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abstract:Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer
Highlights
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- Whole-exome analysis identifies BRCAness OvCa tumors.
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- BRCAness OvCa tumors resemble BRCA deficient OvCa tumors by in similar genome instability.
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- RAD50 deletion predicts BRCAness and augments OvCa cell's drug sensitivity.
Conclusion
Our study
identified the copy number deletion of RAD50 as a candidate marker for
survival and response to PARPis in BRCAwt OvCa tumors.
Abstract
Objective
To identify novel prognostic and therapeutic markers for PARP inhibitors in BRCA wild type ovarian cancer (OvCa).
Methods
BRCAness
status was defined by analyzing whole-exome deep sequencing data from
220 BRCAwt OvCa cases in TCGA. Thirty-three DNA-repair genes were
screened in an integrated manner for BRCA-independent mechanism of
BRCAness using multiple-dimensional genomic data. Publicly available
databases and siRNA knock-down were used for external validation and
evaluation of drug response in OvCa cell lines.
Results
In 220 BRCAwt OvCa patients, tumors exhibiting the BRCAness signature have enhanced OS (HR [95% CI] = 0.33 [0.15–0.69], P = 0.004) and PFS (HR [95% CI] = 0.51 [0.24–1.08], P = 0.077),
strongly suggesting a BRCA-independent mechanism of drug sensitivity in
those patients. Systematic screening of driving molecular events of
BRCAness revealed that RAD50 deletion is a marker of BRCAness. The RAD50
deletion occurred in 18% of BRCAwt OvCa patients. RAD50 deletion led to
its decreased mRNA expression in tumors (fold change = 0.63, P = 3.56 × 10− 13). In BRCAwt patients, RAD50 deletion was associated with significantly better OS (HR [95% CI] = 0.44 [0.25–0.78], P = 0.005) and PFS (HR [95% CI] = 0.60 [0.37–0.99], P = 0.044),
adjusted by age and stage. Knockdown of RAD50 expression augmented OvCa
cell's responses to cisplatin and olaparib. Among 19 OvCa cell lines,
the RAD50 copy number deletion is significantly associated with better
responses to two structurally distinct PARPis (i.e. olaparib and
rucaparib).
Conclusion
Our study
identified the copy number deletion of RAD50 as a candidate marker for
survival and response to PARPis in BRCAwt OvCa tumors.
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