Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Journal of the National Comprehensive Cancer Network : JNCCN	16	4	2018 Apr	352-358	J Natl Compr Canc Netw

URL

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 (UniProt.org). V1067E results in increased Torc1 activity and decreased Tsc2 expression compared to wild-type Tsc2 in culture (PMID: 29632054), and therefore, is predicted to lead to a loss of Tsc2 protein function.

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