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

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. SNP data from 27 and 40 primary triple negative breast cancer tumor samples from two clinical trials treated with cisplatin and cisplatin + bevacizumab. Labeling, hybridization and data processing was performed by Affymetrix using 70k MIP arrays and 330k MIP arrays. In the cisplatin trial, matched normal samples based on blood from all patients and an additional three samples based on FFPE negative lymph nodes were used as references (30 normal references in total). In the cisplatin+bevacizumab trial, mathed normal samples based on blood from 10 patients were used as references.