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Templated Insertions Are Associated Specifically with BRCA2 Deficiency and Overall Survival in Advanced Ovarian
Grace Moore1, Rahul Majumdar1, Simon N Powell1
1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
Cancer cells defective in homologous recombination (HR) are responsive to DNA-crosslinking chemotherapies, PARP inhibitors, and inhibitors of polymerase theta (Pol θ), a key mediator of the backup pathway alternative end-joining. Such cancers include those with pathogenic biallelic alterations in core HR genes and another cohort of cases that exhibit sensitivity to the same agents and harbor genomic hallmarks of HR deficiency (HRD). These HRD signatures include a single-base substitution pattern, large rearrangements, characteristic tandem duplications, and small deletions. Here, we used what is now known about the backup pathway alternative end-joining (Alt-EJ) through the key factor Pol θ to design and test novel signatures of polymerase theta-mediated (TMEJ) repair. We generated two novel signatures; a signature composed of small deletions with microhomology and another consisting of small, templated insertions (TINS). We find that TINS consistent with TMEJ repair are highly specific to tumors with pathogenic biallelic mutations in BRCA2 and that high TINS genomic signature content in advanced ovarian cancers associate with overall survival following treatment with platinum agents. In addition, the combination of TINS with other HRD metrics significantly improves the association of platinum sensitivity with survival compared with current state-of-the-art signatures.
Implications:
Small, templated insertions indicative of theta-mediated end-joining likely can be used in conjunction with other HRD mutational signatures as a prognostic tool for patient response to therapies targeting HR deficiency.
Insights
New genomic signatures, including small templated insertions (TINS), identify cancers with homologous recombination deficiency (HRD). TINS specifically mark BRCA2 mutations and predict patient survival with platinum-based chemotherapy.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Homologous recombination (HR) deficiency (HRD) in cancer predicts response to DNA-crosslinking agents, PARP inhibitors, and polymerase theta (Pol θ) inhibitors.
- HRD is characterized by specific genomic signatures, including single-base substitutions, large rearrangements, tandem duplications, and small deletions.
- Polymerase theta (Pol θ) is a key factor in the alternative end-joining (Alt-EJ) pathway, a backup repair mechanism.
Purpose of the Study:
- To design and test novel genomic signatures associated with polymerase theta-mediated (TMEJ) repair.
- To evaluate the specificity of TMEJ signatures for BRCA2-mutated tumors.
- To assess the association of TMEJ signatures with patient survival following platinum-based chemotherapy in advanced ovarian cancer.
Main Methods:
- Development of two novel signatures: one with small deletions and microhomology, and another with small, templated insertions (TINS).
- Analysis of TINS in tumors with pathogenic biallelic BRCA2 mutations.
- Correlation of TINS genomic signature content with overall survival in advanced ovarian cancer patients treated with platinum agents.
Main Results:
- TINS indicative of TMEJ repair were found to be highly specific to tumors with pathogenic biallelic BRCA2 mutations.
- High TINS genomic signature content in advanced ovarian cancers correlated with improved overall survival after platinum agent treatment.
- Combining TINS with existing HRD metrics enhanced the prediction of platinum sensitivity and survival compared to current signatures.
Conclusions:
- Small, templated insertions (TINS) serve as a specific marker for TMEJ repair and are associated with BRCA2 mutations.
- TINS, when used with other HRD mutational signatures, can serve as a prognostic tool for predicting patient response to therapies targeting HR deficiency.
- The integration of TINS into HRD assessment offers a more robust prediction of platinum sensitivity and patient outcomes.
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