Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, ON P6B 0A8, Canada.
Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada.
Curr Oncol. 2022 Feb 24;29(3):1390-1407. doi: 10.3390/curroncol29030117.
Urothelial bladder carcinomas had traditionally been difficult to treat cancers, with high morbidity and mortality rates when invasive and metastatic. In recent years, immunotherapy with immune checkpoint inhibitors has improved outcomes in several cancers, including bladder carcinomas. Despite positive overall results, many bladder cancer patients do not respond to immunotherapies. Validated predictive biomarkers of response would advance the selection of patients for these treatments. Tumor mutation burden (TMB) has been suggested as an immunotherapy biomarker and thus delineation of attributes of tumors with a high TMB is clinically relevant. Publicly available genomic and clinical data from the urothelial bladder carcinoma cohort of The Cancer Genome Atlas (TCGA) project are used to analyze characteristics and molecular alterations of the subset of cancers with an increased tumor mutation number compared with those with lower number of mutations. The cut-off for the high mutation burden in the analysis was set at 10 mutations per Megabase (MB). In addition to their sensitivity to immune checkpoint inhibitors, urothelial carcinomas with high TMB possess several molecular defects that could be exploited for combinatorial treatments. Compared with bladder carcinomas with low TMB, carcinomas with high TMB display higher prevalence of mutations in tumor suppressor , , in cadherin and in genes encoding for several epigenetic modifier enzymes. The frequency of mutations in mismatch repair and DNA damage response genes is higher in cancers with high TMB. The group of urothelial carcinomas with high TMB has a better prognosis than the group with low TMB. This improved Overall Survival (OS) stems from improved survival of stage III cancers with high TMB compared with stage III cancers with low TMB, while stage II and stage IV cancers have similar OS, independently of their TMB. Differences of the landscape of high and low TMB urothelial cancers provides leads for further pathogenesis investigations and may prove useful for development of combination therapies including immunotherapies with targeted inhibitors.
尿路上皮膀胱癌一直是难以治疗的癌症，侵袭性和转移性膀胱癌的发病率和死亡率都很高。近年来，免疫检查点抑制剂的免疫疗法改善了包括膀胱癌在内的几种癌症的预后。尽管总体结果为阳性，但许多膀胱癌患者对免疫疗法没有反应。有效的反应预测生物标志物将有助于选择这些治疗的患者。肿瘤突变负荷 (TMB) 已被认为是免疫治疗的生物标志物，因此，确定 TMB 较高的肿瘤的特征具有临床相关性。 使用来自癌症基因组图谱 (TCGA) 项目的尿路上皮膀胱癌队列的公开基因组和临床数据，分析与突变数量较低的肿瘤相比，突变数量增加的肿瘤亚组的特征和分子改变。分析中高突变负担的截止值设定为每兆碱基 (MB) 有 10 个突变。 除了对免疫检查点抑制剂敏感外，TMB 较高的尿路上皮癌还具有几种可能用于联合治疗的分子缺陷。与 TMB 较低的膀胱癌相比，TMB 较高的膀胱癌中肿瘤抑制基因 、 、钙黏蛋白和几个表观遗传修饰酶编码基因的突变发生率更高。TMB 较高的癌症中错配修复和 DNA 损伤反应基因的突变频率更高。TMB 较高的尿路上皮癌亚组的总体生存率 (OS) 优于 TMB 较低的亚组。这种改善的总生存率源自与 TMB 较低的 III 期癌症相比，TMB 较高的 III 期癌症的生存率提高，而 II 期和 IV 期癌症的 OS 相似，与 TMB 无关。 TMB 较高和较低的尿路上皮癌的肿瘤景观差异为进一步的发病机制研究提供了线索，并可能有助于开发包括免疫疗法与靶向抑制剂在内的联合疗法。
