Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Center for Precision Environmental Health, Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas.
Clin Cancer Res. 2018 May 1;24(9):2044-2049. doi: 10.1158/1078-0432.CCR-17-3296. Epub 2018 Feb 12.
Renal medullary carcinoma (RMC) is a highly aggressive malignancy that predominantly afflicts young adults and adolescents with sickle hemoglobinopathies. It is characterized by complete loss of expression of the chromatin remodeler and tumor suppressor Despite therapy, the outcomes of patients with RMC remain very poor, highlighting the need to understand the etiology of this cancer, and develop new diagnostic, preventive, and therapeutic strategies. A key knowledge gap in RMC biology is why sickle hemoglobinopathies predispose to the development of this cancer. We propose a model wherein the extreme conditions of hypoxia and hypertonicity of the renal medulla, combined with regional ischemia induced by red blood cell sickling, activate DNA repair mechanisms to drive deletions and translocations in , which is localized in a fragile region of chromosome 22. This mechanism would explain the linkage between RMC and sickle hemoglobinopathies, as well as the age dependence and predilection of RMC toward the right kidney. This perspective proposes an integrated and testable model of renal medullary carcinoma pathogenesis. Insights provided by this model can additionally inform other malignancies arising from the renal medulla and/or associated with loss of the tumor suppressor gene. .
肾髓质癌（RMC）是一种高度侵袭性的恶性肿瘤，主要影响患有镰状血红蛋白病的年轻成年人和青少年。它的特征是染色质重塑剂和肿瘤抑制因子的完全缺失。尽管进行了治疗，但 RMC 患者的预后仍然非常差，这凸显了需要了解这种癌症的病因，并开发新的诊断、预防和治疗策略。RMC 生物学中的一个关键知识空白是为什么镰状血红蛋白病易导致这种癌症的发生。我们提出了一个模型，即在肾脏髓质的极端缺氧和高渗条件下，加上由红细胞镰状化引起的局部缺血，激活 DNA 修复机制，导致 缺失和易位，而 位于染色体 22 的一个脆弱区域。这种机制可以解释 RMC 与镰状血红蛋白病之间的联系，以及 RMC 对右肾的年龄依赖性和偏好性。这种观点提出了一个综合的、可测试的肾髓质癌发病机制模型。该模型提供的见解还可以为其他源自肾脏髓质和/或与 肿瘤抑制基因缺失相关的恶性肿瘤提供信息。
