TCF4
Overview
TCF4 (Transcription Factor 4), also known as E2-2 or ITF2, encodes a basic helix-loop-helix transcription factor involved in neural and lymphoid development. In pheochromocytoma/paraganglioma, TCF4 was identified as the 5’ fusion partner of MAML3 in a recurrent TCF4-MAML3 fusion gene, where the TCF4 promoter drives ectopic overexpression of MAML3, activating Wnt and Hedgehog signaling rather than canonical NOTCH targets.
Alterations observed in the corpus
- TCF4 identified as the 5’ promoter-donor partner in one TCF4-MAML3 fusion gene in the TCGA PCC/PGL cohort (pcpg_tcga_pub, n=173); this fusion is one of 10 MAML3 fusion-positive tumors (the remainder are UBTF-MAML3). TCF4 promoter drives 2.7-fold MAML3 overexpression. PMID:28162975
- The authors note they cannot exclude that TCF4 itself contributes tumorigenic properties beyond simply driving MAML3 overexpression. PMID:28162975
- Recurrently altered candidate driver across medulloblastoma subgroups in the 491-sample ICGC cohort PMID:28726821
Cancer types (linked)
- PHC / PGNG: TCF4-MAML3 fusion defines the Wnt-altered mRNA subtype; all 10 MAML3 fusion-positive tumors (including this one) were adrenal PCCs, associated with metastatic disease and poor ADFS/MFS. PMID:28162975
Co-occurrence and mutual exclusivity
- TCF4-MAML3 fusion is mutually exclusive with UBTF-MAML3 and with germline susceptibility gene mutations in the 21-gene driver set. PMID:28162975
Therapeutic relevance
- MAML3 fusion activates Wnt and STAT3 signaling; downstream antagonists of beta-catenin (e.g., PRI-274) and STAT3 (e.g., BB1608) are proposed as therapeutic strategies. PMID:28162975
Open questions
- Whether TCF4 makes an independent oncogenic contribution beyond serving as a promoter donor in the MAML3 fusion is unresolved; direct binding studies (e.g., ChIP-seq) are not provided. PMID:28162975
Sources
This page was processed by entity-page-writer on 2026-05-15. - PMID:28726821
This page was processed by wiki-cli on 2026-05-15.