A transcriptional signature detects homologous recombination deficiency in pancreatic cancer at the individual level

Zhuang, Shuping; Chen, Tingting; Li, Yawei; Wang, Yuquan; Ai, Liqiang; Geng, Yiding; Zou, Min; Liu, Kaidong; Xu, Huanhuan; Wang, Linzhu; Zhao, Zhangxiang; Chang, Zhiqiang; Gu, Yunyan

doi:10.1016/j.omtn.2021.10.014

Cited by 8 publications

(9 citation statements)

References 42 publications

(47 reference statements)

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“…The FoundationOne®CDX assay uses a cut‐off value of LOH > 16% to predict response to PARPi in ovarian cancers (Coleman et al , 2017 ). Currently, no clinically validated diagnostic test exists for determining HRD ness in soft tissue or bone sarcoma and the designated threshold for the different genomic signatures in ovarian and breast cancer is not necessarily applicable to other tumor entities, as has been reported for pancreatic cancer (Zhuang et al , 2021 ). By assessing the CIN levels in HRR genes, the only signature that showed a bimodal distribution pattern, we could infer an optimal cut‐off value for the HRD score in STS applying the Youden index.…”

Section: Discussionmentioning

confidence: 99%

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Planas-Paz¹,

Pliego-Mendieta²,

Hagedorn³

et al. 2023

EMBO Mol Med

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Defects in homologous recombination repair (HRR) in tumors correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harboring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient-derived sarcoma cells. Concomitantly, HRD high sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.

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Section: Discussionmentioning

confidence: 99%

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Planas-Paz¹,

Pliego-Mendieta²,

Hagedorn³

et al. 2023

EMBO Mol Med

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“…One notable deviation from the predicted rates of HRD+ samples is in pancreatic cancer where, for both metastatic and primary samples, the predicted rates for HRD-RNA are lower than CHORD. Reported rates of HRD in pancreatic cancer vary between 3 and 30% [ 19 , 35 ], where RNA-based approaches have been shown to be prognostic and identify other genetic drivers of HRD [ 35 ]. Given clinical trials have demonstrated no survival benefit using olaparib to treat pancreatic cancer patients with germline BRCA alterations, there remains a poor understanding of HRD manifestation in pancreatic cancer [ 86 ].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to DNA-based approaches, gene expression has the potential to capture the dynamic state of HRD in a manner that is independent from genomic scarring, particularly in cancer types outside breast and ovarian cancer, where DNA-based approaches have not yet reached the clinic. Transcriptional signatures have shown promise in predicting BRCA status or genomic scars in prostate and pancreatic cancer [ 33 – 35 ]. However, it has yet to be demonstrated that a transcriptome-based model can generalize across solid tumors.…”

Section: Introductionmentioning

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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“…Recently, poly ADP-ribose polymerase (PARP) inhibitors were approved for use by the Food and Drug Administration and recommended for the treatment of tumors with BRCA1/2 mutations, including pancreatic cancer and prostate cancer (Rescigno et al, 2018;Li et al, 2021;Zhuang et al, 2021). Tumors with BRCA1/2 mutations are often accompanied by homologous recombination deficiency (HRD), and cancer cells with HRD are more sensitive to PARP inhibitors (Rescigno et al, 2018;Chen et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…However, due to the great heterogeneity among different tumor types, it could be more rational to use different thresholds for classification in different tumor types (Jonsson et al, 2019). In addition, because HRD is a genomic event, its changes can be reflected by transcriptome level assays (Peng et al, 2014;Ladan et al, 2021;Zhuang et al, 2021), and changes in the transcriptome can also provide new insights into the changes in HRD. However, the threshold of HRD score in LGG is not known and the transcriptomic features of HRD in LGG have not been fully investigated.…”

Section: Introductionmentioning

confidence: 99%

A Risk Model Developed Based on Homologous Recombination Deficiency Predicts Overall Survival in Patients With Lower Grade Glioma

Peng

Wang

et al. 2022

Front. Genet.

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The role of homologous recombination deficiency (HRD) in lower grade glioma (LGG) has not been elucidated, and accurate prognostic prediction is also important for the treatment and management of LGG. The aim of this study was to construct an HRD-based risk model and to explore the immunological and molecular characteristics of this risk model. The HRD score threshold = 10 was determined from 506 LGG samples in The Cancer Genome Atlas cohort using the best cut-off value, and patients with high HRD scores had worse overall survival. A total of 251 HRD-related genes were identified by analyzing differentially expressed genes, 182 of which were associated with survival. A risk score model based on HRD-related genes was constructed using univariate Cox regression, least absolute shrinkage and selection operator regression, and stepwise regression, and patients were divided into high- and low-risk groups using the median risk score. High-risk patients had significantly worse overall survival than low-risk patients. The risk model had excellent predictive performance for overall survival in LGG and was found to be an independent risk factor. The prognostic value of the risk model was validated using an independent cohort. In addition, the risk score was associated with tumor mutation burden and immune cell infiltration in LGG. High-risk patients had higher HRD scores and “hot” tumor immune microenvironment, which could benefit from poly-ADP-ribose polymerase inhibitors and immune checkpoint inhibitors. Overall, this big data study determined the threshold of HRD score in LGG, identified HRD-related genes, developed a risk model based on HRD-related genes, and determined the molecular and immunological characteristics of the risk model. This provides potential new targets for future targeted therapies and facilitates the development of individualized immunotherapy to improve prognosis.

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A transcriptional signature detects homologous recombination deficiency in pancreatic cancer at the individual level

Cited by 8 publications

References 42 publications

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

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

A Risk Model Developed Based on Homologous Recombination Deficiency Predicts Overall Survival in Patients With Lower Grade Glioma

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