Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse

Sorrells, Shelly; McKinnon, Kelly E.; McBratney, Ashleigh; Sumey, Christopher

doi:10.1038/s41525-021-00181-0

Cited by 6 publications

(3 citation statements)

References 34 publications

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“…The HRD-RNA model, in contrast to the HRD-DNA model, has the potential to capture a dynamic HRD phenotype. For example, one mechanism for PARP inhibitor resistance is via a BRCA1/2 reversion mutation [ 69 – 71 ]. Though rare, samples with these mutations can serve as a test of the dynamic nature of the HRD-RNA model compared to the HRD-DNA model.…”

Section: Resultsmentioning

confidence: 99%

Validation of genomic and transcriptomic models of homologous recombination deficiency in a real-world pan-cancer cohort

et al. 2022

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Background With the introduction of DNA-damaging therapies into standard of care cancer treatment, there is a growing need for predictive diagnostics assessing homologous recombination deficiency (HRD) status across tumor types. Following the strong clinical evidence for the utility of DNA-sequencing-based HRD testing in ovarian cancer, and growing evidence in breast cancer, we present analytical validation of the Tempus HRD-DNA test. We further developed, validated, and explored the Tempus HRD-RNA model, which uses gene expression data from 16,750 RNA-seq samples to predict HRD status from formalin-fixed paraffin-embedded tumor samples across numerous cancer types. Methods Genomic and transcriptomic profiling was performed using next-generation sequencing from Tempus xT, Tempus xO, Tempus xE, Tempus RS, and Tempus RS.v2 assays on 48,843 samples. Samples were labeled based on their BRCA1, BRCA2 and selected Homologous Recombination Repair pathway gene (CDK12, PALB2, RAD51B, RAD51C, RAD51D) mutational status to train and validate HRD-DNA, a genome-wide loss-of-heterozygosity biomarker, and HRD-RNA, a logistic regression model trained on gene expression. Results In a sample of 2058 breast and 1216 ovarian tumors, BRCA status was predicted by HRD-DNA with F1-scores of 0.98 and 0.96, respectively. Across an independent set of 1363 samples across solid tumor types, the HRD-RNA model was predictive of BRCA status in prostate, pancreatic, and non-small cell lung cancer, with F1-scores of 0.88, 0.69, and 0.62, respectively. Conclusions We predict HRD-positive patients across many cancer types and believe both HRD models may generalize to other mechanisms of HRD outside of BRCA loss. HRD-RNA complements DNA-based HRD detection methods, especially for indications with low prevalence of BRCA alterations.

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Section: Resultsmentioning

confidence: 99%

Validation of genomic and transcriptomic models of homologous recombination deficiency in a real-world pan-cancer cohort

et al. 2022

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“…Usually, mutations in BRCA1/2 are small insertion/deletions that result in a frameshift with a premature stop codon, which lead to a truncated, nonfunctional protein. Reversion or secondary mutations often lead to the conversion of the initial frameshift mutation into an in-frame internal deletion that still produces a partly functional protein, resulting in the restoration of efficient homologous recombination repair (HRR) [98,99]. BRCA1/2 reversion mutations have been identified in smaller breast cancer cohorts with progressive disease on PARPi/platinum-based therapy, with a prevalence of ~40-50% of patients [100,101].…”

Section: Brca1/2 Mutationsmentioning

confidence: 99%

Expanding the Use of PARP Inhibitors as Monotherapy and in Combination in Triple-Negative Breast Cancer

2021

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Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and is known to be associated with a poor prognosis and limited therapeutic options. Poly (ADP-ribose) polymerase inhibitors (PARPi) are targeted therapeutics that have demonstrated efficacy as monotherapy in metastatic BRCA-mutant (BRCAMUT) TNBC patients. Improved efficacy of PARPi has been demonstrated in BRCAMUT breast cancer patients who have either received fewer lines of chemotherapy or in chemotherapy-naïve patients in the metastatic, adjuvant, and neoadjuvant settings. Moreover, recent trials in smaller cohorts have identified anti-tumor activity of PARPi in TNBC patients, regardless of BRCA-mutation status. While there have been concerns regarding the efficacy and toxicity of the use of PARPi in combination with chemotherapy, these challenges can be mitigated with careful attention to PARPi dosing strategies. To better identify a patient subpopulation that will best respond to PARPi, several genomic biomarkers of homologous recombination deficiency have been tested. However, gene expression signatures associated with PARPi response can integrate different pathways in addition to homologous recombination deficiency and can be implemented in the clinic more readily. Taken together, PARPi have great potential for use in TNBC patients beyond BRCAMUT status, both as a single-agent and in combination.

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“…The HRD-RNA model, in contrast to the HRD-DNA model, has the potential to capture a dynamic HRD phenotype. For example, one mechanism for PARP inhibitor resistance is via a BRCA1/2 reversion mutation (61)(62)(63). Though rare, samples with these mutations can serve as a test of the dynamic nature of the HRD-RNA model compared to the HRD-DNA model.…”

Section: The Hrd-dna and Hrd-rna Models Capture An Underlying Hrd-phenotype Consistent With The Literaturementioning

confidence: 99%

Validation of Genomic and Transcriptomic Models of Homologous Recombination Deficiency in a Real-World Pan-Cancer Cohort

Leibowitz

Dougherty

Bell

et al. 2021

Preprint

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Background: With the introduction of DNA-damaging therapies into standard of care cancer treatment, there is a growing need for predictive diagnostics assessing homologous recombination deficiency (HRD) status across tumor types. Following the strong clinical evidence for the utility of DNA-sequencing-based HRD testing in ovarian cancer, and growing evidence in breast cancer, we present analytical validation of the Tempus|HRD-DNA test. We further developed, validated, and explored the Tempus|HRD-RNA model, which uses gene expression data from 16,470 RNA-seq samples to predict HRD status from formalin-fixed paraffin-embedded (FFPE) tumor samples across numerous cancer types. Methods: Genomic and transcriptomic profiling was performed using next-generation sequencing from Tempus|xT, Tempus|xO, Tempus|xE, Tempus|RS, and Tempus|RS.v2 assays on 48,843 samples. Samples were labeled based on their BRCA1, BRCA2 and selected Homologous Recombination Repair (HRR) pathway gene (CDK12, PALB2, RAD51B, RAD51C, RAD51D) mutational status to train and validate HRD-DNA, a genome-wide loss-of-heterozygosity biomarker, and HRD-RNA, a logistic regression model trained on gene expression, using several performance metrics and statistical tests. Results: In a sample of 2,058 breast and 1,216 ovarian tumors, BRCA status was predicted by HRD-DNA with F1-scores of 0.98 and 0.96, respectively. Across an independent set of 1,363 samples across solid tumor types, the HRD-RNA model was predictive of BRCA status in prostate, pancreatic, and non-small cell lung cancer, with F1-scores of 0.88, 0.69, and 0.62, respectively. Conclusions: We predict HRD-positive patients across many cancer types and believe both HRD models may generalize to other mechanisms of HRD outside of BRCA loss. HRD-RNA complements DNA-based HRD detection methods, especially for indications with low prevalence of BRCA alterations.

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Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse

Cited by 6 publications

References 34 publications

Validation of genomic and transcriptomic models of homologous recombination deficiency in a real-world pan-cancer cohort

Validation of genomic and transcriptomic models of homologous recombination deficiency in a real-world pan-cancer cohort

Expanding the Use of PARP Inhibitors as Monotherapy and in Combination in Triple-Negative Breast Cancer

Validation of Genomic and Transcriptomic Models of Homologous Recombination Deficiency in a Real-World Pan-Cancer Cohort

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