Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib

作者：Alan Barnicle, Isabelle Laure Ray-Coquard, Etienne Rouleau, Karen Anne Cadoo, Fiona A. Simpkins, Carol A Aghajanian, Alexandra F. Leary, Andres M. Poveda, Stéphanie Lheureux, Éric Pujade-Lauraine, Benoît You, Jonathan A. Ledermann, Ursula A. Matulonis, Charlie Gourley, Kirsten M. Timms, Zhongwu Lai, Darren Hodgson, Cathy E. Elks, Simon Patrick Dearden, Coumaran Égile, Pierre Lao‐Sirieix, Elizabeth A. Harrington, Jessica S. Brown · 发表于：Genome Medicine · 年份：2024 · DOI：10.1186/s13073-024-01413-5 · 被引用次数：16 · 研究领域：PARP inhibition in cancer therapy、BRCA gene mutations in cancer、Ovarian cancer diagnosis and treatment

BACKGROUND: The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors represented a paradigm shift in the treatment of ovarian cancer. Genomic data from patients with high-grade ovarian cancer in six phase II/III trials involving the PARP inhibitor olaparib were analyzed to better understand patterns and potential causes of genomic instability. PATIENTS AND METHODS: Homologous recombination deficiency (HRD) was assessed in 2147 tumor samples from SOLO1, PAOLA-1, Study 19, SOLO2, OPINION, and LIGHT using next-generation sequencing technology. Genomic instability scores (GIS) were assessed in BRCA1 and/or BRCA2 (BRCA)-mutated (BRCAm), non-BRCA homologous recombination repair-mutated (non-BRCA HRRm), and non-HRRm tumors. RESULTS: BRCAm was identified in 1021/2147 (47.6%) tumors. BRCAm tumors had significantly higher GIS than non-BRCAm tumors (P < 0.001) and high biallelic loss (815/838; 97.3%) regardless of germline (658/672; 97.9%) or somatic (101/108; 93.5%) BRCAm status. In non-BRCA HRRm tumors (n = 121) a similar proportion were HRD-positive (GIS ≥ 42: 55/121; 45.5%) relative to HRD-negative (GIS < 42: 52/121; 43.0%). GIS was highly variable in non-BRCA HRRm (median 42 [interquartile range (IQR) 29-58]) and non-HRRm (n = 1005; median 32 [IQR 20-55]) tumors. Gene mutations with high GIS included HRR genes BRIP1 (median 46 [IQR 41-58]), RAD51C (median 58 [IQR 48-66]), RAD51D (median 62 [IQR 54-69]), and PALB2 (median 64 [IQR 58-74]), and non-HRR genes NF1 (median 49 [I...