Telomeric Allelic Imbalance Indicates Defective DNA Repair and Sensitivity to DNA-Damaging Agents

TLDR

DNA repair competency determines sensitivity to platinum chemotherapy, with intact repair preventing genome damage and BRCA mutations predicting sensitivity, yet some patients without BRCA mutations also benefit. The study aimed to identify genomic signatures of defective DNA repair, specifically telomeric allelic imbalance (NtAI), and correlate them with platinum sensitivity. Researchers analyzed NtAI in cell lines and tumors, correlating its levels with cisplatin sensitivity. Higher NtAI predicted cisplatin sensitivity in vitro and better responses in triple‑negative breast and serous ovarian cancers, and an inverse relationship with BRCA1 expression suggested impaired DNA repair. Cancer Discovery 2(4):366–375; ©2012 AACR.

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. Cancer Discov; 2(4); 366–75. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 288