Mutational analysis of renal angiomyolipoma associated with tuberous sclerosis complex and the outcome of short-term everolimus therapy

Abstract

To identify clinical characteristics and mutation spectra in Chinese patients with renal angiomyolipoma (AML) associated with the tuberous sclerosis complex (TSC, TSC-AML), examined the efficacy and safety of short-term everolimus therapy (12 weeks). We analyzed the frequency distribution of each TSC-related clinical feature and investigated gene mutations by genetic testing. Some subjects received everolimus for 12 weeks at a dose of 10 mg/day, and the efficacy and safety of short-term everolimus therapy were examined. Finally, 82 TSC-AML patients were enrolled for analysis in this study. Of the 47 patients who underwent genetic testing, 22 patients (46.81%) had at least one detectable mutation in the TSC1 or TSC2 gene: 7 were TSC1 gene mutations, 13 were TSC2 gene mutations, and 2 were found in both TSC1 and TSC2. Everolimus treatment had a statistically significant effect on the renal AML volume reduction during follow-up (P < 0.05), and the mean reduction rate of volume for all cases was 56.47 ± 23.32% over 12 weeks. However, 7 patients (7/25; 28.00%) experienced an increase in renal AML tumor volume within 12 weeks after discontinuation of the everolimus treatment. Although most patients (27/30, 90.00%) experienced some adverse events during the treatment period, all such events were mild, and no patients discontinued or needed dose reduction because of adverse events. Overall, in this study, the mutation rate of TSC-AML patients is much lower than other reports. Short-term everolimus treatment for TSC-AML is effective and safe, but the stability is much lower than long-term therapy.

The Correlation Between Tuberous Sclerosis Complex Genotype and Renal Angiomyolipoma Phenotype

“…Currently, there are fragmentary studies that focus on the correlation between TSC gene mutations and phenotypes. Although the genotype-phenotype correlation in patients with TSC-RAML has been conducted in many studies (Li et al, 2018;Ni et al, 2019), the sample size of these remained too small. Thus, a further analysis with a larger sample size is required.…”

“…The estimated incidence rate of TSC is between of 1/6000 and 1/10,000 in live births and 1 in 20,000 in the population (Northrup et al, 2013). TSC is a genetic disorder that is characterized by the growth of benign hamartomas in various organs and is caused by TSC1 or TSC2 gene mutations (Ni et al, 2019). The TSC1 gene is located on chromosome 9q34 and consists of 23 exons that encode the hamartin (Slegtenhorst et al, 1997) and the TSC2 gene is located on chromosome 16p13 and consists of 42 exons that encode the tuberin (European Chromosome 16 Tuberous Sclerosis Consortium,, 1993).…”

Sequential everolimus for angiomyolipoma associated with tuberous sclerosis complex: a prospective cohort study

“…Cai et al reported 14/18 (77.8%) patients had an AML with the longest diameter of at least 8 cm [ 9 ]. Ni et al reported 38/82 (46.3%) patients had an AML with the longest diameter of at least 10 cm [ 15 ]. The median time to tumor response in this study was 1.2 months, compared with 2.9 months in the EXIST-2 study.…”

Large renal leiomyoma: A multidisciplinary approach to diagnosis

“…AMLs are common benign tumors composed of some combination of smooth muscle, vascular, and adipose tissue. AMLs are highly associated with tuberous sclerosis complex (TSC), an autosomal dominant genetic disorder that causes renal AMLs in approximately 80% of patients with this condition [15]. Similar to leiomyomas, asymptomatic AMLs are common, with a prevalence of 0.44% in healthy individuals [16].…”