Relationship Between the Expression of O6-Methylguanine-DNA Methyltransferase (MGMT) and p53, and the Clinical Response in Metastatic Pancreatic Adenocarcinoma Treated with FOLFIRINOX

Vitellius, Carole; Eymerit-Morin, Caroline; Fizanne, Lionel; Foubert, Fanny; Bertrais, Sandrine; Rousselet, Marie‐Christine; Caroli-Bosc, François-Xavier

doi:10.1007/s40261-017-0522-3

Cited by 10 publications

(4 citation statements)

References 36 publications

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“…In a study conducted in 2017, the findings of the study performed for the relation between P53 and MGMT genes on patients with metastatic pancreatic adenocarcinoma showed that MGMT expression was significantly lower in cell lines where P53 gene was mutated. It is observed that when P53 gene is positive, MGMT expression occurs at a lower level than P53 expression level, and when P53 gene is negative, MGMT gene expression was significantly lower [23].…”

Section: Discussionmentioning

confidence: 98%

The Evaluation of the Effects of Temozolomide on MGMT Gene Expression in MCF-7 and SKBR3 Human Breast Cancer Cell Lines

Eroğlu¹,

Sevim²

2019

JCT

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Background and Aim: In this study, it was aimed to examine the cytotoxic effect of temozolomide (TMZ) treatment, on MCF-7 and SKBR3 cell lines, to study the methylation levels of MGMT gene expression and gene promoter region. Methods: The MTT test was performed to determine the effective dose of TMZ. The time-dependent cell survival test was performed after the IC 50 value was found. Western blotting was performed to determine MGMT gene expression levels. High Resolution Melting (HRM) technique was used to determine the methylation levels of MGMT gene promoter region. Results: TMZ has been shown to have a high cytotoxic effect on SKBR3 cell line and low cytotoxicity on MCF-7. When MGMT expression levels before and after TMZ treatment were observed by western blotting, the gene expression levels of TMZ treatment were shown to decrease in both cell lines. It was observed that MGMT gene promoter region was hypermethylated in two cell lines, and that the application of TMZ further increased the methylation levels in the promoter region. Conclusions: It was seen that TMZ could be used as a single agent in SKBR-3 cell line. With this study on breast cancer, it is expected that temozolomide treatment will lead future in vitro and in vivo studies for breast cancer.

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Section: Discussionmentioning

confidence: 98%

The Evaluation of the Effects of Temozolomide on MGMT Gene Expression in MCF-7 and SKBR3 Human Breast Cancer Cell Lines

Eroğlu¹,

Sevim²

2019

JCT

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“…Because of the semiquantitative characteristics of IHC and the discordance of scoring standards, 16,22,23 we referred to previous studies on ovarian carcinoma 24 and compared p53 staining to next-generation sequencing of tumor tissue as the criterion standard reference. We found that 3-tier p53 expression had a moderate correlation with 3 genotypes of TP53, as the previous report 11 .…”

Section: Discussionmentioning

confidence: 99%

Negative p53 Expression Confers Worse Prognosis in Patients With Resected Pancreatic Ductal Adenocarcinoma

Wang

et al. 2022

Pancreas

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The aim of the study is to reinterpret the prognostic prediction of p53 expression categories in pancreatic ductal adenocarcinoma with exploration of the relationship between TP53 mutation genotype and p53 expression pattern.Methods: Data were retrospectively collected from consecutive patients who underwent primary pancreatic resection. Complete loss of function of TP53 is defined as nonsense and frameshift mutations. A tissue microarray was used to evaluate p53 expression by immunohistochemistry and was categorized as regulated, high, or negative. Results:The κ coefficient for agreement between p53 expression and TP53 was 0.761. Cox regression analyses revealed that p53 expression (high vs regulated: hazard ratio [HR], 2.225; P < 0.001; negative vs regulated: HR, 2.788; P < 0.001), tumor-node-metastasis stage (II vs I: HR, 3.471; P < 0.001; III vs I: HR, 6.834; P < 0.001), and tumor grade (G3/4 vs G1/2: HR, 1.958; P < 0.001) were independent prognostic factors in developing cohort and validation cohort. In subgroups of stage I, II, and III, compared with regulated expression, the patients with negative expression had a worse prognosis in both cohorts ( P < 0.05). Conclusions:Our findings indicate that 3-tier p53 expression in resectable pancreatic ductal adenocarcinoma provided independent prognostic information complementary to the tumor-node-metastasis staging system and facilitated patient stratification for personalized therapy.

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“…Although mutations in TP53 increase the stability and accumulation of the p53 protein, immunohistochemical staining for p53 is not related to the overall survival of patients with PDAC who undergo complete pancreatic resection [59,60,97]. However, in patients with metastatic pancreatic cancer treated with FOLFIRINOX, high levels of p53 expression in the tumor are significantly correlated with a poor overall survival rate but not a poor PFS or response rate [98].…”

Section: Tp53 Mutations In Pancreatic Cancermentioning

confidence: 98%

Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications

Zeng

Qin

et al. 2021

Acta Pharmacol Sin

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a minimal difference between its incidence rate and mortality rate. Advances in oncology over the past several decades have dramatically improved the overall survival of patients with multiple cancers due to the implementation of new techniques in early diagnosis, therapeutic drugs, and personalized therapy. However, pancreatic cancers remain recalcitrant, with a 5-year relative survival rate of <9%. The lack of measures for early diagnosis, strong resistance to chemotherapy, ineffective adjuvant chemotherapy and the unavailability of molecularly targeted therapy are responsible for the high mortality rate of this notorious disease. Genetically, PDAC progresses as a complex result of the activation of oncogenes and inactivation of tumor suppressors. Although next-generation sequencing has identified numerous new genetic alterations, their clinical implications remain unknown. Classically, oncogenic mutations in genes such as KRAS and loss-offunction mutations in tumor suppressors, such as TP53, CDNK2A, DPC4/SMAD4, and BRCA2, are frequently observed in PDAC. Currently, research on these key driver genes is still the main focus. Therefore, studies assessing the functions of these genes and their potential clinical implications are of paramount importance. In this review, we summarize the biological function of key driver genes and pharmaceutical targets in PDAC. In addition, we conclude the results of molecularly targeted therapies in clinical trials and discuss how to utilize these genetic alterations in further clinical practice.

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Relationship Between the Expression of O6-Methylguanine-DNA Methyltransferase (MGMT) and p53, and the Clinical Response in Metastatic Pancreatic Adenocarcinoma Treated with FOLFIRINOX

Cited by 10 publications

References 36 publications

The Evaluation of the Effects of Temozolomide on MGMT Gene Expression in MCF-7 and SKBR3 Human Breast Cancer Cell Lines

The Evaluation of the Effects of Temozolomide on MGMT Gene Expression in MCF-7 and SKBR3 Human Breast Cancer Cell Lines

Negative p53 Expression Confers Worse Prognosis in Patients With Resected Pancreatic Ductal Adenocarcinoma

Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications

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