Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania.
Department of Genetics, Penn Genomic Core Analysis.
Am J Surg Pathol. 2020 Nov;44(11):1479-1486. doi: 10.1097/PAS.0000000000001530.
Individuals with acquired cystic kidney disease (ACKD) in the setting of end-stage renal disease (ESRD) have a high risk of developing renal cell carcinoma (RCC). ACKD-RCC is considered a distinct renal neoplasm in the International Society of Urologic Pathologists (ISUP)-World Health Organization (WHO) classification of kidney tumors which may behave aggressively. Since its original description, there have been multiple case reports and series published; however, the pathogenesis of this neoplasm is uncertain and there is limited data on the genetic aberrations of this tumor. Herein, we present our experience with ESRD kidneys, with emphasis on ACKD-RCC, associated cysts, and the somatic mutation analysis of a subset of ACKD-RCCs using next-generation sequencing. Our data on 59 cases with ESRD that underwent nephrectomy, shows that ACKD-RCC represents more than half of the tumors (25/46; 54%) developing in ESRD, followed by papillary RCC (13; 28%). History of dialysis, male sex, and African American race were potential risk factors for developing ACKD-RCCs. Further, ACKD-RCC-like cysts are possible precursors of RCCs in the ACKD setting noted in 40 of 46 (87%) cases with tumors. Next-generation sequencing analysis revealed recurrent mutations in the KMT2C gene in 4 of 5 ACKD-RCCs (80%), exclusively exhibiting cribriform "sieve-like" morphology; whereas the case negative for KMT2C mutations exhibited "type 2" papillary RCC morphology and lacked "sieve-like" growth pattern. Pathogenic mutations in TSC2 were the second common abnormality (3/5; 60%), often coexisting with KMT2C mutations. Deleterious mutations in additional genes such as CBL, PDGFRA, and SYNE1, etc. were noted but were nonrecurrent and always coexisted with mutations in KMT2C or TSC2. To conclude, our study highlights that mutations in a chromatin-modifying gene KMT2C may potentially be oncogenic drivers for the development of ACKD-RCC with classic sieve-like morphology. In addition, pathogenic mutations in TSC2 possibly play a role in the development of cysts/tumors in a subset of ACKD patients. If corroborated in larger cohorts, these findings would be useful in planning surveillance and early intervention in ESRD patients developing ACKD.
患有终末期肾病（ESRD）的获得性囊性肾病（ACKD）患者发生肾细胞癌（RCC）的风险很高。ACKD-RCC 在国际泌尿病理学会（ISUP）-世界卫生组织（WHO）肾脏肿瘤分类中被认为是一种独特的肾肿瘤，可能具有侵袭性。自最初描述以来，已经发表了多个病例报告和系列研究；然而，这种肿瘤的发病机制尚不确定，关于这种肿瘤的遗传异常数据有限。在此，我们介绍了我们在 ESRD 肾脏方面的经验，重点介绍了 ACKD-RCC、相关囊肿以及使用下一代测序对一部分 ACKD-RCC 进行的体细胞突变分析。我们的数据显示，在 59 例接受肾切除术的 ESRD 患者中，ACKD-RCC 代表了在 ESRD 中发展的肿瘤的一半以上（25/46；54%），其次是乳头状 RCC（13；28%）。透析史、男性和非裔美国人种族是发生 ACKD-RCC 的潜在危险因素。此外，在 46 例肿瘤患者中，ACKD 环境中的 ACKD-RCC 样囊肿是 RCC 的可能前体，在 40 例（87%）中均有发现。下一代测序分析显示，在 5 例 ACKD-RCC 中有 4 例（80%）存在 KMT2C 基因的复发性突变，仅表现出筛状“筛状”形态；而 KMT2C 突变阴性的病例表现出“2 型”乳头状 RCC 形态，缺乏“筛状”生长模式。TSC2 中的致病性突变是第二种常见异常（3/5；60%），通常与 KMT2C 突变共存。还注意到其他基因如 CBL、PDGFRA 和 SYNE1 等的有害突变，但非复发性且总是与 KMT2C 或 TSC2 的突变共存。总之，我们的研究表明，染色质修饰基因 KMT2C 的突变可能是具有经典筛状形态的 ACKD-RCC 发展的致癌驱动因素。此外，TSC2 中的致病性突变可能在一部分 ACKD 患者的囊肿/肿瘤发生中发挥作用。如果在更大的队列中得到证实，这些发现将有助于规划 ESRD 患者发生 ACKD 时的监测和早期干预。
