Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD, 20892, USA.
Molecular Imaging Program, National Cancer Institute, NIH, 10 Center Drive, Bethesda, MD, 20892, USA.
Nat Commun. 2020 Feb 13;11(1):837. doi: 10.1038/s41467-020-14657-7.
Localized prostate cancers are genetically variable and frequently multifocal, comprising spatially distinct regions with multiple independently-evolving clones. To date there is no understanding of whether this variability can influence management decisions for patients with prostate tumors. Here, we present a single case from a clinical trial of neoadjuvant intense androgen deprivation therapy. A patient was diagnosed with a large semi-contiguous tumor by imaging, histologically composed of a large Gleason score 9 tumor with an adjacent Gleason score 7 nodule. DNA sequencing demonstrates these are two independent tumors, as only the Gleason 9 tumor harbors single-copy losses of PTEN and TP53. The PTEN/TP53-deficient tumor demonstrates treatment resistance, selecting for subclones with mutations to the remaining copies of PTEN and TP53, while the Gleason 7 PTEN-intact tumor is almost entirely ablated. These findings indicate that spatiogenetic variability is a major confounder for personalized treatment of patients with prostate cancer.
局部前列腺癌在遗传上具有变异性，并且经常是多灶性的，包含具有多个独立进化克隆的空间上不同的区域。迄今为止，尚不清楚这种可变性是否会影响前列腺肿瘤患者的治疗决策。在这里，我们展示了一项新辅助强化雄激素剥夺治疗临床试验中的一个单一病例。通过影像学检查，患者被诊断为一个大的半连续肿瘤，组织学上由一个大的 Gleason 评分 9 肿瘤和一个相邻的 Gleason 评分 7 结节组成。DNA 测序表明这是两个独立的肿瘤，因为只有 Gleason 9 肿瘤存在 PTEN 和 TP53 的单拷贝缺失。PTEN/TP53 缺陷肿瘤表现出治疗耐药性，选择了对剩余 PTEN 和 TP53 拷贝具有突变的亚克隆，而 Gleason 7 PTEN 完整的肿瘤几乎完全被消融。这些发现表明，空间遗传变异性是前列腺癌患者个体化治疗的主要混杂因素。
