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|Ref Type||Journal Article|
|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|
|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.|
|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 (UniProt.org). 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|