Implication of KMT2C and TSC2 variants in the tumorigenesis of acquired cystic disease-associated renal cell carcinomas

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. •Approximately half of ACD-RCCs harbored KMT2C and TSC2 variants.•Most ACD-RCC-like cysts and background kidneys did not harbor both variants.•KMT2C and TSC2 are unlikely to be the primary drivers of ACD-RCC development.