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Optical Genome Mapping: Integrating Structural Variations for Precise Homologous Recombination Deficiency Score
Nikhil Shri Sahajpal1, Ashis K Mondal2, Ashutosh Vashisht2
1Greenwood Genetic Center, Greenwood, SC 29646, USA.
Genes
|September 28, 2023
Summary
Optical genome mapping (OGM) offers higher sensitivity for detecting homologous recombination deficiency (HRD) signatures compared to current methods. This advanced technique may improve patient stratification for targeted therapies like PARP inhibitors and platinum drugs.
Area of Science:
- Genomics and Cancer Biology
- Molecular Diagnostics
- Precision Medicine
Background:
- Homologous recombination deficiency (HRD) impairs DNA double-strand break repair, leading to genomic instability and cancer development.
- HRD presence predicts sensitivity to platinum-based therapies and poly(ADP-ribose) polymerase inhibitors (PARPi).
- Standardized methods for measuring HRD phenotypes are currently lacking.
Purpose of the Study:
- To compare the efficacy of optical genome mapping (OGM), chromosomal microarray (CMA), and a 523-gene next-generation sequencing (NGS) panel in calculating homologous recombination deficiency (HRD) scores.
- To evaluate the sensitivity of OGM in detecting HRD signatures compared to standard-of-care methods.
- To assess the potential of OGM for more accurate patient stratification for targeted cancer therapies.
Main Methods:
- Retrospective analysis of 196 samples, including gliomas, hematological malignancies, and controls.
- Comparison of HRD scores derived from OGM, CMA, and a 523-gene NGS panel using loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transitions (LST) signatures.
- Direct comparison of OGM and CMA in 10 glioma cases and OGM and NGS panel in 30 hematological malignancy cases.
Main Results:
- OGM yielded significantly higher HRD scores compared to CMA in gliomas (13.2 vs. 3.7) and the NGS panel in hematological malignancies (7.6 vs. 2.6).
- OGM detected a higher percentage of HRD signature variants (70.8% in gliomas, 66.8% in hematological malignancies) compared to the other methods.
- OGM demonstrated superior resolution and sensitivity in identifying HRD signatures, including those cryptic to current standard methods.
Conclusions:
- Optical genome mapping (OGM) exhibits enhanced sensitivity for detecting homologous recombination deficiency (HRD) signatures.
- OGM offers a more comprehensive assessment of the HRD phenotype compared to CMA and NGS-based approaches.
- OGM presents a promising alternative for accurate HRD assessment, potentially improving patient selection for PARPi and platinum-based therapies.
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