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

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 sub-chromosomal 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 NtAI forecast 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 tAI is a marker of platinum sensitivity and suggests impaired DNA repair.

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

“…Other biomarkers for homologous recombination defi ciency have been assessed in previous studies, 4,35,36 for example, through retrospective analysis of BRCA mutations in ovarian carcinoma 21 or prospective identifi cation of homozygous deletions or mutations through next-generation sequencing in prostate cancer. 22 Additionally, the NOVA trial (NCT01847274) prospectively tested a homologous recombination defi ciency-based assay in a trial of niraparib as maintenance therapy in patients with platinum-sensitive ovarian cancer.…”

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

“…Copy number profiles were evaluated for various measures of genomic instability, including overall aberration type, the fraction of the genome altered by copy number and a measure of homologous recombination deficiency, the number of telomeric allelic imbalances. 33 Seven cases had simple profiles (all were low or intermediate grade and ER positive), three cases had a background of simple copy number change but with two or more high-level amplifications, and the remaining eight cases had highly complex profiles, most with high level amplifications. No cases had chromothripsis.…”

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

“…The Homologous Recombination Deficiency ('HRD') assay measures levels of genomic instability or 'scarring' caused by any number of alterations in DNA repair capacity. At present, the HRD assay incorporates three measures of genomic instability: telomeric allelic imbalance (TAI; the number of regions with allelic imbalance that extend to the subtelomere, but do not cross the centromere), loss of heterozygosity (LOH; the number of regions > 15 Mb and less than one chromosome lost across the genome), and large-scale state transitions (LST; the number of chromosomal breaks between adjacent genomic regions longer than 10 Mb after filtering regions < 3 Mb) [25][26][27]. The HRD score is currently calculated by adding the LOH, TAI, and LST scores and is a continuous score from 0 to 100 with a score of < 41 (previously < 10) as HR proficient and ≥ 42 (previously ≥ 10) as HR deficient.…”