Vlachostergios Panagiotis J
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
Precis Clin Med. 2020 Jun 3;3(3):153-160. doi: 10.1093/pcmedi/pbaa020. eCollection 2020 Sep.
Upper tract urothelial carcinoma (UTUC) is rare but can occur sporadically outside the context of Lynch syndrome. In these cases, knowing whether non-mismatch repair (MMR), DNA damage response and repair (DDR), and cell cycle gene alterations may predict responses to chemotherapy or immunotherapy and survival is of clinical importance. This study examined the germline and somatic mutational landscape of two UTUC patients with differential responses to programmed death 1 (PD-1)/PD-ligand 1 (PD-L1) immune checkpoint inhibitors and queried three independent UTUC cohort studies for co-occurrence of key cell cycle and DDR genes, as well as for their associations with overall survival (OS). TP53 and RB1 emerged as potential determinants of shorter OS in UTUC cohort patients, regardless of concurrent DDR alterations, and if prospectively assessed in larger studies they might also explain resistance to PD-1/PD-L1 blockade despite PD-L1 expression.
上尿路尿路上皮癌（UTUC）较为罕见，但可在林奇综合征背景之外散发性发生。在这些病例中，了解非错配修复（MMR）、DNA损伤反应与修复（DDR）以及细胞周期基因改变是否可预测化疗或免疫治疗反应及生存情况具有临床重要性。本研究检测了两名对程序性死亡1（PD-1）/程序性死亡配体1（PD-L1）免疫检查点抑制剂反应不同的UTUC患者的种系和体细胞突变图谱，并查询了三项独立的UTUC队列研究，以了解关键细胞周期和DDR基因的共发生情况及其与总生存期（OS）的关联。TP53和RB1成为UTUC队列患者OS缩短的潜在决定因素，无论DDR改变是否同时存在，并且如果在更大规模研究中进行前瞻性评估，它们可能还能解释尽管有PD-L1表达但对PD-1/PD-L1阻断产生耐药的原因。
