TSC1

Overview

TSC1 (TSC Complex Subunit 1), encoding hamartin, forms a heterodimeric complex with TSC2 (tuberin) that functions as a GTPase-activating protein for RHEB, thereby inhibiting mTORC1 signaling. Loss of TSC1 or TSC2 leads to constitutive mTOR activation, driving cellular growth and proliferation. Germline mutations cause tuberous sclerosis complex (TSC), and somatic mutations are a therapeutic target across multiple cancer types.

Alterations observed in the corpus

  • TSC1 c.2503-1G>C splice-site somatic mutation identified in an osteosarcoma (OS) patient in the PIPseq pediatric precision sequencing program (n=101, Columbia University); designated as an mTOR-inhibitor target. PMID:28007021
  • TSC1 combined with TSC2: together mutated in 6.3% of HR+/HER2− metastatic breast cancer (mBC) vs 0.7% of HR+/HER2− early breast cancer (eBC; p=0.0004) in 216 mBC patients; all in previously endocrine-therapy-treated patients. Authors hypothesize TSC1/2-mutant tumors may be outlier responders to mTOR inhibitor everolimus. PMID:28027327
  • TSC1 truncating alterations in 3 patients (0.3%) in 860 metastatic LUAD patients profiled by MSK-IMPACT; classified as OncoKB level 2B; no patient received matched mTOR-inhibitor therapy in this cohort despite open basket trials NCT02201212 and NCT02675829 PMID:28336552.
  • V46Wfs frameshift mutation in 1/19 sequenced oligodendroglioma tumors; OncoKB Level 2B PMID:28472509

Cancer types (linked)

  • OS: TSC1 splice-site mutation is a targetable mTOR-pathway event in pediatric osteosarcoma; mTOR inhibitors (everolimus, temsirolimus) are the relevant class. PMID:28007021
  • BRCA (HR+/HER2− mBC): TSC1/TSC2 combined mutation rate is significantly enriched in the metastatic vs early breast cancer setting (6.3% vs 0.7%, p=0.0004); all cases had prior endocrine therapy, suggesting mTOR-pathway activation as a potential endocrine-resistance mechanism. PMID:28027327

Co-occurrence and mutual exclusivity

  • In HR+/HER2− mBC, TSC1/TSC2 mutations occur in the context of prior endocrine therapy — consistent with mTOR pathway activation as a resistance mechanism. PMID:28027327

Therapeutic relevance

  • mTOR inhibitors (everolimus, temsirolimus) are the designated targeted class for TSC1-mutant tumors; everolimus is FDA-approved in HR+/HER2− mBC. TSC1/2-mutant tumors are hypothesized to be outlier responders to everolimus in HR+/HER2− mBC. PMID:28007021 PMID:28027327

Open questions

  • The TSC1/2 → everolimus outlier-response hypothesis in HR+/HER2− mBC requires prospective clinical validation. PMID:28027327
  • Whether pediatric osteosarcoma patients with TSC1 mutations show superior mTOR-inhibitor response compared to unselected OS is not established. PMID:28007021

Sources

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This page was processed by wiki-cli on 2026-05-15.