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| Gene Symbol | TSC1 | ||||||||||
| Synonyms | LAM | TSC | ||||||||||
| Gene Description | TSC1, TSC complex subunit 1, is a tumor suppressor (PMID: 30562755) that forms a complex with Tsc2 and inhibits mTOR pathway signaling, thus regulating cell growth and metabolism (PMID: 27226234). Germline TSC1 inactivating mutations cause tuberous sclerosis complex and somatic TSC1 mutations have been identified in various cancers, including renal cell carcinoma, mucosal melanoma, and breast cancer (PMID: 27226234, PMID: 30327302, PMID: 29185092, PMID: 28027327). | ||||||||||
| ACMG Incidental List v3.0: |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| TSC1 E636fs | bladder carcinoma | sensitive | Everolimus | Case Reports/Case Series | Actionable | A retrospective study of a Phase II trial correlated increased sensitivity to the mTOR inhibitor Afinitor (everolimus) with TSC1 mutations in bladder cancer patients, including one patient harboring TSC1 E636fs* who had a durable complete response (PMID: 22923433). | 22923433 |
| TSC1 mutant | bladder carcinoma | sensitive | Everolimus | Phase II | Actionable | A retrospective study of a Phase II trial correlated increased sensitivity to the mTOR inhibitor Afinitor (everolimus) with TSC1 mutations in bladder cancer patients (PMID: 22923433). | 22923433 |
| TSC1 mutant | renal cell carcinoma | conflicting | Everolimus | Case Reports/Case Series | Actionable | In a clinical study, treatment with Afinitor (everolimus) or Torisel (temsirolimus) resulted in more partial responses (odds ratio = 0.08, p=0.030) in patients with renal cell carcinoma harboring mTOR pathway mutations, including MTOR (n=8), TSC1 (n=1), and TSC2 (n=2), than those without mutations (n=76) (PMID: 31335987). | 31335987 |
| TSC1 mutant | renal cell carcinoma | conflicting | Everolimus | Clinical Study - Cohort | Actionable | In a retrospective analysis, TSC1, TSC2, or MTOR mutation status was not associated with progression-free survival in renal cell carcinoma patients treated with Afinitor (everolimus) (PMID: 30327302). | 30327302 |
| TSC1 mutant | subependymal giant cell astrocytoma | predicted - sensitive | Everolimus | Phase III | Actionable | In a Phase III trial (EXIST-1), Afinitor (everolimus) treatment resulted in a 50% or more tumor reduction in 35% (27/78) of adult and pediatric patients diagnosed with tuberous sclerosis complex and had subependymal giant cell astrocytoma, compared to 0% (0/39) in the placebo group, 85% (99/117) of the patients harbored mutations in TSC1 and/or TSC2 (PMID: 23158522; NCT00789828). | 23158522 |
| TSC1 mutant | hepatocellular carcinoma | decreased response | Sorafenib | Clinical Study - Cohort | Actionable | In a clinical case study, Nexavar (sorafenib) treatment of patients with hepatocellular carcinoma harboring Mtor pathway mutations in PIK3CA, PTEN, TSC2, or TSC1 (n=12), resulted in a lower disease control rate (8.3% vs. 40.2%), shorter progression-free survival (1.9 months vs. 5.3 months) and shorter overall survival (10.4 months vs. 17.9 months) compared to patients without mutations in this pathway (n=67) (PMID: 30373752; NCT01775072). | 30373752 |
| TSC1 mutant | renal cell carcinoma | predicted - sensitive | Temsirolimus | Case Reports/Case Series | Actionable | In a clinical study, treatment with Afinitor (everolimus) or Torisel (temsirolimus) resulted in more partial responses (odds ratio = 0.08, p=0.030) in patients with renal cell carcinoma harboring mTOR pathway mutations, including MTOR (n=8), TSC1 (n=1), and TSC2 (n=2), than those without mutations (n=76) (PMID: 31335987). | 31335987 |
| TSC1 mutant | lung non-small cell carcinoma | no benefit | Vistusertib | Case Reports/Case Series | Actionable | In a Phase II trial (NLMT), Vistusertib (AZD2014) treatment did not result in a confirmed response (0/5) or durable clinical benefit (0/5) in patients with non-small cell lung cancer harboring TSC1 or TSC2 mutations, thus the cohort was closed due to futility (PMID: 32669708, NCT02664935). | 32669708 |
| TSC1 inact mut | renal cell carcinoma | predicted - sensitive | Everolimus | Clinical Study - Cohort | Actionable | In a retrospective analysis, 28% (12/43) of metastatic renal cell carcinoma patients who responded to rapalogs, Afinitor (everolimus) or Torisel (temsirolimus), harbored inactivating TSC1, TSC2 mutations and/or activating MTOR mutations, compared to 11% (4/36) in patients who did not respond to therapy (PMID: 26831717). | 26831717 |
| TSC1 inact mut | Advanced Solid Tumor | no benefit | Everolimus | Phase II | Actionable | In a Phase II trial, Afinitor (everolimus) treatment resulted in limited activity with an objective response rate of 7% (2/30, 2 partial responses), stable disease in an additional 40% (12/30), a clinical benefit rate of 13% (4/30), a median progression-free survival of 2.3 months, and a median overall survival of 7.3 months in patients with advanced solid tumors harboring inactivating TSC1 or TSC2 mutations or activating MTOR mutations (PMID: 33727259; NCT02201212). | 33727259 |
| TSC1 inact mut | renal cell carcinoma | predicted - sensitive | Temsirolimus | Clinical Study - Cohort | Actionable | In a retrospective analysis, 28% (12/43) of metastatic renal cell carcinoma patients who responded to rapalogs, Afinitor (everolimus) or Torisel (temsirolimus), harbored inactivating TSC1, TSC2 mutations and/or activating MTOR mutations, compared to 11% (4/36) in patients who did not respond to therapy (PMID: 26831717). | 26831717 |
| TSC1 inact mut | transitional cell carcinoma | no benefit | Sapanisertib | Phase II | Actionable | In a Phase II trial, treatment with Sapanisertib (MLN0128) in metastatic urothelial carcinoma patients with either a TSC1 or TSC2 activating mutation (n=13) did not result in an objective response and led to a median overall survival of 3.4 months, and the trial was terminated early due to limited clinical activity and poor drug tolerability (Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021) 431-431; NCT03047213). | detail... |
| TSC1 inact mut | islet cell tumor | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in TSC1 result in tuberous sclerosis complex (TSC), which is associated with increased risk of developing pancreatic neuroendocrine tumors (NCCN.org). | detail... |
| TSC1 inact mut | clear cell renal cell carcinoma | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in TSC1 result in tuberous sclerosis complex (TSC), which is associated with increased risk of developing clear cell renal cell carcinoma (NCCN.org). | detail... |
| TSC1 inact mut | perivascular epithelioid cell tumor | predicted - sensitive | Nab-rapamycin | Phase II | Actionable | In a Phase II trial (AMPECT), Fyarro (nab-rapamycin) treatment in patients with perivascular epithelioid cell tumors (PEComas) resulted in partial response in 20% (1/5) of patients with TSC1 mutations, 89% (8/9) of patients with TSC2 mutations, and 9% (1/11) of patients without a TSC1 or TSC2 mutation (PMID: 34637337; NCT02494570). | 34637337 |
| TSC1 inact mut | Advanced Solid Tumor | predicted - sensitive | Nab-rapamycin | Clinical Study | Actionable | In a clinical study, Fyarro (nab-rapamycin) treatment in patients with advanced solid tumors harboring mutations in TSC1 or TSC2 led to a partial response in 4 patients, stable disease in 2 patients, and progressive disease in 1 patient of 7 enrolled patients (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 3111-3111; NCT03817515). | detail... |
| TSC1 inact mut | castration-resistant prostate carcinoma | predicted - sensitive | CC-115 + Enzalutamide | Phase I | Actionable | In a Phase Ib trial, Xtandi (enzalutamide) plus CC-115 was safe and led to a PSA reduction >= 50% (PSA50) in 80% (32/40) and >=90% (PSA90) in 58% (23/40) of metastatic castration-resistant prostate cancer patients at 12 weeks, and patients with PIK3CA activating mutations or PTEN or TSC1/2 loss of function (n=16) achieved a PSA50, PSA90, and median radiographic progression-free survival of 94%, 63%, and 19.6 mo vs 67%, 47%, and 22.1 mo in PI3K pathway wild-type patients (n=15) (PMID: 37980367; NCT02833883). | 37980367 |
| TSC1 loss | urinary bladder cancer | sensitive | Sirolimus | Preclinical | Actionable | In a preclinical study, Rapamune (sirolimus) inhibited proliferation of cultured bladder cancer cells lacking TSC1 (PMID: 23401075). | 23401075 |
| TSC1 loss | urinary bladder cancer | sensitive | Torin 1 | Preclinical | Actionable | In a preclinical study, Torin 1 inhibited proliferation of cultured bladder cancer cells lacking TSC1 (PMID: 23401075). | 23401075 |
| TSC1 loss | urinary bladder cancer | sensitive | Luminespib + Sirolimus | Preclinical | Actionable | In a preclinical study, Luminespib (AUY922), in combination with Rapamune (sirolimus), inhibited growth of bladder cancer cells lacking TSC1 to a greater extent than either therapy alone (PMID: 23401075). | 23401075 |
| TSC1 loss | urinary bladder cancer | sensitive | Luminespib + Torin 1 | Preclinical | Actionable | In a preclinical study, Luminespib (AUY922), in combination with Torin 1 inhibited growth of bladder cancer cells lacking TSC1 to a greater extent than either therapy alone (PMID: 23401075). | 23401075 |
| TSC1 Q516* | transitional cell carcinoma | no benefit | Buparlisib | Case Reports/Case Series | Actionable | In a Phase II trial, Buparlisib (BKM120) treatment resulted in progressive disease in a patient with metastatic urothelial carcinoma harboring TSC1 Q516* (PMID: 32767682; NCT01551030). | 32767682 |
| TSC1 del | urinary bladder cancer | sensitive | Metformin | Preclinical | Actionable | In a preclinical study, bladder cancer cells harboring a deletion of TSC1 were sensitive to Glucophage (metformin) in culture, resulting in cell growth inhibition (PMID: 26921394). | 26921394 |
| PIK3CA act mut TSC1 del | estrogen-receptor positive breast cancer | resistant | Alpelisib | Preclinical - Cell culture | Actionable | In a preclinical study, PIK3CA-mutant, ESR1 (ER)-positive breast cancer cells with knockout of TSC1 demonstrated resistance to growth inhibition by Piqray (alpelisib) in culture, and decreased sensitivity to Piqray (alpelisib) in a cell line xenograft model (PMID: 33685991). | 33685991 |
| PIK3CA act mut TSC1 del | estrogen-receptor positive breast cancer | resistant | Taselisib | Preclinical - Cell culture | Actionable | In a preclinical study, PIK3CA-mutant, ESR1 (ER)-positive breast cancer cell lines with knockout of TSC1 were resistant to treatment with Taselisib (GDC-0032) in culture (PMID: 33685991). | 33685991 |
| TSC1 M271T TSC2 L604P | endometrial cancer | sensitive | Miransertib | Preclinical - Pdx | Actionable | In a preclinical study, a patient-derived xenograft (PDX) model of endometrial cancer harboring TSC1 M271T and TSC2 L604P was sensitive to Miransertib (ARQ092), demonstrating greater than 90% inhibition of tumor growth (PMID: 26469692). | 26469692 |
| TSC1 S331Efs*10 TSC1 LOH | transitional cell carcinoma | predicted - sensitive | Buparlisib | Case Reports/Case Series | Actionable | In a Phase II trial, Buparlisib (BKM120) treatment resulted in stable disease in a patient with metastatic urothelial carcinoma harboring TSC1 S331Efs*10 and TSC1 loss of heterozygosity (PMID: 32767682; NCT01551030). | 32767682 |
| TSC1 R98* | hepatocellular carcinoma | predicted - sensitive | Everolimus | Case Reports/Case Series | Actionable | In a clinical study, a hepatocellular carcinoma patient harboring TSC1 R98* achieved stable disease following treatment with Afinitor (everolimus) (PMID: 30373752). | 30373752 |
| TSC1 R500* TSC1 LOH | transitional cell carcinoma | predicted - sensitive | Buparlisib | Case Reports/Case Series | Actionable | In a Phase II trial, Buparlisib (BKM120) treatment resulted in a partial response in a patient with metastatic urothelial carcinoma harboring TSC1 R500* and TSC1 loss of heterozygosity (PMID: 32767682; NCT01551030). | 32767682 |
| PIK3CA amp TSC1 LOH | transitional cell carcinoma | predicted - sensitive | Buparlisib | Case Reports/Case Series | Actionable | In a Phase II trial, Buparlisib (BKM120) treatment resulted in a partial response in a patient with metastatic urothelial carcinoma harboring PIK3CA amplification and TSC1 loss of heterozygosity (PMID: 32767682; NCT01551030). | 32767682 |
| PIK3CA E542K TSC1 LOH | transitional cell carcinoma | no benefit | Buparlisib | Case Reports/Case Series | Actionable | In a Phase II trial, Buparlisib (BKM120) treatment resulted in progressive disease in a patient with metastatic urothelial carcinoma harboring PIK3CA E542K and TSC1 loss of heterozygosity (PMID: 32767682; NCT01551030). | 32767682 |
| TSC1 Y185* | transitional cell carcinoma | no benefit | Buparlisib | Case Reports/Case Series | Actionable | In a Phase II trial, Buparlisib (BKM120) treatment resulted in progressive disease in a patient with metastatic urothelial carcinoma harboring TSC1 Y185* (PMID: 32767682; NCT01551030). | 32767682 |
| TSC1 R424fs | transitional cell carcinoma | no benefit | Buparlisib | Case Reports/Case Series | Actionable | In a Phase II trial, Buparlisib (BKM120) treatment resulted in progressive disease in a patient with metastatic urothelial carcinoma harboring TSC1 R424fs (PMID: 32767682; NCT01551030). | 32767682 |
| FGFR3 S249C TSC1 S561fs | bladder urothelial carcinoma | predicted - sensitive | Erdafitinib | Case Reports/Case Series | Actionable | In a clinical case study, Balversa (erdafitinib) treatment resulted in a partial response with a progression-free survival of 19.6 months in a patient with upper tract urothelial carcinoma harboring FGFR3 S249C and TSC1 S561fs (PMID: 37377403). | 37377403 |
| FGFR3 S249C FGFR3 E587Q FGFR3 amp PIK3CA E726K TSC1 S561fs | bladder urothelial carcinoma | predicted - resistant | Erdafitinib | Case Reports/Case Series | Actionable | In a clinical case study, FGFR3 E587Q was identified in the post-progression circulating tumor DNA and FGFR3 amplification (>10 copies) and PIK3CA E726K were identified in the post-progression tissue biopsy of a patient with bladder urothelial cancer harboring FGFR3 S249C and TSC1 S561fs who previously responded to Balversa (erdafitinib) treatment (PMID: 37377403). | 37377403 |
| FGFR3 S249C TSC1 Q830* | bladder urothelial carcinoma | predicted - resistant | Erdafitinib | Case Reports/Case Series | Actionable | In a clinical case study, TSC1 Q830* was identified in the post-progression tissue biopsy and circulating tumor DNA (ctDNA) together with TSC1 Q830* in the post-progression ctDNA of a patient with bladder urothelial cancer harboring FGFR3 S249C who previously responded to Balversa (erdafitinib) treatment (PMID: 37377403). | 37377403 |
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