A Renal Cell Carcinoma with Biallelic Somatic TSC2 Mutation: Clinical Study and Literature Review

Abstract

OBJECTIVETo elucidate the effect of the biallelic somatic TSC2 mutations, identified in one adolescent patient, in renal cell carcinoma (RCC). METHODSMutation analyses, immunohistochemistry and real-time polymerase chain reaction (PCR) were conducted. RESULTSTwo novel somatic mutations of TSC2 in unilateral and solitary RCC samples from a 14-year-old female were identified. The pathological features suggest the tumor as a clear-cell renal cell carcinoma. In addition, immunohistochemistry revealed elevated levels of phosphorylated S6K1. Results from in vitro cellular experiments suggest that the mutant TSC2 proteins were quickly degraded and they failed to repress the phosphorylation of S6K1 and STAT3, which leads to constitutive activation of mTORC1 pathway and ultimately cause the development of RCC. CONCLUSIONDetecting TSC2 mutation in patients with early RCC onset would be beneficial and mTOR inhibitor could be a therapeutic option for TSC2 mutation-induced RCC. UROLOGY 133: 96−102, 2019. © 2019 Elsevier Inc. R enal cell carcinoma (RCC) represents about 90% of renal malignancies, which is the 13th most common malignancy among all cancers. Approximately 2%-3% of RCC occurs in patients with hereditary diseases including von Hippel-Lindau (VHL) syndrome, hereditary papillary RCC, and Birt-Hogg-Dube' syndrome. 1 In addition, 2%-4% of tuberous sclerosis (TSC) patients suffer from RCC, which is higher than the estimated incidence among the general population. Multiple lines of evidence suggest that loss of function of either TSC1 or TSC2 could result in RCC. [2][3][4] The TSC1 and TSC2 genes are located on 9q34 and 16q13.3, respectively. 5 The protein complex composed of hamartin and tuberin, which is translated from TSC1 and TSC2 respectively, possesses GTPase activity responsible for turning GTP-Rheb to GDP-Rheb. Therefore, both TSC1 and TSC2 were also known as cancer suppressors partially due to their inhibitory role on mammalian target of rapamycin complex 1 (mTORC1). Mechanistically, loss-of-function mutations in TSC1 and/or TSC2 result in inactivation of the hamartin-tuberin complex and subsequently inactivate GTPase and ultimately lead to constitutive activation of the mTORC1 pathway. 3 TSC is an autosomal dominant disease and almost all organs in these patients were affected 5 characterized by facial angiofibroma, seizures, and cognitive disability. TSC also can cause renal lesions including RCC. 6 Since the first reported RCC in a patient with TSC in 1986, 7 numerous cases of RCC have been reported in familial TSC with germ line mutations in either TSC1 or TSC2. However, cases of RCC due to a somatic mutation of TSC2 are relatively rare. Here we present a case of clear cell RCC (ccRCC) in an adolescent with 2 novel biallelic somatic mutations in TSC2.

The Neurodevelopmental Pathogenesis of Tuberous Sclerosis Complex (TSC)

“…Pten/Tsc1 deletion tumors may reflect the potent tumor suppressor functions of PTEN. Evidence has not yet linked the loss of a TSC gene and a second non-TSC gene in patient SEGAs (Henske et al, 1997;Chan et al, 2004;Bongaarts et al, 2017). Moreover, this same group did not find evidence that PTEN is mutated in SEGAs (Zordan et al, 2018).…”

“…And Tsc2 loss of heterozygosity (LOH), the genetic manifestation of the two-hit hypothesis, was detected in Eker renal tumors induced by mutagens and in Tsc2 heterozygous mice (Kubo et al, 1994;Kobayashi et al, 1997;Hino et al, 2002;Ma et al, 2005). Subsequent studies confirmed that LOH, also referred to as biallelic inactivation, occurs in TSC patient tumors and malformations including SEGAs and cortical tubers (Chan et al, 2004;Crino et al, 2010;Qin et al, 2010a;Bongaarts et al, 2017;Martin et al, 2017).…”

“…An example of this theoretical timing is that mutations in TSC2 that cause hemimegalencephaly may occur in early neuroepithelial stem cells, those that occur later in embryonic radial glia may cause cortical tubers or focal cortical dysplasias, and later mutations in SVZ NSCs may cause SEGAs (Figures 2F-H; Henske et al, 1997;Chan et al, 2004;Crino et al, 2010;Qin et al, 2010a;D'Gama et al, 2017;Lim et al, 2017;Martin et al, 2017). Evidence of this phenomenon has historically been easier to detect in cells with a clonal origin that are in a confined location as occurs with tumors.…”

Longitudinal Genomic Evolution of Conventional Papillary Thyroid Cancer With Brain Metastasis

“…Actually, TSC2 encodes a tumor suppressor, which is capable of stimulating specific GTPases ( 32 , 33 ) and negatively regulate mTOR signaling ( 34 ). Somatic TSC2 mutation contributes to tumorigenesis, including renal cancer ( 35 ). Therefore, we speculated that these two mutations may inactivate both alleles of TCS2 , which unfortunately cannot be experimentally validated due to the long distance of these two mutations.…”

Mutation Profile Variability in the Primary Tumor and Multiple Pulmonary Metastases of Clear Cell Renal Cell Carcinoma. A Review of the Literature and Analysis of Four Metastatic Cases

“…The mutation of the TSC genes in CCRCC is unusual but has been documented. Pang et al [ 43 ] reported a rare case of CCRCC with novel biallelic somatic mutations in TSC2 . This was a case of a 14-year-old female with VHL syndrome, where histologic findings were typical of CCRCC morphology.…”