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Published on: February 2, 2024
The Utility of NGS Analysis in Homologous Recombination Deficiency Tracking
Aikaterini Tsantikidi1, Eirini Papadopoulou1, Vasiliki Metaxa-Mariatou1
1Genekor Medical S.A., 15344 Athens, Greece.
Abstract:
Several tumor types have been efficiently treated with PARP inhibitors (PARPis), which are now approved for the treatment of ovarian, breast, prostate, and pancreatic cancers. The BRCA1/2 genes and mutations in many additional genes involved in the HR pathway may be responsible for the HRD phenomenon. The aim of the present study was to investigate the association between genomic loss of heterozygosity (gLOH) and alterations in 513 genes with targeted and immuno-oncology therapies in 406 samples using an NGS assay. In addition, the %gLOHs of 24 samples were calculated using the Affymetrix technology in order to compare the results obtained via the two methodologies. HR variations occurred in 20.93% of the malignancies, while BRCA1/2 gene alterations occurred in 5.17% of the malignancies. The %LOH was highly correlated with alterations in the BRCA1/2 genes, since 76.19% (16/21) of the BRCA1/2 positive tumors had a high %LOH value (p = 0.007). Moreover, the LOH status was highly correlated with the TP53 and KRAS statuses, but there was no association with the TMB value. Lin's concordance correlation coefficient for the 24 samples simultaneously examined via both assays was 0.87, indicating a nearly perfect agreement. In conclusion, the addition of gLOH analysis could assist in the detection of additional patients eligible for treatment with PARPis.
Insights
Genomic loss of heterozygosity (gLOH) analysis can identify more cancer patients eligible for PARP inhibitor (PARPi) therapy. This study found gLOH strongly correlates with BRCA1/2 gene alterations and treatment response.
Area of Science:
- Oncology
- Genomics
- Cancer Therapeutics
Background:
- PARP inhibitors (PARPis) are effective for ovarian, breast, prostate, and pancreatic cancers.
- Homologous Recombination Deficiency (HRD) is linked to PARPi efficacy, often associated with BRCA1/2 mutations.
- Identifying HRD is crucial for expanding PARPi eligibility.
Purpose of the Study:
- To investigate the association between genomic loss of heterozygosity (gLOH) and gene alterations in 406 cancer samples.
- To evaluate gLOH as a biomarker for targeted and immuno-oncology therapies.
- To compare gLOH assessment using NGS and Affymetrix technologies.
Main Methods:
- Next-Generation Sequencing (NGS) assay analyzed 513 genes in 406 samples.
- Affymetrix technology assessed %gLOH in 24 samples for cross-validation.
- Statistical analysis correlated gLOH with gene alterations (BRCA1/2, TP53, KRAS) and TMB.
Main Results:
- HR variations were found in 20.93% of malignancies; BRCA1/2 alterations in 5.17%.
- High %LOH strongly correlated with BRCA1/2 gene alterations (76.19%, p=0.007).
- LOH status showed high correlation with TP53 and KRAS, but not TMB. NGS and Affymetrix showed high agreement (CCC=0.87).
Conclusions:
- gLOH analysis is a valuable tool for identifying patients eligible for PARPi therapy.
- gLOH complements existing biomarkers for predicting response to targeted cancer treatments.
- This approach can expand the patient population benefiting from PARPi therapy.
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