CDH1

Overview

CDH1 encodes E-cadherin, a calcium-dependent cell adhesion protein essential for epithelial cell-cell cohesion and epithelial integrity. Loss-of-function mutations in CDH1 are the hallmark of hereditary diffuse gastric cancer (HDGC) syndrome and are a defining feature of the diffuse/signet ring cell gastric cancer subtype. Somatic CDH1 mutations are enriched in early-onset esophagogastric cancers with diffuse-type histology.

Alterations observed in the corpus

  • Mutations enriched in early-onset esophagogastric cancer (12% vs. 6% in average-onset, P=0.004, Q=0.03), consistent with the enrichment of signet ring cell/diffuse-type histology in younger patients PMID:37699004.
  • One CDH1 mutation found upon resequencing in dedifferentiated liposarcoma (DDLS) as part of a 722-gene targeted panel applied to 207 high-grade soft tissue sarcomas (sarc_mskcc); functional impact was not established PMID:20601955.
  • CDH1 somatic mutations identified in HNSCC by whole-exome sequencing of 74 tumor-normal pairs (Broad Institute cohort) PMID:21798893
  • CDH1 truncating mutations identified in breast cancer WES of 100 tumors; enriched in lobular subtype PMID:22722201
  • CDH1 mutations observed in medulloblastoma WGS of 37 tumors (PCGP) PMID:22722829
  • CDH1 expression and pharmacogenomic associations analyzed in NCI-60 cell line panel via CellMiner PMID:22802077
  • Mutated in breast cancer (TCGA, 510 tumors); CDH1 truncating mutations highly enriched in lobular breast carcinoma (luminal A subtype), causing loss of E-cadherin expression and epithelial-mesenchymal transition PMID:23000897
  • Mutated in EAC; co-occurs with APC mutations (two tumors with co-occurring APC + CDH1) in the beta-catenin pathway, which is altered in only 9% of EACs PMID:23525077
  • Germline loss-of-function defines Hereditary Diffuse Gastric Cancer (HDGC); in mutation-negative HDGC-like families ~17% of tumors show somatic CDH1 promoter hypermethylation and ~9% LOH; standard multigene GC panel includes CDH1 PMID:24816255
  • Downregulated (E-cadherin loss) in GBC cells as an EMT readout downstream of paracrine SEMA7A signaling from stiff-matrix-activated CAFs; E-cadherin restored by SEMA7A knockdown in GFs in co-injection xenografts PMID:24997986
  • Somatic mutations in 11% of gastric adenocarcinoma overall and 26-37% of GS tumours; no germline-pathogenic CDH1 variants identified in this sporadic cohort PMID:25079317
  • Somatic mutations in 21/294 (7.1%) gastric cancer cases; enriched in diffuse-type and cardia tumors; LoF events common; associated with shorter survival; cardia GCs are enriched for CDH1, connecting to the diffuse-type/poor-prognosis axis PMID:25583476
  • Subclonal mutation in breast adenoid cystic carcinoma (AdCC); identified as a non-passenger subclonal event suggesting it may contribute to clonal evolution and therapeutic escape PMID:26095796
  • Biallelic CDH1 loss (truncating mutation + 16q loss) detected in 95% of ILC (107/127 cases carry CDH1 mutations); no CDH1 promoter hypermethylation observed, contradicting prior MSP-based reports; CDH1 status is the dominant feature distinguishing ILC-like from IDC-like tumors among mixed histology cases PMID:26451490
  • CDH1 truncating somatic mutations (nonsense, frameshift) in 84% of plasmacytoid-variant bladder cancers vs 0% in 127 TCGA urothelial NOS tumors; promoter hypermethylation in 4/5 mutation-negative cases; the defining molecular event of the plasmacytoid variant driving E-cadherin loss, enhanced migration, and peritoneal dissemination PMID:26901067
  • CDH1 (E-cadherin) was down-regulated in non-responders to anti-PD-1 therapy in melanoma, one of only three FDR-significant (q≤0.25) differentially expressed genes; CDH1 loss is part of the epithelial-mesenchymal transition component of the IPRES innate resistance signature PMID:26997480.
  • CDH1 inactivating mutations found in 52.6% of lobular breast carcinomas (hallmark of invasive lobular); 96.0% of mutant tumors show LOH; co-mutated with PIK3CA, TBX3, RUNX1, and ERBB2; strongly mutually exclusive with TP53 (OR=0.23); homozygous deletions in 18 ductal/NST and 4 lobular cases; associated with older age at diagnosis (OR=4.5 for SF3B1 context) PMID:27161491.
  • CDH1 is a significantly mutated driver in metastatic breast cancer (mBC), also recurrent in early breast cancer (eBC); identified by MutSig analysis of 216 mBC whole-exome sequences PMID:28027327
  • CDH1-linked upregulated E-cadherin signalling pathway identified in EAC vs ESCC by gene-expression analysis in the TCGA multi-platform esophageal carcinoma study PMID:28052061
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Cancer types (linked)

  • EGC/STAD/ESCA/GEJ: CDH1 mutations enriched in early-onset (age <50) esophagogastric cancer, driven by the increased prevalence of signet ring cell and diffuse-type histology in this subgroup PMID:37699004.

Co-occurrence and mutual exclusivity

  • CDH1 mutations associate with the genomically stable (GS) molecular subtype of gastric cancer, which is characterized by diffuse histology and early-onset presentation PMID:37699004.

Therapeutic relevance

  • Diffuse-type gastric cancers with CDH1 loss are typically resistant to standard chemotherapy; the lack of molecularly matched targeted therapies for this subtype remains a clinical challenge.

Open questions

  • Whether the higher CDH1 mutation frequency in early-onset EGC is attributable to germline predisposition (HDGC syndrome) vs. somatic acquisition has not been systematically assessed in this cohort PMID:37699004.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:21798893

This page was processed by crosslinker on 2026-05-14. - PMID:22722201

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

This page was processed by crosslinker on 2026-05-14. - PMID:22802077

This page was processed by crosslinker on 2026-05-14. - PMID:23000897

This page was processed by crosslinker on 2026-05-14. - PMID:23525077

This page was processed by crosslinker on 2026-05-14. - PMID:24816255

This page was processed by crosslinker on 2026-05-14. - PMID:24997986

This page was processed by crosslinker on 2026-05-14. - PMID:25079317

This page was processed by crosslinker on 2026-05-14. - PMID:25583476

This page was processed by crosslinker on 2026-05-14. - PMID:26095796

This page was processed by crosslinker on 2026-05-14. - PMID:26451490

This page was processed by crosslinker on 2026-05-14. - PMID:26901067

This page was processed by entity-page-writer on 2026-05-15. - PMID:26997480

This page was processed by wiki-cli on 2026-05-14. - PMID:27161491

This page was processed by wiki-cli on 2026-05-14. - PMID:28027327

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

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

This page was processed by entity-page-writer on 2026-05-15. - PMID:28988769

This page was processed by wiki-cli on 2026-05-15. - PMID:29122777

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