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Association of somatic ERCC2 mutations with cisplatin sensitivity in muscle-invasive urothelial carcinoma.
J Clin Oncol 32:5s, 2014 (suppl; abstr 4510)
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: Cisplatin-based combination chemotherapy is the standard of care for patients with muscle invasive urothelial carcinoma. Pathologic downstaging to pT0/pTis after neoadjuvant cisplatin-based chemotherapy is associated with improved survival, although the molecular determinants of cisplatin sensitivity are incompletely understood. Recent reports have identified somatic mutations in ERCC2, a nucleotide excision repair gene, in 7-12% of bladder cancers. Preclinical evidence suggests that defects in the nucleotide excision repair (NER) pathway mediate cisplatin sensitivity. Methods: We performed whole exome sequencing of pre-treatment tumor and germline DNA from 51 patients with muscle invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (26 pT0/pTis “responders”, 25 pT2+ “non-responders”). Computational methods were employed to identify somatic mutations that occurred preferentially in cisplatin responders. Functional validation of significantly enriched mutations was performed using cellular cisplatin and UV sensitivity assays. Results: Somatic ERCC2 mutations were observed in 38.5% of responders and 0% of non-responders (q < 0.01). ERCC2 was the only gene enriched in the cisplatin responders compared with non-responders. ERCC2 mutations clustered within or near conserved helicase domains required for ERCC2 function. Expression of the identified ERCC2 mutants in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared to wild-type ERCC2. Conclusions: Somatic ERCC2 mutation is associated with cisplatin sensitivity in muscle invasive urothelial carcinoma. These results may inform the use of cisplatin-containing regimens in muscle invasive urothelial carcinoma, and potentially other ERCC2-mutated tumors.
Abstracts by Jonathan E. Rosenberg:
Clonality of bladder tumors following radical nephroureterectomy: Against the field defect hypothesis.
Comparison of genetic alterations from the bladder cancer genome atlas (TCGA) and a prospective set of high-grade urothelial carcinoma tumors using a CLIA laboratory next generation sequencing assay.
Impact of chemotherapy (CTX) on venous thromboembolism (VTE) and prognostic implications in patients with metastatic urinary tract tumors (UTT).
Educational Book Articles by Jonathan E. Rosenberg:
Presentations by Jonathan E. Rosenberg:
Meeting: 2014 Genitourinary Cancers Symposium
Session: General Session 5: Advances in Therapy for Urothelial Carcinoma (General Session)
Meeting: 2012 ASCO Annual Meeting
Session: Genitourinary (Nonprostate) Cancer (Poster Discussion Session)