TP53 Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy

Graziano, Francesco; Fischer, Nicholas W.; Bagaloni, Irene; Bartolomeo, Maria Di; Vincenzi, Bruno; Perrone, Giuseppe; Fornaro, Lorenzo; Ongaro, Elena; Aprile, Giuseppe; Bisonni, Renato; Prisciandaro, Michele; Malkin, David; Gariépy, Jean; Fassan, Matteo; Loupakis, Fotios; Sarti, Donatella; Prete, Michela Del; Catalano, Vincenzo; Alessandroni, Paolo; Magnani, Mauro; Ruzzo, Annamaria

doi:10.3390/cancers12082049

Cited by 12 publications

(8 citation statements)

References 34 publications

(71 reference statements)

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“…aggressiveness. TP53 was found to be the most commonly mutated gene, in line with previous reports on TP53 mutations detected in up to two-thirds of metastatic GEC patients [28].…”

Section: Discussionsupporting

confidence: 90%

Circulating tumor DNA predicts outcome in metastatic gastroesophageal cancer

et al. 2022

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Background Circulating tumor DNA (ctDNA) has predictive and prognostic value in localized and metastatic cancer. This study analyzed the prognostic value of baseline and on-treatment ctDNA in metastatic gastroesophageal cancer (mGEC) using a region-specific next generation sequencing (NGS) panel. Methods Cell free DNA was isolated from plasma of patients before start of first-line palliative systemic treatment and after 9 and 18 weeks. Two NGS panels were designed comprising the most frequently mutated genes and targetable mutations in GEC. Tumor-derived mutations in matched metastatic biopsies were used to validate that the sequencing panels assessed true tumor-derived variants. Tumor volumes were calculated from baseline CT scans and correlated to variant allele frequency (VAF). Survival analyses were performed using univariable and multivariable Cox-regression analyses. Results ctDNA was detected in pretreatment plasma in 75% of 72 patients and correlated well with mutations in metastatic biopsies (86% accordance). The VAF correlated with baseline tumor volume (Pearson’s R 0.53, p < 0.0001). Detection of multiple gene mutations at baseline in plasma was associated with worse overall survival (OS, HR 2.16, 95% CI 1.10–4.28; p = 0.027) and progression free survival (PFS, HR 2.71, 95% CI 1.28–5.73; p = 0.009). OS and PFS were inferior in patients with residual detectable ctDNA after 9 weeks of treatment (OS: HR 4.95, 95% CI 1.53–16.04; p = 0.008; PFS: HR 4.08, 95% CI 1.31–12.75; p = 0.016). Conclusion Based on our NGS panel, the number of ctDNA mutations before start of first-line chemotherapy has prognostic value. Moreover, residual ctDNA after three cycles of systemic treatment is associated with inferior survival.

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“…aggressiveness. TP53 was found to be the most commonly mutated gene, in line with previous reports on TP53 mutations detected in up to two-thirds of metastatic GEC patients [28].…”

Section: Discussionsupporting

confidence: 90%

Circulating tumor DNA predicts outcome in metastatic gastroesophageal cancer

et al. 2022

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“…The mutation rate of the tumor suppressor gene TP53 is 46% in GC. Deletion of TP53 may upregulate vascular endothelial growth factor A (VEGF-A) expression and promote cancer cell angiogenesis, leading to a poor prognosis ( 36 ). Gurzu et al ( 37 ) analyzed a large number of human gastric cancer samples and found that mutation of exon 7 in TP53 may induce downregulation of the expression of the tumor suppressor gene Maspin, which leads to GC invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Identification of Stemness Characteristics Associated With the Immune Microenvironment and Prognosis in Gastric Cancer

et al. 2021

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BackgroundGastric cancer (GC) is a highly heterogeneous disease. In recent years, the prognostic value of the mRNA expression-based stemness index (mRNAsi) across cancers has been reported. We intended to identify stemness index-associated genes (SI-genes) for clinical characteristic, gene mutation status, immune response, and tumor microenvironment evaluation as well as risk stratification and survival prediction.MethodsThe correlations between the mRNAsi and GC prognosis, clinical characteristics, gene mutation status, immune cell infiltration and tumor microenvironment were evaluated. Weighted gene correlation network analysis (WGCNA) was performed to identify SI-genes from differentially expressed genes (DEGs) in The Cancer Genome Atlas (TCGA). Single-sample gene set enrichment analysis (ssGSEA) was employed to calculate the sample SI-gene-based ssGSEA score according to the SI-genes. Then, the correlations between the ssGSEA score and GC prognosis, clinical characteristics, gene mutation status, immune cell infiltration and tumor microenvironment were analyzed. Finally, the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to construct a prognostic signature with prognostic SI-genes. The ssGSEA score and prognostic signature were validated using the Gene Expression Omnibus (GEO) database.ResultsThe mRNAsi could predict overall survival (OS), clinical characteristics, the gene mutation status, immune cell infiltration, and the tumor microenvironment composition. Fourteen positive SI-genes and 178 negative SI-genes were screened out using WGCNA. The ssGSEA score, similar to the mRNAsi, was found to be closely related to OS, clinical characteristics, the gene mutation status, immune cell infiltration, and the tumor microenvironment composition. Finally, a prognostic signature based on 18 prognostic SI-genes was verified to more accurately predict GC 1-year, 3-year, and 5-year OS than traditional clinical prediction models.ConclusionThe ssGSEA score and prognostic signature based on 18 prognostic SI-genes are of great value for immune response evaluation, risk stratification and survival prediction in GC and suggest that stemness features are crucial drivers of GC progression.

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“…To improve the diagnosis rate, we further analyze the abnormally expressed genes in patients with aggressive pituitary adenomas from the perspective of genetics. It has been found that the expression of Ki67, P53, and VEGF is significantly increased in malignant tumors such as gastric cancer, bladder cancer renal cell carcinoma, and glioma (19)(20)(21)(22). We speculate they are also abnormally expressed in aggressive pituitary adenomas.…”

Section: Discussionmentioning

confidence: 75%

Identification and Verification of SLC27A1, PTBP1 and EIF5A With Significantly Altered Expression in Aggressive Pituitary Adenomas

Cheng

Sun²,

Nie³

et al. 2022

Front. Surg.

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BackgroundAggressive pituitary adenoma encircling the internal carotid artery has a poor clinical prognosis because of a high surgical risk and a high recurrence rate. This seriously affects patients’ quality of life and yet there is no effective medical treatment. The European Diagnostic Guidelines have recommended the use of temozolomide (TMZ) for these aggressive pituitary adenomas, but the treatment remission rate has been less than 50%.MethodsIn this study, transcriptome sequencing of pituitary tumour tissues and TMZ-treated pituitary tumour cell lines were employed to explore the significance gene expressions affecting the efficacy of TMZ treatment for pituitary tumours. To clarify the roles of these gene expressions, six adult patients with pituitary adenomas treated in Tiantan Hospital from 2015 to 2020 and a pituitary adenoma cell line (Att20 sensitive to TMZ treatment) were analyzed by mRNA transcriptome sequencing. The differentially expressed genes were assayed by analyzing the sequencing results, and the expression level of these genes was further verified by immunohistochemistry. In addition, Ki67, VEGF, and p53 of the tumour tissues were also verified by immunohistochemistry.ResultsIn tumour tissues, mRNA sequencing showed that PTBP1 and EIF5A were significantly overexpressed in primary pituitary adenomas and SLC27A1 was significantly overexpressed in aggressive pituitary adenomas. Also in the pituitary adenoma cell line (AtT20), SLC27A1 expression levels were suppressed by TMZ treatment. Subsequent immunohistochemistry confirmed the sequencing results.ConclusionHigh expression of SLC27A1 and low expression of EIF5A and PTBP1 may be potential indicators to predict the progression of aggressive pituitary adenomas, and patients with high SLC27A1 subtype may be sensitive to TMZ in clinical treatments.

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TP53 Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy

Cited by 12 publications

References 34 publications

Circulating tumor DNA predicts outcome in metastatic gastroesophageal cancer

Circulating tumor DNA predicts outcome in metastatic gastroesophageal cancer

Identification of Stemness Characteristics Associated With the Immune Microenvironment and Prognosis in Gastric Cancer

Identification and Verification of SLC27A1, PTBP1 and EIF5A With Significantly Altered Expression in Aggressive Pituitary Adenomas

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