TSC2
Overview
TSC2 (TSC Complex Subunit 2), encoding tuberin, forms a GTPase-activating protein complex with TSC1 (hamartin) to inhibit RHEB and consequently mTORC1 signaling. Loss of TSC2 leads to constitutive mTOR activation, driving cellular growth. Germline mutations cause tuberous sclerosis complex; somatic mutations are enriched in the metastatic breast cancer setting, particularly following endocrine therapy, suggesting a role in treatment resistance.
Alterations observed in the corpus
- TSC2 combined with TSC1: 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 from French prospective trials (SAFIR01, SAFIR02, SHIVA, MOSCATO); all cases in prior-endocrine-therapy-treated patients. Authors hypothesize outlier response to mTOR inhibitor everolimus. PMID:28027327
- TSC2 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 PMID:28336552.
Cancer types (linked)
- BRCA (HR+/HER2− mBC): TSC2 (combined with TSC1) mutations are significantly enriched in metastatic versus early breast cancer (6.3% vs 0.7%, p=0.0004). All mutant cases had prior endocrine therapy, consistent with mTOR activation as an acquired endocrine-resistance mechanism. PMID:28027327
Co-occurrence and mutual exclusivity
- TSC2 mutations cluster with prior endocrine therapy in HR+/HER2− mBC; no specific co-mutation partner analysis reported in the corpus. PMID:28027327
Therapeutic relevance
- TSC1/2-mutant HR+/HER2− mBC is hypothesized to be an outlier responder to everolimus (mTOR inhibitor, FDA-approved in HR+/HER2− mBC); current evidence is enrichment data, not prospective biomarker trial. PMID:28027327
Open questions
- The TSC1/2 → everolimus outlier-response hypothesis requires a prospective biomarker-selected clinical trial for validation. PMID:28027327
- Whether TSC2 vs TSC1 mutations have differential mTOR-inhibitor sensitivity is not addressed in the corpus. PMID:28027327
Sources
This page was processed by entity-page-writer on 2026-05-15. - PMID:28336552
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