High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection

Oshi, Masanori; Newman, Stephanie; Tokumaru, Yoshihisa; Yan, Li; Matsuyama, Ryusei; Endo, Itaru; Katz, Matthew H.; Takabe, Kazuaki

doi:10.3390/cancers12102871

Cited by 39 publications

(41 citation statements)

References 74 publications

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“…In order to quantify the activity of the DNA repair pathway, we defined the DNA repair pathway score based on the gene set variation analysis (GSVA) score of the Molecular Signatures Database Hallmark DNA repair gene set ( Table S1 ), using the methodology we previously reported [ 4 , 5 , 9 , 10 , 11 ]. The DNA repair score correlated with expression of BRCA1 and BRCA2, arguably the most clinically significant DNA repair genes associated with cancer prognosis and treatment sensitivity ( Figure S1 ; Spearman’s rank correlation coefficient (r) = 0.576 ( p < 0.01) and 0.471 ( p < 0.01), respectively).…”

Section: Resultsmentioning

confidence: 99%

“…We have previously reported the association of several pathways with clinical outcomes in various cancers. The G2M checkpoint pathway score identified poor survival in pancreatic and breast cancer patients, and it demonstrated potential as a predictive biomarker for chemotherapy in breast cancer [ 4 , 5 ]. The E2F target pathway score also demonstrated potential as a predictive biomarker for neoadjuvant therapy in breast cancer [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…The DNA repair score was measured as the gene set variation analysis (GSVA) score for the “Hallmark DNA repair” gene set of the Molecular Signatures Database (MSigDB) Hallmark gene set collections [ 23 ] using the GSVA algorithm [ 51 ] in the Bioconductor package (version 3.10), as we previously reported [ 4 , 5 , 9 , 10 , 11 ].…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported the utility of scoring the expression profile of hundreds of genes to understand the relationship between cancer and pathways such as the cell cycle and angiogenesis. For example, the G2M checkpoint pathway score identified poor survival in pancreatic and breast cancer patients, and it showed potential as a predictive biomarker for chemotherapy in breast cancer [ 4 , 5 ]. In this study, we aim to investigate the clinical relevance of DNA repair pathway activity using the “Hallmark DNA repair” gene set of the MSigDB Hallmark gene set variation analysis (GSVA) as the DNA repair score in HCC cohorts.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced DNA Repair Pathway is Associated with Cell Proliferation and Worse Survival in Hepatocellular Carcinoma (HCC)

Oshi

Kim

Tokumaru

et al. 2021

Cancers

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Hepatocellular carcinoma (HCC) is one of the most common malignancies and a leading cause of cancer-related deaths worldwide. In this study, a total of 749 HCC patients from 5 cohorts were studied to examine the relationships between enhancement of DNA repair and cancer aggressiveness, tumor immune microenvironment, and patient survival in HCC, utilizing a DNA repair pathway score. Our findings suggest that the DNA repair pathway was not only enhanced by the stepwise carcinogenic process of HCC, but also significantly enhanced in grade 3 HCC compared with grade 1 and 2 tumors. DNA repair high HCC was associated with worse survival, elevated intratumor heterogeneity, and mutation load, but not with the fraction of immune cell infiltration nor immune response. HCC tumors with a DNA repair high score enriched the cell proliferation- and other cancer aggressiveness-related gene sets. Interestingly, these features were more pronounced in grade 1 and 2 HCC compared to grade 3 HCC. To our knowledge, this is the first study to use DNA repair pathway-related gene set expression data to examine and validate the clinical relevance of DNA repair pathway activity in HCC. The DNA repair score may be used to better understand and predict prognosis in HCC.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhanced DNA Repair Pathway is Associated with Cell Proliferation and Worse Survival in Hepatocellular Carcinoma (HCC)

Oshi

Kim

Tokumaru

et al. 2021

Cancers

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“…Yamazaki et al reported that epithelial–mesenchymal transition (EMT) activity in PC is a promising prognostic biomarker. Our group reported that high activity of the G2M checkpoint pathway [ 5 ] and lympho-vascular invasion [ 6 ] is associated with worse survival. In contrast, the abundance of mature blood vessels [ 7 ] and fibroblasts in PC [ 8 ] is associated with better survival.…”

Section: Introductionmentioning

confidence: 99%

Annexin A1 Expression Is Associated with Epithelial–Mesenchymal Transition (EMT), Cell Proliferation, Prognosis, and Drug Response in Pancreatic Cancer

Oshi

Tokumaru

Mukhopadhyay

et al. 2021

Cells

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Annexin A1 (ANXA1) is a calcium-dependent phospholipid-binding protein overexpressed in pancreatic cancer (PC). ANXA1 expression has been shown to take part in a wide variety of cancer biology, including carcinogenesis, cell proliferation, invasion, apoptosis, and metastasis, in addition to the initially identified anti-inflammatory effect in experimental settings. We hypothesized that ANXA1 expression is associated with cell proliferation and survival in PC patients. To test this hypothesis, we analyzed 239 PC patients in The Cancer Genome Atlas (TCGA) and GSE57495 cohorts. ANXA1 expression correlated with epithelial–mesenchymal transition (EMT) but weakly with angiogenesis in PC patients. ANXA1-high PC was significantly associated with a high fraction of fibroblasts and keratinocytes in the tumor microenvironment. ANXA1 high PC enriched multiple malignant gene sets, including hypoxia, tumor necrosis factor (TNF)-α signaling via nuclear factor-kappa B (NF-kB), and MTORC1, as well as apoptosis, protein secretion, glycolysis, and the androgen response gene sets consistently in both cohorts. ANXA1 expression was associated with TP53 mutation alone but associated with all KRAS, p53, E2F, and transforming growth factor (TGF)-β signaling pathways and also associated with homologous recombination deficiency in the TCGA cohort. ANXA1 high PC was associated with a high infiltration of T-helper type 2 cells in the TME, with advanced histological grade and MKI67 expression, as well as with a worse prognosis regardless of the grade. ANXA1 expression correlated with a sensitivity to gemcitabine, doxorubicin, and 5-fluorouracil in PC cell lines. In conclusion, ANXA1 expression is associated with EMT, cell proliferation, survival, and the drug response in PC.

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A novel subtype based on driver methylation–transcription in lung adenocarcinoma

Wang,

Xu,

Zhao

et al. 2024

J Cancer Res Clin Oncol

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Aims To identify driver methylation genes and a novel subtype of lung adenocarcinoma (LUAD) by multi-omics and elucidate its molecular features and clinical significance. Methods We collected LUAD patients from public databases, and identified driver methylation genes (DMGs) by MethSig and MethylMix algrothms. And novel driver methylation multi-omics subtypes were identified by similarity network fusion (SNF). Furthermore, the prognosis, tumor microenvironment (TME), molecular features and therapy efficiency among subtypes were comprehensively evaluated. Results 147 overlapped driver methylation were identified and validated. By integrating the mRNA expression and methylation of DMGs using SNF, four distinct patterns, termed as S1-S4, were characterized by differences in prognosis, biological features, and TME. The S2 subtype showed unfavorable prognosis. By comparing the characteristics of the DMGs subtypes with the traditional subtypes, S3 was concentrated in proximal-inflammatory (PI) subtype, and S4 was consisted of terminal respiratory unit (TRU) subtype and PI subtype. By analyzing TME and epithelial mesenchymal transition (EMT) features, increased immune infiltration and higher expression of immune checkpoint genes were found in S3 and S4. While S4 showed higher EMT score and expression of EMT associated genes, indicating S4 may not be as immunosensitive as the S3. Additionally, S3 had lower TIDE and higher IPS score, indicating its increased sensitivity to immunotherapy. Conclusion The driver methylation-related subtypes of LUAD demonstrate prognostic predictive ability that could help inform treatment response and provide complementary information to the existing subtypes.

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High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection

Cited by 39 publications

References 74 publications

Enhanced DNA Repair Pathway is Associated with Cell Proliferation and Worse Survival in Hepatocellular Carcinoma (HCC)

Enhanced DNA Repair Pathway is Associated with Cell Proliferation and Worse Survival in Hepatocellular Carcinoma (HCC)

Annexin A1 Expression Is Associated with Epithelial–Mesenchymal Transition (EMT), Cell Proliferation, Prognosis, and Drug Response in Pancreatic Cancer

A novel subtype based on driver methylation–transcription in lung adenocarcinoma

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