Publications

Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma

Van Allen, E.M., Mouw, K.W., Kim, P., Iyer, G., Wagle, N., Al-Ahmadie, H., Zhu, C., Ostrovnaya, I., Kryukov, G.V., O’Connor, K.W., Sfakianos, J., Garcia-Grossman, I., Kim, J., Guancial, E.A., Bambury, R., Bahl, S., Gupta, N., Farlow, D., Qu, A., Signoretti, S., Barletta, J.A., Reuter, V., Boehm, J., Lawrence, M., Getz, G., Kantoff, P., Bochner, B.H., Choueiri, T.K., Bajorin, D.F., Solit, D.B., Gabriel, S., D’Andrea, A., Garraway, L.A., Rosenberg, J.E.

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 pre-treatment 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+ “non-responders”) 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 non-responders (q < 0.01). Expression of representative ERCC2 mutations in an ERCC2-deficient cell line failed to rescue cisplatin and UV sensitivity compared to wild-type ERCC2. 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..

Citation

Van Allen, E.M., Mouw, K.W., Kim, P., Iyer, G., Wagle, N., Al-Ahmadie, H., Zhu, C., Ostrovnaya, I., Kryukov, G.V., O’Connor, K.W., Sfakianos, J., Garcia-Grossman, I., Kim, J., Guancial, E.A., Bambury, R., Bahl, S., Gupta, N., Farlow, D., Qu, A., Signoretti, S., Barletta, J.A., Reuter, V., Boehm, J., Lawrence, M., Getz, G., Kantoff, P., Bochner, B.H., Choueiri, T.K., Bajorin, D.F., Solit, D.B., Gabriel, S., D’Andrea, A., Garraway, L.A., Rosenberg, J.E. "Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma" Cancer Discovery (2014): 1,140–53