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Van Allen, Eliezer M.; Mouw, Kent W.; Kim, Philip; Iyer, Gopa; Wagle, Nikhil; Al-Ahmadie, Hikmat; Zhu, Cong; Ostrovnaya, Irina; Kryukov, Gregory V.; O'Connor, Kevin W.; Sfakianos, John; Garcia-Grossman, Ilana; Kim, Jaegil; Guancial, Elizabeth A.; Bambury, Richard; Bahl, Samira; Gupta, Namrata; Farlow, Deborah; Qu, Angela; Signoretti, Sabina; Barletta, Justine A.; Reuter, Victor; Boehm, Jesse; Lawrence, Michael; [...]

Somatic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma

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  • Medientyp: E-Artikel
  • Titel: Somatic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma
  • Beteiligte: Van Allen, Eliezer M.; Mouw, Kent W.; Kim, Philip; Iyer, Gopa; Wagle, Nikhil; Al-Ahmadie, Hikmat; Zhu, Cong; Ostrovnaya, Irina; Kryukov, Gregory V.; O'Connor, Kevin W.; Sfakianos, John; Garcia-Grossman, Ilana; Kim, Jaegil; Guancial, Elizabeth A.; Bambury, Richard; Bahl, Samira; Gupta, Namrata; Farlow, Deborah; Qu, Angela; Signoretti, Sabina; Barletta, Justine A.; Reuter, Victor; Boehm, Jesse; Lawrence, Michael; [...]
  • Erschienen: American Association for Cancer Research (AACR), 2014
  • Erschienen in: Cancer Discovery
  • Sprache: Englisch
  • DOI: 10.1158/2159-8290.cd-14-0623
  • ISSN: 2159-8274; 2159-8290
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>Cisplatin-based 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 molecular determinants of cisplatin response are incompletely understood. We performed whole-exome sequencing on pretreatment tumor and germline DNA from 50 patients with muscle-invasive urothelial carcinoma who received neoadjuvant cisplatin-based chemotherapy followed by cystectomy (25 pT0/pTis “responders,” 25 pT2+ “nonresponders”) to identify somatic mutations that occurred preferentially in responders. ERCC2, a nucleotide excision repair gene, was the only significantly mutated gene enriched in the cisplatin responders compared with nonresponders (q &amp;lt; 0.01). Expression of representative ERCC2 mutants in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared with wild-type ERCC2. The lack of normal ERCC2 function may contribute to cisplatin sensitivity in urothelial cancer, and somatic ERCC2 mutation status may inform cisplatin-containing regimen usage in muscle-invasive urothelial carcinoma.</jats:p> <jats:p>Significance: Somatic ERCC2 mutations correlate with complete response to cisplatin-based chemosensitivity in muscle-invasive urothelial carcinoma, and clinically identified mutations lead to cisplatin sensitivity in vitro. Nucleotide excision repair pathway defects may drive exceptional response to conventional chemotherapy. Cancer Discov; 4(10); 1140–53. ©2014 AACR.</jats:p> <jats:p>See related commentary by Turchi et al., p. 1118</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 1103</jats:p>
  • Zugangsstatus: Freier Zugang