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Multiple Perspectives Reveal the Role of DNA Damage Repair Genes in the Molecular Classification and Prognosis of Pancreatic Adenocarcinoma.

ABSTRACT: Pancreatic adenocarcinoma (PAAD) is a highly heterogeneous and immunosuppressive cancer. This study investigated the diversity of DNA damage repair (DDR) and immune microenvironment in PAAD by transcriptomic and genomic analysis. Patients with PAAD were divided into two DDR-based subtypes with distinct prognosis and molecular characteristics. The differential expression genes were mostly enriched in DDR and immune-related pathways. In order to distinguish high- and low-risk groups clinically, a DDR- and immune-based 5-gene prognostic signature (termed DPRS) was established. Patients in the high-risk group had inferior prognosis, a low level of immune checkpoint gene expression and low sensitivity to DDR-associated inhibitors. Furthermore, single-cell sequencing was used to observe the performance of the DDR-based signature in a high dimension, and immunohistochemistry was used to verify the relationship between the genes we identified and the prognosis of patients with PAAD. In conclusion, the DDR heterogeneity of PAAD was demonstrated, and a novel DDR- and immune-based risk-scoring model was constructed, which indicated the feasibility of DPRS in predicting prognosis and drug response in PAAD patients.

SUBMITTER: Li Y

PROVIDER: S-EPMC9499455 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Multiple Perspectives Reveal the Role of DNA Damage Repair Genes in the Molecular Classification and Prognosis of Pancreatic Adenocarcinoma.

Li Yujie Y Zhang Ke K Peng Linjia L Chen Lianyu L Gao Huifeng H Chen Hao H

International journal of molecular sciences 20220906 18

Pancreatic adenocarcinoma (PAAD) is a highly heterogeneous and immunosuppressive cancer. This study investigated the diversity of DNA damage repair (DDR) and immune microenvironment in PAAD by transcriptomic and genomic analysis. Patients with PAAD were divided into two DDR-based subtypes with distinct prognosis and molecular characteristics. The differential expression genes were mostly enriched in DDR and immune-related pathways. In order to distinguish high- and low-risk groups clinically, a ...[more]

PMID: 36142142

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Project description:Opinion statementMetastatic (and locally advanced) pancreatic adenocarcinoma (mPDA) represents a major challenge for the oncology community given the rising mortality burden from the disease and the preponderance of patients diagnosed with unresectable disease. Although systemic therapies have become more potent with the development of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel as first-line treatments, the median overall survival for patients treated with either of these regimens remains just above 1 year. A significant need exists to build upon the effectiveness of first-line regimens, incorporate tolerable maintenance treatments, and add effective later-line options for patients with this disease. We believe every newly diagnosed mPDA patient should undergo next-generation sequencing (NGS) testing, preferably from tumor tissue, to assess for the presence of DNA damage repair (DDR) defects, microsatellite instability, and other possible actionable molecular alterations (such as neurotrophic tropomysin receptor kinase (NTRK) fusions, anaplastic lymphoma kinase (ALK) rearrangements, or human epidermal growth factor receptor 2 (HER2) amplification). Existing clinical data suggests that patients, whose tumors harbor DDR defects, benefit from treatment with platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. Preclinically, inhibitors of other critical players in DDR such as ataxia-telangiectasia and Rad3 related (ATR), ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and WEE1 have demonstrated promising anti-tumor activity in PDA cell lines and xenografts. How to move forward the preclinical promise of these newer DDR-targeting therapies into rational clinical trial combinations and sequence PARP inhibitors in relation to platinum chemotherapy remain areas of tremendous clinical research interest. We believe clinical trials should be considered early for mPDA patients, in all treatment lines, so that novel therapies may be added to the treatment armamentarium for patients with this disease. Beyond NGS testing from tumor tissue, we believe it is important to consider germline genetic testing for all patients diagnosed with PDA given recent data suggesting a much stronger hereditary component of the disease than previously understood, and the potential screening implications for family members.

Dataset Information

Multiple Perspectives Reveal the Role of DNA Damage Repair Genes in the Molecular Classification and Prognosis of Pancreatic Adenocarcinoma.

Publications

Multiple Perspectives Reveal the Role of DNA Damage Repair Genes in the Molecular Classification and Prognosis of Pancreatic Adenocarcinoma.

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