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Ref Type Journal Article
PMID (29632054)
Authors Maroto P, Anguera G, Roldan-Romero JM, Apellániz-Ruiz M, Algaba F, Boonman J, Nellist M, Montero-Conde C, Cascón A, Robledo M, Rodríguez-Antona C
Title Biallelic TSC2 Mutations in a Patient With Chromophobe Renal Cell Carcinoma Showing Extraordinary Response to Temsirolimus.
Journal Journal of the National Comprehensive Cancer Network : JNCCN
Vol 16
Issue 4
Date 2018 Apr
Abstract Text mTOR inhibitors are used to treat renal cell carcinoma (RCC). Treatment response is variable and appears to correlate with genetic alterations that activate mTOR signaling. Recently, everolimus was suggested to be more effective than sunitinib in chromophobe RCC (chRCC), a tumor with frequent mTOR pathway defects. This report presents the genomic and functional characterization of a metastatic chRCC that showed complete response at metastatic sites and 80% reduction in primary tumor size upon temsirolimus treatment. After surgery, the patient remained disease-free for 8 years after temsirolimus therapy. Whole-exome sequencing (WES) revealed 2 somatic variants in TSC2, a critical negative regulator of mTOR: a splicing defect (c.5069-1G>C) and a novel missense variant [c.3200_3201delinsAA; p.(V1067E)]. In vitro functional assessment demonstrated that the V1067E substitution disrupted TSC2 function. Immunohistochemistry in the tumor tissues revealed increased phosphorylated S6 ribosomal protein, indicating mTOR pathway activation. In conclusion, WES revealed TSC2 inactivation as the likely mechanism for this extraordinary response to temsirolimus. These findings support high efficacy of mTOR inhibitors in a subset of patients with chRCC and propose sequencing of mTOR pathway genes to help guide therapy.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
TSC2 V1067E missense loss of function - predicted TSC2 V1067E does not lie within any known functional domains of the Tsc2 protein ( V1067E is predicted to confer a loss of function on the Tsc2 protein, as indicated by increased Torc1 activity and decreased Tsc2 expression compared to wild-type Tsc2 in culture (PMID: 29632054).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TSC2 V1067E chromophobe renal cell carcinoma predicted - sensitive Temsirolimus Case Reports/Case Series Actionable In a clinical case study, Torisel (temsirolimus) treatment led to a complete response in metastatic sites and an 80% decrease in primary tumor size in a patient with chromophobe renal cell carcinoma harboring biallelic mutations, TSC2 splice site mutation and TSC2 V1067E (PMID: 29632054). 29632054