Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents

Nicolai J. Birkbak, Zhigang C. Wang, Ji Young Kim, Aron C. Eklund, Qiyuan Li, Ruiyang Tian, Christian Bowman-Colin, Yang Li, April Greene-Colozzi, J. Dirk Iglehart, Nadine Tung, Paula D. Ryan, Judy E. Garber, Daniel P. Silver, Zoltan Szallasi, Andrea L. Richardson

Research output: Contribution to journalArticle

Abstract

DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation of genome damage during growth and also can repair platinum-induced DNA damage. We sought genomic signatures indicative of defective DNA repair in cell lines and tumors and correlated these signatures to platinum sensitivity. The number of subchromosomal regions with allelic imbalance extending to the telomere (NtAI) predicted cisplatin sensitivity in vitro and pathologic response to preoperative cisplatin treatment in patients with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher levels of NtAI forecast a better initial response. We found an inverse relationship between BRCA1 expression and NtAI in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of telomeric allelic imbalance is a marker of platinum sensitivity and suggests impaired DNA repair. SIGNIFICANCE: Mutations in BRCA genes cause defects in DNA repair that predict sensitivity to DNA damaging agents, including platinum; however, some patients without BRCA mutations also benefit from these agents. NtAI, a genomic measure of unfaithfully repaired DNA, may identify cancer patients likely to benefit from treatments targeting defective DNA repair.

Original languageEnglish (US)
Pages (from-to)366-375
Number of pages10
JournalCancer discovery
Volume2
Issue number4
DOIs
StatePublished - Apr 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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    Birkbak, N. J., Wang, Z. C., Kim, J. Y., Eklund, A. C., Li, Q., Tian, R., Bowman-Colin, C., Li, Y., Greene-Colozzi, A., Dirk Iglehart, J., Tung, N., Ryan, P. D., Garber, J. E., Silver, D. P., Szallasi, Z., & Richardson, A. L. (2012). Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer discovery, 2(4), 366-375. https://doi.org/10.1158/2159-8290.CD-11-0206