Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer

Toffalorio, Francesca; Giovannetti, Elisa; Pas, Tommaso De; Radice, Davide; Pelosi, Giuseppe; Manzotti, Michela; Minocci, D.; Spaggiari, Lorenzo; Spitaleri, Gianluca; Noberasco, Cristina; Catania, Chiara; Boselli, Sabrina; Danesi, Romano; Braud, Filippo de

doi:10.1038/tpj.2009.53

Cited by 18 publications

(7 citation statements)

References 43 publications

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“…Our analyses suggested these inhibitors may be effective for the majority of the 13 cancers, which suggests possible broader applications of these inhibitors. For example, gemcitabine targeting RRM2 are validated for the treatment of non-small-cell lung cancer, 50 ovarian cancer, 51 pancreatic cancer, 52 adrenocortical cancer, 53 and oral squamous cell carcinoma. 54 We speculate that gemcitabine can be used to treat bladder, colon, kidney, liver and prostate cancers.…”

Section: Resultsmentioning

confidence: 99%

Integrative analysis with expanded DNA methylation data reveals common key regulators and pathways in cancers

Fan

Tang

et al. 2019

npj Genomic Med

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The integration of genomic and DNA methylation data has been demonstrated as a powerful strategy in understanding cancer mechanisms and identifying therapeutic targets. The TCGA consortium has mapped DNA methylation in thousands of cancer samples using Illumina Infinium Human Methylation 450 K BeadChip (Illumina 450 K array) that only covers about 1.5% of CpGs in the human genome. Therefore, increasing the coverage of the DNA methylome would significantly leverage the usage of the TCGA data. Here, we present a new model called EAGLING that can expand the Illumina 450 K array data 18 times to cover about 30% of the CpGs in the human genome. We applied it to analyze 13 cancers in TCGA. By integrating the expanded methylation, gene expression, and somatic mutation data, we identified the genes showing differential patterns in each of the 13 cancers. Many of the triple-evidenced genes identified in majority of the cancers are biomarkers or potential biomarkers. Pan-cancer analysis also revealed the pathways in which the triple-evidenced genes are enriched, which include well known ones as well as new ones, such as axonal guidance signaling pathway and pathways related to inflammatory processing or inflammation response. Triple-evidenced genes, particularly TNXB, RRM2, CELSR3, SLC16A3, FANCI, MMP9, MMP11, SIK1, and TRIM59 showed superior predictive power in both tumor diagnosis and prognosis. These results have demonstrated that the integrative analysis using the expanded methylation data is powerful in identifying critical genes/pathways that may serve as new therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Integrative analysis with expanded DNA methylation data reveals common key regulators and pathways in cancers

Fan

Tang

et al. 2019

npj Genomic Med

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“…C. Graph comparing the relative expression of USP1 mRNA normalized to GAPDH internal control in normal lung tissue (white bar; four individual samples) with the expression in pooled samples of the three different NSCLC histological subtypes (grey bar; adenocarcinoma, squamous cell carcinoma and large cell carcinoma). Each pooled sample included laser-microdissected specimens from five different patients, as described previously [88]. qRT-PCR analysis was carried out as described above.…”

Section: Introductionmentioning

confidence: 99%

USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy

et al. 2013

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Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocleavage/degradation and phosphorylation, ensuring that USP1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy. This view has gained recent support with the finding that USP1 inhibition may contribute to revert cisplatin resistance in an in vitro model of non-small cell lung cancer (NSCLC). Here, we describe the current knowledge on the cellular functions and regulatory mechanisms of USP1. We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data. Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells.

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“…Since mutations of the CDA gene can alter the functional activity of CDA, this will ultimately affect the efficacy and safety of gemcitabine in patients. Toffalorio et al 29 identified a correlation between the CDA A79C polymorphism and gene expression levels, with patients carrying wild-type genes (AA) having lower CDA activity than patients carrying mutant genes (AC and CC). Studies by Tibaldi et al 16,17 found that patients with low CDA activity showed a better response to gemcitabine chemotherapy, longer PFS, and longer overall survival than patients with a high CDA activity.…”

Section: Discussionmentioning

confidence: 99%

Associations of cytosine deaminase gene polymorphisms with effectiveness of gemcitabine/cisplatin chemotherapy in patients of Xinjiang Uyghur and Han nationality with non-small cell lung cancer

Huang

et al. 2019

Int J Biol Markers

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Background: Cytidine deaminase (CDA) polymorphisms may affect the response to gemcitabine/cisplatin chemotherapy in patients with non-small cell lung cancer (NSCLC). This study is designed to investigate the associations of CDA-79A>C and 208G>A polymorphisms and gemcitabine/cisplatin chemotherapy effectiveness in Xinjiang Uyghur and Han patients. Methods: This prospective cohort study enrolled consecutive patients with stage IIIb/IV NSCLC administered gemcitabine/cisplatin chemotherapy at the First Affiliated Hospital, Medical College of Shihezi University and the First People’s Hospital, Kashgar Region. CDA-A79C and CDA-G208A polymorphisms were detected by direct sequencing. Progression-free survival was analyzed by the Kaplan-Meier method. Associations of A79C and G208A polymorphisms with treatment effectiveness and progression-free survival were analyzed using logistic regression and multivariate Cox regression analyses. Subgroup analyses based on ethnicity were performed. Results: The study enrolled 120 patients. A79C and G208A polymorphisms followed the Hardy-Weinberg equilibrium. The frequencies of the AA, AC, and CC genotypes and the A and C alleles of A79C were 52.2%, 29.9%, 17.9%, 67.2%, and 32.8%, respectively, in Han patients and 75.4%, 18.9%, 5.7%, 84.9%, and 5.1%, respectively, in Uyghur patients. Uyghur patients had lower frequencies of A79C-AC/CC genotypes, A79C-C allele, G208A-GA genotype, and G208A-A allele ( P<0.05). Compared with A79C-AA, the odds of ineffective chemotherapy were increased for A79C-AC (odds ratio [OR] 2.818; 95% confidence interval [95% CI] 1.031, 7.705; P=0.043) and A79C-CC (OR 9.864; 95% CI 1.232, 78.966; P=0.031). G208A polymorphisms did not influence chemotherapy effectiveness. Chemotherapy was more effective in Han patients than in Uyghur patients for A79C-AC and G208A-GG. Progression-free survival was longer for A79C-AA versus A79C-AC/CC (10 vs. 7 months, P=0.004) and G208A-GA/AA vs. G208A-AA (12 vs. 8 months, P=0.010). Polymorphisms of A79C (hazard ratio [HR] 1.617; 95% CI 1.009, 2.592; P=0.046) and G208A (HR 2.193; 95% CI 1.055, 4.557; P=0.035) were associated with progression-free survival. Conclusion: For Uyghur and Han ethnic groups, A79C and G208A polymorphisms can be used as a promising biomarker for the chemotherapy efficacy and prognosis of NSCLC.

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Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer

Cited by 18 publications

References 43 publications

Integrative analysis with expanded DNA methylation data reveals common key regulators and pathways in cancers

Integrative analysis with expanded DNA methylation data reveals common key regulators and pathways in cancers

USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy

Associations of cytosine deaminase gene polymorphisms with effectiveness of gemcitabine/cisplatin chemotherapy in patients of Xinjiang Uyghur and Han nationality with non-small cell lung cancer

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