Kittler Ralf, Shiang Christine, Hutchinson Ryan, Kollipara Rahul K, Kapur Payal, Franto Francis, Lotan Yair
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Oncotarget. 2018 Jan 6;9(10):9415-9424. doi: 10.18632/oncotarget.24072. eCollection 2018 Feb 6.
Low-grade (LG) urothelial carcinomas of the bladder (UCB) are common malignancies that are costly to surveil and rarely progress to life threatening, high-grade (HG) malignancies. It is unknown if the progression of LG to HG is a result of second primary tumors or transformation of existing LG tumors. We examined tumor genetics in patients with grade progression in urothelial carcinoma and compared to patients with no progression.
Five patients were identified with progression. Median time from initial LG diagnosis to HG diagnosis in those experiencing progression was 19 months. Progression with both high and low mutational homology was identified. Gene alterations associated with tumor grade progression in initial low grade tumors include FBN3, CIT and HECTD4.
An institutional cancer database at a tertiary referral center in the United States identified patients who progressed from LG to HG UCB. Histologic re-review was performed by a genitourinary pathologist. Whole exome sequencing with correction for germline mutations by buffy coat subtraction was performed. Mutations were assessed between LG tumors and subsequent same-patient HG tumors and for LG patients who did not progress. Individual genes were assessed as potential predictors of risk for progression.
Tumor grade progression occurred with both high mutational homology and low mutational homology, which may represent both true tumor progression and de-novo growth. Validation of the identified tumor genes that appeared associated with progression may provide a clinically valuable tool to providers managing patients with LG urothelial carcinomas.
膀胱低度（LG）尿路上皮癌（UCB）是常见的恶性肿瘤，监测成本高昂，且很少进展为危及生命的高度（HG）恶性肿瘤。尚不清楚LG向HG的进展是继发原发性肿瘤还是现有LG肿瘤发生转化的结果。我们研究了尿路上皮癌分级进展患者的肿瘤遗传学，并与无进展患者进行了比较。
确定了5例有进展的患者。进展患者从最初LG诊断到HG诊断的中位时间为19个月。发现了高突变同源性和低突变同源性的进展情况。初始低度肿瘤中与肿瘤分级进展相关的基因改变包括FBN3、CIT和HECTD4。
美国一家三级转诊中心的机构癌症数据库确定了从LG进展为HG UCB的患者。由泌尿生殖病理学家进行组织学重新评估。通过去除血沉棕黄层对种系突变进行校正后进行全外显子测序。在LG肿瘤与随后同一患者的HG肿瘤之间以及未进展的LG患者中评估突变情况。评估单个基因作为进展风险的潜在预测指标。
肿瘤分级进展在高突变同源性和低突变同源性情况下均有发生，这可能分别代表真正的肿瘤进展和新生肿瘤生长。对所确定的与进展相关的肿瘤基因进行验证，可能为管理LG尿路上皮癌患者的医疗人员提供一种具有临床价值的工具。
