PTCH1

Overview

PTCH1 (Patched 1) is the primary receptor for Hedgehog (HH) ligands and a key tumor suppressor in the HH signaling pathway. Loss-of-function mutations relieve inhibition of Smoothened (SMO), activating downstream HH signaling. PTCH1 mutations have been associated with basal cell carcinoma (germline, Gorlin syndrome) and occur in various solid tumors, including gynecologic cancers.

Alterations observed in the corpus

  • PTCH1 mutations observed in 18% of dMMR/MSI-H gynecologic cancers treated with nivolumab; enriched in responders (26%) vs. non-responders (7%), though the association did not reach statistical significance PMID:38653864.
  • As a negative regulator of Hedgehog signaling, PTCH1 loss may promote an immunosuppressive tumor microenvironment (TME), a potential mechanism explaining the trend toward enrichment in responders (given the MEGF8 negative-HH-regulator association with immunotherapy benefit) PMID:38653864.
  • Biallelic inactivation and focal deletion in SHH-subgroup medulloblastoma (PCGP WGS, 37 tumors); canonical SHH-pathway driver PMID:22722829
  • Inactivating mutations exclusive to SHH-subgroup medulloblastoma in WES of 92 tumors (Broad cohort); associated with 9q loss of heterozygosity PMID:22820256
  • Altered in 8/125 cases (6%), predominantly in SHH-subgroup medulloblastoma (ICGC WGS/WES cohort); frameshift indels in 6 cases, SNVs in 2 PMID:22832583
  • PTCH1-mutated NPC tumors targeted by SMO inhibitor taladegib (Hedgehog pathway; phase II trial in solid tumors) PMID:24952746
  • Mutated in 17% of aggressive cSCC cases; only 2 of 6 mutations were inactivating — contrasts with 75% inactivating rate in basal cell carcinoma; not identified as a driver in cSCC PMID:25303977
  • Gene with at least one identical previously COSMIC-reported mutation in the HNSCC TCGA cohort (n=279) PMID:25631445
  • In PAAD, PTCH1 alterations occur in 2% of cases as part of the Hedgehog-pathway alterations (GLI3 8%, SMO 8%, LRP2 6%, GLI2 3%, PTCH1 2%) in the 109-case exome cohort. PMID:25855536
  • Homozygous driver in primary medulloblastoma MB-REC-12 (heterozygous mutation + chr9q LOH); the PTCH1-driven primary clone was eradicated at recurrence, replaced by an ancestral chr9q-wild-type sister clone PMID:26760213
  • PTCH1 mutated as a single-case hit replicating findings from a prior whole-exome sequencing study of ATC in a targeted-sequencing study of poorly differentiated and anaplastic thyroid cancers. PMID:26878173
  • PTCH1 mutations detected in 3 of 4 basal cell carcinoma (BCC) patients in a recurrent/metastatic head and neck NGS cohort; all 3 had responded to hedgehog-pathway inhibitors prior to NGS PMID:27442865.
  • Overexpression in medulloblastoma (MBL) alongside SUFU and ZIC3; SMO-inhibitor target identified in a pediatric precision-oncology cohort PMID:28007021
  • Inactivating alterations in 6% of ESCCs (no EACs), suggesting active hedgehog signalling in esophageal squamous cell carcinoma PMID:28052061
  • Germline PTCH1 variants predominantly restricted to SHH medulloblastoma subgroup PMID:28726821

Cancer types (linked)

  • Endometrial cancer (UCEC) / ovarian cancer (OVT) — PTCH1 mutations in 18% of dMMR gynecologic cancers; trend toward enrichment in nivolumab responders (26% vs. 7%) PMID:38653864.

Co-occurrence and mutual exclusivity

  • PTCH1 mutations co-occur with other dMMR-associated genomic alterations including PTEN (76%), ARID1A (82%), and PIK3CA (48%) in gynecologic cancers PMID:38653864.

Therapeutic relevance

  • Trend toward enrichment of PTCH1 mutations in nivolumab responders suggests potential interaction between HH pathway loss and immune surveillance; further prospective validation is warranted PMID:38653864.

Open questions

  • The non-significant association between PTCH1 mutation and nivolumab response (26% vs. 7%) requires validation in larger cohorts; the small sample size (n=35) limits statistical power PMID:38653864.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:22722829

This page was processed by crosslinker on 2026-05-14. - PMID:22820256

This page was processed by crosslinker on 2026-05-14. - PMID:22832583

This page was processed by crosslinker on 2026-05-14. - PMID:24952746

This page was processed by crosslinker on 2026-05-14. - PMID:25303977

This page was processed by crosslinker on 2026-05-14. - PMID:25631445

This page was processed by crosslinker on 2026-05-14. - PMID:25855536

This page was processed by crosslinker on 2026-05-14. - PMID:26760213

This page was processed by entity-page-writer on 2026-05-15. - PMID:26878173

This page was processed by entity-page-writer on 2026-05-15. - PMID:27442865

This page was processed by entity-page-writer on 2026-05-15. - PMID:28007021

This page was processed by wiki-cli on 2026-05-14. - PMID:28052061

This page was processed by wiki-cli on 2026-05-14. - PMID:28726821

This page was processed by entity-page-writer on 2026-05-15.