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

ABSTRACT: Pancreatic cancer (PC) with homologous recombination deficiency (HRD) has been reported to benefit from poly ADP-ribose polymerase (PARP) inhibitors. However, accurate identification of HRD status for PC patients from the transcriptional level is still a great challenge. Here, based on a relative expression ordering (REO)-based algorithm, we developed an HRD signature including 24 gene pairs (24-GPS) using PC transcriptional profiles from The Cancer Genome Atlas (TCGA). HRD samples classified by 24-GPS showed worse overall survival (p = 4.4E-3 for TCGA; p = 1.2E-3 for International Cancer Genome Consortium-Australia cohort; p = 6.4E-2 for GSE17891; p = 7.5E-2 for GSE57495) and higher HRD scores than non-HRD samples (p = 1.4E-4). HRD samples showed highly unstable genomic characteristics and also displayed HRD-related alterations at the epigenomic and proteomic levels. Moreover, HRD cell lines identified by 24-GPS tended to be sensitive to PARP inhibitors (p = 6.6E-2 for olaparib; p = 2.6E-3 for niraparib). Compared with the non-HRD group, the HRD group presented lower immune scores and CD4/CD8 T cell infiltration proportion. Interestingly, PC tumor cells with co-inhibition of PARP-related genes and ATR showed reduced survival ability. In conclusion, 24-GPS can robustly identify PC patients with HRD status at the individualized level.

SUBMITTER: Zhuang S

PROVIDER: S-EPMC8571416 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Zhuang Shuping S Chen Tingting T Li Yawei Y Wang Yuquan Y Ai Liqiang L Geng Yiding Y Zou Min M Liu Kaidong K Xu Huanhuan H Wang Linzhu L Zhao Zhangxiang Z Chang Zhiqiang Z Gu Yunyan Y

Molecular therapy. Nucleic acids 20211020

Pancreatic cancer (PC) with homologous recombination deficiency (HRD) has been reported to benefit from poly ADP-ribose polymerase (PARP) inhibitors. However, accurate identification of HRD status for PC patients from the transcriptional level is still a great challenge. Here, based on a relative expression ordering (REO)-based algorithm, we developed an HRD signature including 24 gene pairs (24-GPS) using PC transcriptional profiles from The Cancer Genome Atlas (TCGA). HRD samples classified by ...[more]

PMID: 34786207

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Project description:BackgroundGlioblastoma (GBM) is a frequent malignant tumor in neurosurgery characterized by a high degree of heterogeneity and genetic instability. DNA double-strand breaks generated by homologous recombination deficiency (HRD) are a well-known contributor to genomic instability, which can encourage tumor development. It is unknown, however, whether the molecular characteristics linked with HRD have a predictive role in GBM. The study aims to assess the extent of genomic instability in GBM using HRD score and investigate the prognostic significance of HRD-related molecular features in GBM.MethodsThe discovery cohort comprised 567 GBM patients from The Cancer Genome Atlas (TCGA) database. We established HRD scores using the single nucleotide polymorphism (SNP) array data and analyzed transcriptomic data from patients with different HRD scores to identify biomarkers associated with HRD. A prognostic model was built by using HRD-related differentially expressed genes (DEGs) and validated in a distinct cohort from the Chinese Glioma Genome Atlas (CGGA) database.ResultsBased on the SNP array data, the gene expression profile data, and the clinical characteristics of GBM patients, we found that patients with a high HRD score had a better prognosis than those with a low HRD score. The DNA damage repair (DDR) signaling pathways were notably enriched in the HRD-positive subgroup. The prognostic model was developed by including HRD-related DEGs that could evaluate the clinical prognosis of patients more efficiently than the HRD score. In addition, patients with a low-risk score had a considerably augmented signature of γδT cells. Finally, through univariate and multivariate Cox regression analyses, it was demonstrated that the prognostic model was superior to other prognostic markers.ConclusionsIn conclusion, our research has not only demonstrated that a high HRD score is a valid prognostic biomarker in GBM patients but also built a stable prognosis model [odds ratio (OR) 0.18, 95% confidence interval (CI): 0.11-0.23, P<0.001] that is more accurate than conventional prognostic markers such as O6-methylguanine-DNA methyltransferase (MGMT) methylation (OR 0.55, 95% CI: 0.33-0.91, P=0.02).

Dataset Information

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

Publications

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

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