体细胞，可以说是来自胸腺的重编程原始生殖细胞的胚胎癌细胞。对大量 PMN 患者的突变和拷贝数变异分析也表明，TP53 突变的患病率很高，而在睾丸非精原细胞瘤中并未发现这些突变。这些数据可能解释了为什么 PMN 患者经常对铂类化疗产生耐药性，并为 TP53 突变提供了潜在的治疗靶点。
