ERCC2

Overview

ERCC2 (excision repair cross-complementation group 2), also known as XPD, encodes a DNA helicase component of the TFIIH complex involved in nucleotide excision repair. In urothelial carcinoma, ERCC2 mutations have been hypothesized to predict sensitivity to cisplatin-based chemotherapy due to impaired DNA repair, though clinical evidence is inconsistent.

Alterations observed in the corpus

  • Oncogenic ERCC2 alterations detected in 9/201 (4.5%) of metastatic urothelial carcinoma (mUC) patients in pretreatment plasma cfDNA (MSK-ACCESS 129-gene panel) nested within the phase 3 CALGB 90601 trial. No statistically significant association with response to gemcitabine/cisplatin (response rate 45% DDR-altered [including ERCC2] vs 41% DDR-negative, p = 0.4), OS (HR 0.93, 95% CI 0.50–1.72; p = 0.8), or PFS (HR 0.85, 95% CI 0.46–1.58; p = 0.6); analysis was severely underpowered given the 4.5% ERCC2 frequency versus the expected ~11% from TCGA muscle-invasive bladder data PMID:40256659.
  • ERCC2 detection rate was numerically higher in cfDNA (6.5%) than in matched archival tumor sequencing (4.7%) in the 107-patient paired concordance subset, consistent with cfDNA capturing spatial heterogeneity or clonal evolution PMID:40256659.
  • ERCC2 mutations enriched in chemotherapy responders in metastatic UC; validates this biomarker beyond the neoadjuvant setting (p = 0.0134) PMID:36333289
  • ERCC2 assessed in gallbladder carcinoma (GBC) genomic landscape study PMID:36228155
  • Newly identified mutated gene in bladder TCC; functional characterization in TCC is not yet performed and is explicitly recommended PMID:24121792
  • ERCC2 mutated in 12% of muscle-invasive bladder cancers; 15 of 16 mutations were deleterious missense (dominant-negative mechanism); ERCC2-mutant tumors showed significantly fewer C→G mutations and trended toward higher overall mutation rate PMID:24476821
  • Nine non-synonymous somatic mutations in 9/25 (36%) cisplatin responders in muscle-invasive urothelial carcinoma, all clustered in helicase domains; functional assays show loss-of-function; proposed as predictive biomarker for cisplatin sensitivity PMID:25096233
  • Significantly mutated gene in renal oncocytoma (ROCY) identified by whole-exome sequencing of 167 non-clear cell RCCs; driver status requires functional validation in larger cohorts PMID:25401301
  • Rare in chemotherapy-progressing urothelial carcinoma, consistent with prior data that ERCC2 mutations mark cisplatin responders and are selected against in progressing tumors PMID:27749842
  • Most common DNA damage repair (DDR) gene alteration in NMIBC (17% of high-grade cases); missense mutations cluster in conserved helicase domains and associate with markedly elevated mutational burden PMID:28583311
  • Missense mutations in 9% of MIBC (n=40), preferentially in/around the helicase domain (suggested dominant-negative effect); defines the MSig4 mutational-signature cluster (24/39 ERCC2-mutant tumors; p=10⁻¹³); ERCC2-signature mutations highest in smokers with ERCC2 mutations (p=6.9×10⁻¹¹) PMID:28988769

Cancer types (linked)

  • BLCA (metastatic urothelial carcinoma) — ERCC2 oncogenic alterations in 4.5% of pretreatment cfDNA; no statistically significant association with platinum chemotherapy outcomes in CALGB 90601 (n = 201); analysis underpowered due to low alteration frequency PMID:40256659.

Co-occurrence and mutual exclusivity

  • Pooled with ATM (5.5%), BRCA1 (3%), and BRCA2 (1%) in the DDR-positive grouping (total 13%); individual gene frequencies are too low for pairwise co-occurrence analysis PMID:40256659.

Therapeutic relevance

  • The null result for ERCC2 as a predictive biomarker of cisplatin response in this dataset is limited by low statistical power (n = 9 ERCC2-altered cases). Authors call for completion of larger randomized trials (NCT03609216) to definitively clarify the DDR-predictive value PMID:40256659.
  • Despite supplantation of platinum chemotherapy by enfortumab vedotin plus pembrolizumab as first-line standard, gemcitabine/cisplatin remains relevant as second-line mUC therapy — maintaining ERCC2’s potential clinical relevance PMID:40256659.

Open questions

  • Whether ERCC2 mutations predict cisplatin sensitivity in mUC remains open; the 4.5% alteration frequency in cfDNA is substantially below the TCGA muscle-invasive cohort rate of 11%, limiting inference PMID:40256659.

Sources

This page was processed by crosslinker on 2026-05-06. - PMID:36333289

This page was processed by crosslinker on 2026-05-06. - PMID:36228155

This page was processed by crosslinker on 2026-05-06. - PMID:24121792

This page was processed by wiki-cli on 2026-05-09. - PMID:24476821

This page was processed by wiki-cli on 2026-05-09. - PMID:25096233

This page was processed by wiki-cli on 2026-05-11. - PMID:25401301

This page was processed by wiki-cli on 2026-05-12. - PMID:27749842

This page was processed by entity-page-writer on 2026-05-15. - PMID:28583311

This page was processed by wiki-cli on 2026-05-15. - PMID:28988769

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