Inactivating Mutations of<i>RB1</i>and<i>TP53</i>Correlate With Sarcomatous Histomorphology and Metastasis/Recurrence in Gastrointestinal Stromal Tumors

Merten, Larissa; Agaimy, Abbas; Moskalev, Evgeny A.; Giedl, Johannes; Kayser, Claudia; Geddert, Helene; Schaefer, Inga‐Marie; Cameron, Silke; Werner, Martin; Ströbel, Philip; Hartmann, Arndt; Haller, Florian

doi:10.1093/ajcp/aqw193

Cited by 26 publications

(16 citation statements)

References 20 publications

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“…However, as a result of insufficient decreased mRNA levels, these genes were not identified as altered TSG. Inactivating mutations of other cell cycle pathway genes, including RB1 and TP53 , occur in high‐risk GIST, showing activation of the cell cycle pathway . We also observed inactivation of RB1 , but not of TP53 .…”

Section: Discussionsupporting

confidence: 48%

Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors

et al. 2019

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractMutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification-dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high-risk GIST) and less malignant GIST (low-and very low-risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K-related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals Correspondence

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Section: Discussionsupporting

confidence: 48%

Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors

et al. 2019

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“…The screening of the whole cohort for TP53 mutations revealed an overall frequency of 3.5%. This is in concordance with other studies showing a very low TP53 mutation frequency despite a high TP53 protein expression in a higher number of GIST [ 11 , 32 – 35 ]. One explanation of this mutation independent activation of p53 (TP53) might be amplification or posttranscriptional modifications such as phosphorylation, acetylation or sumoylation [ 36 , 37 ].…”

Section: Discussionsupporting

confidence: 93%

Expression of cell cycle regulators and frequency of TP53 mutations in high risk gastrointestinal stromal tumors prior to adjuvant imatinib treatment

et al. 2018

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Despite of multitude investigations no reliable prognostic immunohistochemical biomarkers in GIST have been established so far with added value to predict the recurrence risk of high risk GIST besides mitotic count, primary location and size. In this study, we analyzed the prognostic relevance of eight cell cycle and apoptosis modulators and of TP53 mutations for prognosis in GIST with high risk of recurrence prior to adjuvant treatment with imatinib. In total, 400 patients with high risk for GIST recurrence were randomly assigned for adjuvant imatinib either for one or for three years following laparotomy. 320 primary tumor samples with available tumor tissue were immunohistochemically analyzed prior to treatment for the expression of cell cycle regulators and apoptosis modulators cyclin D1, p21, p16, CDK4, E2F1, MDM2, p53 and p-RB1. TP53 mutational analysis was possible in 245 cases. A high expression of CDK4 was observed in 32.8% of all cases and was associated with a favorable recurrence free survival (RFS), whereas high expression of MDM2 (12.2%) or p53 (35.3%) was associated with a shorter RFS. These results were independent from the primary KIT or PDGFRA mutation. In GISTs with higher mitotic counts was a significantly increased expression of cyclin D1, p53 and E2F1. The expression of p16 and E2F1 significantly correlated to a non-gastric localization. Furthermore, we observed a significant higher expression of p21 and E2F1 in KIT mutant GISTs compared to PDGFRA mutant and wt GISTs. The overall frequency of TP53 mutations was low (n = 8; 3.5%) and could not be predicted by the immunohistochemical expression of p53. In summary, mutation analysis in TP53 plays a minor role in the subgroup of high-risk GIST before adjuvant treatment with imatinib. Strong expression of MDM2 and p53 correlated with a shorter recurrence free survival, whereas a strong expression of CDK4 correlated to a better recurrence free survival.

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“…In addition to the 1 case in Antonescu’s series, recurrent inactivating TP53 mutations were reported in 2 tumors with dedifferentiation by Merten and colleagues. 11 Although upon close manual review we did not appreciate TP53 alterations in our sequencing or copy number data, it is well documented that protein expression and mutational status of TP53 are not always correlative. 12 The significance of these findings is not immediately clear, however, and both computational limitations and alternative pathway aberrations causing p53 protein overexpression are possible.…”

Section: Discussionmentioning

confidence: 88%

Dedifferentiation in SDH-Deficient Gastrointestinal Stromal Tumor: A Report With Histologic, Immunophenotypic, and Molecular Characterization

et al. 2019

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One-third of gastrointestinal stromal tumors (GISTs) that lack KIT or PDGFRA mutations show succinate dehydrogenase (SDH) mutations or promoter hypermethylation. Most SDH-deficient GISTs occur in the pediatric, adolescent, or young adult setting and have unique features including predilection for the stomach, multinodular plexiform architecture, epithelioid cytology, prominence of lymphovascular invasion, and predilection for nodal metastasis. Dedifferentiation in GIST is a rare histologic change which may occur de novo or secondary to imatinib therapy and is characterized by abrupt transition of well-differentiated (WD) GIST to a subclonal anaplastic process that shows loss of immunohistochemical marks (CD117, DOG1). We describe the case of a previously healthy 18-year-old man who presented with a large gastric wall mass that contained 2 distinct morphologic populations. The first was WD and characterized by sweeping fascicles of bland spindled cells. This population abruptly transitioned to dedifferentiated (DD) foci composed of large sheets of discohesive cells that displayed a spectrum of rhabdoid and epithelioid morphologies with marked pleomorphism and mitotic activity. Immunohistochemically, the tumor showed variable staining in the 2 components with diffuse DOG-1 and CD117 positivity in the WD component and complete absence in the DD foci. SDH-B staining was lost in both components. Whole exome and transcriptome analysis was performed on tissue from both components and both showed an SDHB mutation (c.286G>A) as well as unique mutational burden and copy number profiles. Herein, we describe the first case of a DD SDH-deficient GIST with morphologic, immunophenotypic, and molecular characterization.

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Inactivating Mutations ofRB1andTP53Correlate With Sarcomatous Histomorphology and Metastasis/Recurrence in Gastrointestinal Stromal Tumors

Abstract: TP53 and RB1 mutations seem to be restricted to high-risk/malignant GISTs and occur at an equal although relatively low frequency.

Cited by 26 publications

References 20 publications

Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors

Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors

Expression of cell cycle regulators and frequency of TP53 mutations in high risk gastrointestinal stromal tumors prior to adjuvant imatinib treatment

Dedifferentiation in SDH-Deficient Gastrointestinal Stromal Tumor: A Report With Histologic, Immunophenotypic, and Molecular Characterization

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