Platinum Drug Sensitivity Polymorphisms in Stage III Non-small Cell Lung Cancer With Invasion of Mediastinal Lymph Nodes

Năstase, Anca; Lupo, Audrey; Laszlo, Victoria; Damotte, Diane; Dima, Simona; Canny, Emelyne; Alifano, Marco; Popescu, Irinel; Klepetko, Walter; Grigoroiu, Mădălina

doi:10.21873/cgp.20215

Cited by 8 publications

(8 citation statements)

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“…The unique risk value for each LC patient was calculated based on the risk score formula. Among of them, NCBP2 has the maximum weighting coefficient and has been reported to interfere with the drug sensitivity of platinum in non-small cell lung cancer [ 31 ]. Then, LC patients were divided into low-risk group and high-risk group according to the median value of the risk score (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of DNA repair-related genes predicting pathogenesis and prognosis for liver cancer

et al. 2021

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Background Liver cancer (LC) is one of the most fatal cancers throughout the world. More efficient and sensitive gene signatures that could accurately predict survival in LC patients are vitally needed to promote a better individualized and effective treatment. Material/methods 422 LC and adjacent normal tissues with both RNA-Seq and clinical data in TCGA were embedded in our study. Gene set enrichment analysis (GSEA) was applied to identify genes and hallmark gene sets that are more valuable for liver cancer therapy. Cox regression analysis was used to identify genes related to overall survival (OS) and build the prediction model. cBioPortal database was used to examine the alterations of the panel mRNA signature. ROC curves and Kaplan–Meier curves were used to validate the prediction model. Besides, the expression of the genes in the model were validated using quantitative real-time PCR in clinical tissue specimens. Results The panel of DNA repair-related mRNA signature consisted of seven mRNAs: RFC4 (replication factor C subunit 4), ZWINT (ZW10 interacting kinetochore protein), UPF3B (UPF3B regulator of nonsense mediated mRNA decay), NCBP2 (nuclear cap binding protein subunit 2), ADA (adenosine deaminase), SF3A3 (splicing factor 3a subunit 3) and GTF2H1 (general transcription factor IIH subunit 1). On-line analysis of cBioPortal database found that the expression of the panel mRNA has a wide variation ranging from 7 to 10%. All the mRNAs were significantly upregulated in LC tissues compared to normal tissues (P < 0.05). The risk model is closely related to the OS of LC patients. The hazard ratio (HR) is 2.184 [95% CI (confidence interval) 1.523–3.132] and log-rank P-value < 0.0001. For clinical specimen validation, we found that all of the genes in the model upregulated in liver cancer tissues versus normal liver tissues, which was consistent with the results predicted. Conclusions Our study demonstrated a mRNA signature including seven mRNA for prognosis prediction of LC. This panel gene signature provides a new criterion for accurate diagnosis and therapeutic target of LC.

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Section: Resultsmentioning

confidence: 99%

Identification of DNA repair-related genes predicting pathogenesis and prognosis for liver cancer

et al. 2021

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“…A variant in GBA has been shown to cause alternative splicing leading to Gaucher disease [40], so the possibility of GBA2 mutations leading to over production of inactive isoforms should be considered. Although nonpathological variants of GBA2 have rarely been described [41], recently it was reported that GBA2 variants are predictive for response to chemotherapy in non-small-cell lung cancer [42]. Further studies should be considered to see whether these variants affect activity or alternative splicing.…”

Section: Discussionmentioning

confidence: 99%

Effect of Expression of Human Glucosylceramidase 2 Isoforms on Lipid Profiles in COS-7 Cells

et al. 2020

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Glucosylceramide (GlcCer) is a major membrane lipid and the precursor of gangliosides. GlcCer is mainly degraded by two enzymes, lysosomal acid β-glucosidase (GBA) and nonlysosomal β-glucosidase (GBA2), which may have different isoforms because of alternative splicing. To understand which GBA2 isoforms are active and how they affect glycosphingolipid levels in cells, we expressed nine human GBA2 isoforms in COS-7 cells, confirmed their expression by qRT-PCR and Western blotting, and assayed their activity to hydrolyze 4-methylumbelliferyl-β-D-glucopyranoside (4MUG) in cell extracts. Human GBA2 isoform 1 showed high activity, while the other isoforms had activity similar to the background. Comparison of sphingolipid levels by ultra-high resolution/accurate mass spectrometry (UHRAMS) analysis showed that isoform 1 overexpression increased ceramide and decreased hexosylceramide levels. Comparison of ratios of glucosylceramides to the corresponding ceramides in the extracts indicated that GBA2 isoform 1 has broad specificity for the lipid component of glucosylceramide, suggesting that only one GBA2 isoform 1 is active and affects sphingolipid levels in the cell. Our study provides new insights into how increased breakdown of GlcCer affects cellular lipid metabolic networks.

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“…Patient groups. The patient inclusion and exclusion criteria have already been published in extenso (15,16).…”

Section: Methodsmentioning

confidence: 99%

“…There were no differentially expressed genes between responders versus non-responders, but the main pathways differentially expressed between groups were cytokine pathways, focal adhesion or extracellular matrix receptor interaction. We also performed whole-exome sequencing (WES) of preoperative tumoral samples from 16 patients (16) and identified SNPs that associated with response to chemotherapy in NSCLC stage IIIA (N2). A higher alternative allele frequency was found on SENP5, rs63736860, rs1602 and NCBP2, rs553783 in the non-responder group, and on RGP1, rs1570248, SLFN12L, rs2304968, rs9905892, and GBA2, rs3833700 in the responder group.…”

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confidence: 99%

Molecular Markers for Long-term Survival in Stage IIIA (N2) NSCLC Patients

Năstase

Dima

Lupo

et al. 2021

Cancer Genomics Proteomics

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Background: Survival rates among non-small cell lung cancer (NSCLC) stage IIIA (N2) patients are generally low and depend on the treatment. Patients and methods: We aimed to identify predictive markers for long term survival in responders and non-responders to chemotherapy, analyzing tumour and non-tumour samples by microarray (n=35) and whole exome sequencing (WES, n=25). Results: WES data showed correlation of overall survival of all patients with rs9905892 in the SLFN12L gene. High frequency of mutations (4/6, 66.7%) was identified in members of SWI/SNF complex in responder patients and in patients that were alive after seven years. Microarray data for immune components showed that VISTA (VSIR) was down-regulated in tumoral tissue. Conclusion: Our research suggests that mutations in SWI/SNF complex associate with long term survival after multimodal treatment, while down-regulation of VISTA might indicate its immunomodulatory role in NSCLC stage III (N2) patients.Patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) are a heterogeneous group. Ruckdeschel et al. (1) divides these patients into three groups: N2 lymph nodes with minimum or microscopic invasion, randomly detected during or after surgical intervention; N2 lymph nodes detected before the surgical intervention either by imaging or surgery, and patients with massive N2 lymph nodes from multiple lymph node stations. Several treatment strategies have been suggested for stage IIIA NSCLC patients during the past two decades (2), including chemotherapy or neoadjuvant chemoradiotherapeutic treatment followed by surgery, primary surgery followed by adjuvant chemotherapy, with or without sequential radiotherapy, and definitive chemo-radiotherapy without surgical intervention (3-5).Multiple phase II and III clinical trials proved the clinical practicality and improved survival of neoadjuvant chemotherapy (3,(5)(6)(7)(8)(9)(10)(11)(12). In many of these studies, the downstaging of the lymph nodes and complete surgical resection are predictors of long-term survival (6,7,13).The global 5-year survival of the N2 NSCLC patients is 20-25% but analysing the patients' subgroups, the 5-year survival is 42% for those responding to chemotherapy and 10%, respectively, for those without chemotherapeutic response ( 14).In our previous study (15), we performed microarray experiments on tumoral and non-tumoral tissue samples derived from tumoral and non-tumoral mediastinal lymph node surgically removed before neoadjuvant chemotherapy treatment from 27 patients with stage IIIA (N2) NSCLC. Based on the response to neoadjuvant chemotherapy, patients were divided in two groups: non-responders (group A), patients with progression or pathological confirmation of persistent mediastinal disease and responders (group B), patients with pathological confirmation of mediastinal down staging. A total of 1,127 genes were identified with modified expression in tumoral tissue compared to normal tissue at p≤0.05 and 44 genes at p≤0.01 (15). Genes with the highest difference in gene ...

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Platinum Drug Sensitivity Polymorphisms in Stage III Non-small Cell Lung Cancer With Invasion of Mediastinal Lymph Nodes

Cited by 8 publications

References 37 publications

Identification of DNA repair-related genes predicting pathogenesis and prognosis for liver cancer

Identification of DNA repair-related genes predicting pathogenesis and prognosis for liver cancer

Effect of Expression of Human Glucosylceramidase 2 Isoforms on Lipid Profiles in COS-7 Cells

Molecular Markers for Long-term Survival in Stage IIIA (N2) NSCLC Patients

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