2020年,获得性囊性疾病相关肾细胞癌(ACD-RCCs)据报道含有KMT2C和TSC2变体:然而,它们的致癌意义尚未被报道。本研究旨在探讨KMT2C和TSC2在ACD-RCC中的变异特征及其在ACD-RCC肿瘤发生中的意义。11个ACD-RCC,10个ACD-RCC样囊肿,并取回了18个背景肾脏。背景肾脏由萎缩性甲状腺滤泡样小管组成。其中包括四个簇状囊肿,两个有嗜酸性粒细胞变化,每个都有清晰的细胞变化和肾小管中的筛状变化。首先,对8个ACD-RCC样品进行KMT2C和TSC2全外显子的DNA靶向测序。随后,我们根据测序结果设计了一个定制DNA组,以包括复发的KMT2C和TSC2变异体.第二,使用靶向复发变体的定制组对剩余样品进行DNA靶向测序。此外,对KMTC进行了免疫组织化学,ACD-RCC上的H3K4me1、H3K4me3、TSC2和GPNMB。11例ACD-RCC病例中有6例包含KMT2C和TSC2变体,包括九种可能的致病变异。与ACD-RCC相比,9个ACD-RCC样囊肿中有1个具有两种变体。免疫组织化学分析不支持携带KMT2C和TSC2变体的ACD-RCC的功能丧失。ACD-RCC中的KMT2C和TSC2变异频率高于其他肾细胞癌。然而,KMT2C和TSC2不太可能成为ACD-RCC发展的主要驱动力。
In 2020, acquired cystic disease-associated renal cell carcinomas (ACD-RCCs) were reported to harbor KMT2C and
TSC2 variants: however, their carcinogenic implication has not yet been reported. This study aimed to explore the variant features of KMT2C and
TSC2 in ACD-RCC and their implication in ACD-RCC tumorigenesis. Eleven ACD-RCCs, 10 ACD-RCC-like cysts, and 18 background kidneys were retrieved. The background kidneys consisted of atrophic thyroid follicle-like tubules. They included four with clustered cysts, two with eosinophilic changes, and one each with clear cell changes and sieve-like changes in the renal tubules. First, DNA-targeted sequencing of KMT2C and
TSC2 whole exons was performed on eight ACD-RCC samples. Subsequently, a custom DNA panel was designed to include the recurrent KMT2C and TSC2 variants based on the sequencing results. Second, DNA-targeted sequencing was performed on the remaining samples using a custom panel targeting the recurrent variants. Additionally, immunohistochemistry was performed for KMTC, H3K4me1, H3K4me3, TSC2, and GPNMB on the ACD-RCCs. Six of the 11 ACD-RCC cases harbored KMT2C and TSC2 variants, including nine likely pathogenic variants. In contrast to ACD-RCC, 1 of the 9 ACD-RCC-like cysts harbored both variants. Immunohistochemical analysis did not support the loss of function in ACD-RCCs harboring KMT2C and TSC2 variants. KMT2C and
TSC2 variant frequencies were higher in ACD-RCC than in other renal cell carcinomas. However, KMT2C and
TSC2 are unlikely to be the primary drivers of ACD-RCC development.