Acquired Cystic Kidney Disease–associated Renal Cell Carcinoma (ACKD-RCC) Harbor Recurrent Mutations in KMT2C and TSC2 Genes

Abstract

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.

From kidney injury to kidney cancer

“…89 Second hits can be identified in the remaining allele of TSC1 or TSC2 in most sporadic angiomyolipomas 92 and TSC-related RCCs. 93 Mutations in TSC2 were observed in 60% of acquired cystic kidney disease patients, 94 suggesting a role in the development of sporadic cysts/RCC. A strong association between age, angiomyolipoma size, and CKD has been reported; patients with worse CKD stage tend to be older and have more advanced angiomyolipoma.…”

Xanthomatous Giant Cell Renal Cell Carcinoma

“…Lymphocytes and hemosiderin-laden macrophages were present among the neoplastic cells, and the latter were also found in the adjacent draining perirenal lymph nodes which harbored metastasis. Neither case demonstrated oxalate crystals or cribriform growth, typical of acquired cystic disease associated renal cell carcinoma 18…”

“…Neither case demonstrated oxalate crystals or cribriform growth, typical of acquired cystic disease associated renal cell carcinoma. 18…”

“…In contrast, however, LOT typically features transitions from solid growth to elongated cords/sheaths of neoplastic cells in edematous stroma, has fewer nuclear irregularities, has less well-developed perinuclear halos, and does not label diffusely for CD117. Other renal cell carcinomas apparently driven by TSC/MTOR mutations include renal cell carcinoma with leiomyomatous stroma,15–17 and acquired cystic disease associated renal cell carcinoma 18…”

Renal cell carcinoma associated with tuberous sclerosis complex (TSC)/mammalian target of rapamycin (MTOR) genetic alterations

“…One query is whether there are other distinctive RCCs that may prove to be associated with TSC1/ 2 or MTOR gene mutations. Along these lines, a recent report described TSC2 mutations in a subset of acquired cystic diseaseassociated RCC 29 . Another is how frequent are TSC1/2 or MTORmutated RCC that do not cleanly fit a given category but instead have overlapping features of ESC, LOT, and/or EVT.…”