22 results on '"Biasco, Guido"'
Search Results
2. Late recurrences of gastrointestinal stromal tumours (GISTs) after 5 years of follow-up
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Nannini, Margherita, Biasco, Guido, Pallotti, Maria Caterina, Di Battista, Monica, Santini, Donatella, Paterini, Paola, Maleddu, Alessandra, Mandrioli, Anna, Lolli, Cristian, Saponara, Maristella, Di Scioscio, Valerio, Zompatori, Maurizio, Catena, Fausto, Fusaroli, Pietro, Dei Tos, Angelo Paolo, and Pantaleo, Maria Abbondanza
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- 2012
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3. Laparoscopic Treatment of Gastric Gist: Report of 21 Cases and Literature’s Review
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Catena, Fausto, Di Battista, Monica, Fusaroli, Pietro, Ansaloni, Luca, Di Scioscio, Valerio, Santini, Donatella, Pantaleo, Maria, Biasco, Guido, Caletti, Giancarlo, and Pinna, Antonio
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- 2008
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4. Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene.
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Indio, Valentina, Astolfi, Annalisa, Tarantino, Giuseppe, Urbini, Milena, Patterson, Janice, Nannini, Margherita, Saponara, Maristella, Gatto, Lidia, Santini, Donatella, do Valle, Italo F., Castellani, Gastone, Remondini, Daniel, Fiorentino, Michelangelo, von Mehren, Margaret, Brandi, Giovanni, Biasco, Guido, Heinrich, Michael C., and Pantaleo, Maria Abbondanza
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GASTROINTESTINAL stromal tumors ,GENETIC mutation ,PLATELET-derived growth factor ,MUTANT proteins ,CELL cycle - Abstract
Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein-ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein-coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (TP53, IDH1, FBXW7, SDH-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST. [ABSTRACT FROM AUTHOR]
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- 2018
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5. Personalization of regorafenib treatment in metastatic gastrointestinal stromal tumours in real-life clinical practice.
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Nannini, Margherita, Nigro, Maria Concetta, Vincenzi, Bruno, Fumagalli, Elena, Grignani, Giovanni, D’Ambrosio, Lorenzo, Badalamenti, Giuseppe, Incorvaia, Lorena, Bracci, Raffaella, Gasperoni, Silvia, Saponara, Maristella, Gatto, Lidia, Indio, Valentina, Astolfi, Annalisa, Di Scioscio, Valerio, Casali, Paolo G., Tonini, Giuseppe, Aglietta, Massimo, Russo, Antonio, and Biasco, Guido
- Abstract
Background: Regorafenib (REG) has now been approved as the standard third-line therapy in metastatic gastrointestinal stromal tumour (GIST) patients at the recommended dose and schedule of 160 mg once daily for the first 3 weeks of each 4-week cycle. However, it has a relevant toxicity profile that mainly occurs within the first cycles of therapy, and dose and schedule adjustments are often required to reduce the frequency or severity of adverse events and to avoid early treatment discontinuation. To date, large amounts of data on the use of REG in metastatic GIST patients in daily clinical practice are not available, and we lack information about how this treatment personalization really affects the quality of life (QoL) of patients. The aim of the present retrospective study is to build a comprehensive picture of all alternative REG strategies adopted in daily clinical practice for use in metastatic GIST patients. Methods: Metastatic GIST patients treated with dose adjustment or alternative schedules of REG at seven reference Italian centres were retrospectively included. Results: For a total of 62 metastatic GIST patients, we confirmed that REG treatment adjustment is common in clinical practice and that it is very heterogeneous, with approximately 20 different strategies being adopted. Independent of which strategy is chosen, treatment personalization has led to a clinical benefit defined as complete or partial resolution of side effects in almost all patients, affecting the duration of REG treatment. Conclusions: The personalization of REG, even if it is heterogeneous, seems to be crucial to maximize the overall treatment duration. [ABSTRACT FROM AUTHOR]
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- 2017
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6. Differential expression of neural markers in KIT and PDGFRA wild-type gastrointestinal stromal tumours
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Pantaleo, Maria A., Astolfi, Annalisa, Nannini, Margherita, Ceccarelli, Claudio, Formica, Serena, Santini, Donatella, Heinrich, Michael C., Corless, Christopher, Dei Tos, Angelo Paolo, Paterini, Paola, Catena, Fausto, Maleddu, Alessandra, Saponara, Maristella, Di Battista, Monica, Biasco, Guido, Pantaleo M.A., Astolfi A., Nannini M., Ceccarelli C., Formica S., Santini D., Heinrich M.C., Corless C., Dei Tos A.P., Paterini P., Catena F., Maleddu A., Saponara M., Di Battista M., and Biasco G.
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Adult ,Histology ,DNA Mutational Analysis ,Polymerase Chain Reaction ,Receptor, Platelet-Derived Growth Factor beta ,Mice ,IGF1R ,Biomarkers, Tumor ,Animals ,Humans ,GENE EXPRESSION PROFILING ,ICC precursor ,neoplasms ,Aged ,Aged, 80 and over ,Stem Cell Factor ,ICC ,GASTROINTESTINAL STROMAL TUMORS ,Gene expression profiling ,GIST ,ICC mature ,KIT ,PDGFRA ,2734 ,Middle Aged ,Interstitial Cells of Cajal ,Immunohistochemistry ,digestive system diseases ,Gene Expression Regulation, Neoplastic - Abstract
AIMS: To compare the genomic signatures of wild-type (WT) and mutated GISTs and the murine interstitial cells of Cajal (ICCs) to find markers of cell differentiation and other functions that may identify cells that give rise to WT tumours. METHODS AND RESULTS: We analysed the gene expression profiles of a total of 30 tumour samples (four WT GISTs and 26 mutated GISTs), selected the genes most differentially expressed (P < 0.001:448 probe sets) and validated these results by quantitative polymerase chain reaction (PCR) and immunohistochemistry. In addition, we conducted a meta-analysis merging data from human GISTs with a genomic data set from murine ICCs. The gene expression profiles of WT and mutated GISTs differed profoundly, especially in the expression of those genes restricted primarily to neural tissues. We found that mature ICCs are more similar to mutated GISTs than WT GISTs. CONCLUSIONS: WT GISTs have different genomic profiles from both mutated GISTs and murine mature ICCs. Considering that IGF1R expression is common to both WT GISTs and putative precursor ICCs, this study suggests that WT GISTs may derive either from ICCs at a different step of differentiation or from a different cell of origin.
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- 2011
7. CRITICAL ANALYSIS ON MANAGEMENT OF GIST PATIENTS WITH EVENT TREE MODEL
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DI BATTISTA, MONICA, PANTALEO, MARIA ABBONDANZA, SAPONARA, MARISTELLA, ASTORINO, MARIA, LOLLI, CRISTIAN, SANTINI, DONATELLA, TOMASSETTI, PAOLA, BRANDI, GIOVANNI, BIASCO, GUIDO, Catena F, Di Scioscio V, Castellucci P, FUSAROLI, PIETRO, Di Battista M, Pantaleo MA, Saponara M, Astorino M, Catena F, Lolli C, Di Scioscio V, Santini D, Castellucci P, Fusaroli P, Tomassetti P, Brandi G, and Biasco G
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GIST - Published
- 2008
8. The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST).
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Nannini, Margherita, Urbini, Milena, Astolfi, Annalisa, Biasco, Guido, Pantaleo, Mara A., and Pantaleo, Maria A
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GASTROINTESTINAL stromal tumors ,GENETIC mutation ,RENIN-angiotensin system ,FRAGMENTATION reactions ,DNA fingerprinting - Abstract
Recent advances in molecular biology have revolutionized the concept of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumors (GIST) than the past. Indeed, from being defined as GIST without KIT or PDGFRA mutations, we are now faced with the opposite scenario, where KIT/PDGFRA WT GIST are "positively" defined according to their specific molecular alterations. In particular, if until recently KIT/PDGFRA GIST without abnormalities of KIT, PDGFRA, SDH, and the RAS signaling pathway were referred as quadruple WT GIST, today also this small subset of GIST is emerging out as a group of heterogeneous distinct entities with multiple different molecular alterations. Therefore, given this still growing and rapidly evolving scenario, the progressive molecular fragmentation may inevitably lead over the time to the disappearance of KIT/PDGFRA WT GIST, destined to be singularly defined by their molecular fingerprint. [ABSTRACT FROM AUTHOR]
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- 2017
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9. Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis.
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Ravegnini, Gloria, Sammarini, Giulia, Nannini, Margherita, Pantaleo, Maria A., Biasco, Guido, Hrelia, Patrizia, and Angelini, Sabrina
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Autophagy and apoptosis are 2 fundamental biological mechanisms that may cooperate or be antagonistic, although both are involved in deciding the fate of cells in physiological or pathological conditions. These 2 mechanisms coexist simultaneously in cells and share common upstream signals and stimuli. Autophagy and apoptosis play pivotal roles in cancer development. Autophagy plays a key function in maintaining tumor cell survival by providing energy during unfavorable metabolic conditions through its recycling mechanism, and supporting the high energy requirement for metabolism and growth. This review focuses on gastrointestinal stromal tumors and cell death through autophagy and apoptosis, taking into account the involvement of both of these processes in tumor development and growth and as mechanisms of drug resistance. We also focus on the crosstalk between autophagy and apoptosis as an emerging field with major implications for the development of novel therapeutic options. [ABSTRACT FROM PUBLISHER]
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- 2017
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10. Polymorphisms in DNA repair genes in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome.
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Ravegnini, Gloria, Nannini, Margherita, Simeon, Vittorio, Musti, Muriel, Sammarini, Giulia, Saponara, Maristella, Gatto, Lidia, Urbini, Milena, Astolfi, Annalisa, Biasco, Guido, Pantaleo, Maria, Venturoli, Nicola, Hrelia, Patrizia, and Angelini, Sabrina
- Abstract
DNA repair pathways play an essential role in cancer susceptibility by maintaining genomic integrity. This led us to investigate the influence of polymorphisms in the genes coding repair pathway enzymes on gastrointestinal stromal tumours (GIST) susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 20 polymorphisms in 11 genes in 81 cases and 147 controls. The XPD rs13181 wild-type allele and hOGG1 rs1052133 and XPF rs1800067 minor alleles were significantly associated with disease susceptibility. XPA rs1800975 and rs2808668 were associated with tumour size ( P = 0.018), metastatic status at onset ( P = 0.035) and mitotic index ( P = 0.002). With regards to outcome treatment, the XPD rs50872 minor allele had a significant favourable impact on time to progression (TTP). Similarly, the XPC rs2228000 minor allele was correlated with a longer TTP ( P = 0.03). On the contrary, the XPC rs2228001 and hOGG1 rs1052133 minor alleles were associated with a diminished TTP ( P = 0.005 and P = 0.01, respectively). Regarding OS, we found the presence of at least one hOGG1 (rs1052133) minor allele that had a 60 % lower risk to die compared to the wild-type carriers ( P = 0.04). Furthermore, the XRCC3 rs861539 variant allele is associated with a hazard of early death compared with the wild-type genotype ( P = 0.04). To the best of our knowledge, this is the first study on polymorphisms in DNA repair genes, belonging to the different pathways, extensively evaluated in GIST patients. Through this multiple candidate gene approach, we report for the first time the significant associations between polymorphisms in DNA repair genes, susceptibility, clinical pathological features and clinical outcome in GIST. [ABSTRACT FROM AUTHOR]
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- 2016
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11. SDHC methylation in gastrointestinal stromal tumors (GIST): a case report.
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Urbini, Milena, Astolfi, Annalisa, Indio, Valentina, Heinrich, Michael C., Corless, Christopher L., Nannini, Margherita, Ravegnini, Gloria, Biasco, Guido, and Pantaleo, Maria A.
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DNA methylation ,SUCCINATE dehydrogenase ,GASTROINTESTINAL stromal tumors ,GENETIC mutation ,GENE expression ,GENETICS - Abstract
Background: Gastrointestinal stromal tumors (GIST) recently have been recognized as a genetically and biologically heterogeneous disease. In addition to KIT or PDGFRA mutated GIST, mutational inactivation of succinate dehydrogenase (SDH) subunits has been detected in the KIT/PDGFRA wild-type subgroup, referred to as SDH deficient (dSDH). Even though most dSDH GIST harbor mutations in SDHx subunit genes, some are SDHx wild type. Epigenetic regulation by DNA methylation of CpG islands recently has been found to be an alternative mechanism underlying the lack of SDH complex in GIST. Case presentation: We report a particular case of dSDH GIST, previously analyzed with microarrays and next-generation sequencing, for which no molecular pathogenetic events have been identified. Gene expression analysis showed remarkable down-modulation of SDHC mRNA with respect to all other GIST samples, both SDHA-mutant and KIT/PDGFRA-mutant GIST. By a bisulfite methylation assay targeted to 2 SDHC CpG islands, we detected hypermethylation of the SDHC promoter. Conclusion: Herein we report an additional case of dSDH GIST without SDHx mutation but harboring hypermethylation in the SDHC promoter, thus confirming the complexity of the molecular background of this subtype of GIST. [ABSTRACT FROM AUTHOR]
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- 2015
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12. Personalized Medicine in Gastrointestinal Stromal Tumor (GIST): Clinical Implications of the Somatic and Germline DNA Analysis.
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Ravegnini, Gloria, Nannini, Margherita, Sammarini, Giulia, Astolfi, Annalisa, Biasco, Guido, Pantaleo, Maria A., Hrelia, Patrizia, and Angelini, Sabrina
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GASTROINTESTINAL stromal tumors ,INDIVIDUALIZED medicine ,SOMATIC cells ,PROTEIN-tyrosine kinases ,DNA ,BIOMARKERS - Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. They are characterized by gain of function mutations in KIT or PDGFRA tyrosine kinase receptors, with their consequent constitutive activation. The gold standard therapy is imatinib that offers a good and stable response for approximately 18-36 months. However, resistance is very common and it is vital to identify new biomarkers. Up until now, there have been two main approaches with focus to characterize novel targets. On the one hand, the focus is on the tumor genome, as the final clinical outcome depends mainly from the cancer specific mutations/alterations patterns. However, the germline DNA is important as well, and it is inconceivable to think the patients response to the drug is not related to it. Therefore the aim of this review is to outline the state of the art of the personalized medicine in GIST taking into account both the tumor DNA (somatic) and the patient DNA (germline). [ABSTRACT FROM AUTHOR]
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- 2015
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13. Expression of IGF-1 receptor in KIT/PDGF receptor-α wild-type gastrointestinal stromal tumors with succinate dehydrogenase complex dysfunction.
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Nannini, Margherita, Astolfi, Annalisa, Paterini, Paola, Urbini, Milena, Santini, Donatella, Catena, Fausto, Indio, Valentina, Casadio, Rita, Daniele Pinna, Antonio, Biasco, Guido, and Pantaleo, Maria A
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- 2013
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14. Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis
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Margherita Nannini, Maria Abbondanza Pantaleo, Patrizia Hrelia, Gloria Ravegnini, Guido Biasco, Sabrina Angelini, Giulia Sammarini, Ravegnini, Gloria, Sammarini, Giulia, Nannini, Margherita, Pantaleo, Maria A., Biasco, Guido, Hrelia, Patrizia, and Angelini, Sabrina
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0301 basic medicine ,Programmed cell death ,High energy ,Stromal cell ,Gastrointestinal Stromal Tumors ,Apoptosis ,Review ,Biology ,Models, Biological ,03 medical and health sciences ,0302 clinical medicine ,Autophagy ,Animals ,Humans ,Molecular Biology ,miRNA ,Gastrointestinal Neoplasms ,GiST ,Mechanism (biology) ,Cell Biology ,apoptosi ,Cell biology ,Crosstalk (biology) ,030104 developmental biology ,imatinib ,030220 oncology & carcinogenesis ,GIST ,Signal Transduction - Abstract
Autophagy and apoptosis are 2 fundamental biological mechanisms that may cooperate or be antagonistic, although both are involved in deciding the fate of cells in physiological or pathological conditions. These 2 mechanisms coexist simultaneously in cells and share common upstream signals and stimuli. Autophagy and apoptosis play pivotal roles in cancer development. Autophagy plays a key function in maintaining tumor cell survival by providing energy during unfavorable metabolic conditions through its recycling mechanism, and supporting the high energy requirement for metabolism and growth. This review focuses on gastrointestinal stromal tumors and cell death through autophagy and apoptosis, taking into account the involvement of both of these processes in tumor development and growth and as mechanisms of drug resistance. We also focus on the crosstalk between autophagy and apoptosis as an emerging field with major implications for the development of novel therapeutic options.
- Published
- 2017
15. An exploratory association of polymorphisms in angiogenesis-related genes with susceptibility, clinical response and toxicity in gastrointestinal stromal tumors receiving sunitinib after imatinib failure
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Milena Urbini, Guido Biasco, Maria Abbondanza Pantaleo, Vittorio Simeon, Nicola Venturoli, Giulia Sammarini, Gloria Ravegnini, Margherita Nannini, Corrado Zenesini, Patrizia Hrelia, Sabrina Angelini, Maristella Saponara, Lidia Gatto, Ravegnini, G, Nannini, M, Zenesini, C, Simeon, V, Sammarini, G, Urbini, M, Gatto, L, Saponara, M, Biasco, G, Pantaleo, Ma, Venturoli, N, Hrelia, P, Angelini, S, Ravegnini, Gloria, Nannini, Margherita, Zenesini, Corrado, Simeon, Vittorio, Sammarini, Giulia, Urbini, Milena, Gatto, Lidia, Saponara, Maristella, Biasco, Guido, Pantaleo, Maria A, Venturoli, Nicola, Hrelia, Patrizia, and Angelini, Sabrina
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Male ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,Oncology ,Cancer Research ,Candidate gene ,Indoles ,Time Factors ,Physiology ,Angiogenesis ,Clinical Biochemistry ,Kaplan-Meier Estimate ,Pharmacology ,Metastasis ,0302 clinical medicine ,VEGF pathway ,Sunitinib ,Treatment Failure ,Aged, 80 and over ,Neovascularization, Pathologic ,GiST ,Clinical outcome ,Pharmacogenetic ,OS ,Middle Aged ,Angiogenesi ,VEGFR2 ,VEGFR1 ,030220 oncology & carcinogenesis ,Toxicity ,Disease Progression ,Imatinib Mesylate ,Female ,VEGFR3 ,GIST ,medicine.drug ,VEGFA ,Adult ,medicine.medical_specialty ,TTP ,Gastrointestinal Stromal Tumors ,SNP ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Pyrroles ,Polymorphism ,Genetic Association Studies ,Aged ,Demography ,Vascular Endothelial Growth Factor Receptor-1 ,business.industry ,Vascular Endothelial Growth Factor Receptor-3 ,medicine.disease ,030104 developmental biology ,Haplotypes ,Multivariate Analysis ,Clinical response ,business ,Pharmacogenetics - Abstract
The angiogenic pathway plays a pivotal role in tumor growth, invasiveness and metastasis. The most important actors in the angiogenic pathway are VEGFA and its receptors VEGFR1, 2 and 3. These genes are polymorphic, and the presence of single nucleotide polymorphisms may result in angiogenic deregulation. Herein, we hypothesized that germline variants may affect sunitinib efficacy (TTP and OS) and/or toxicity. Therefore, we investigated 19 polymorphisms, in four genes, in 54 GIST patients, treated with second-line sunitinib and 147 healthy controls. Through a multiple candidate gene approach, we also investigated, for the first time, any possible significant associations with GIST susceptibility and clinical pathological features. The most important result shows two associations between polymorphisms in VEGFR3 rs6877011 (CC vs. CG, OR 9.7, 95% CI 3.31-28.4; P < 0.001) and rs7709359 (AA+AG vs. GG, OR 5.01, 95% CI 1.33-18.8; P = 0.017) and TTP. Interestingly, the association between VEGFR3 rs6877011 and TTP maintained the significance after applying the Bonferroni correction for multiple testing (P = 0.017). We also highlighted the association with sunitinib-related toxicity; in particular, VEGFA polymorphism rs3025039 (CT+TT vs. CC, OR 15.3, 95% CI 2.2-102.1; P = 0.005) is associated with severe toxicity, with the presence of the variant T allele associated with a grade a 3 AE. Because of the small sample size and large number of tests performed, we cannot ignore the possibility that some associations have been retrieved by chance. However, the influence of VEGF polymorphisms in angiogenesis is a hypothesis worthy of exploration in cellular models and confirmation in a sizeable cohort of patients.
- Published
- 2016
16. Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS)
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Maria Abbondanza Pantaleo, Margherita Nannini, Giorgio Ercolani, Cristian Lolli, Donatella Santini, Valentina Indio, Milena Urbini, Antonio Daniele Pinna, Michelangelo Fiorentino, Maristella Saponara, Annalisa Astolfi, Massimo Del Gaudio, Guido Biasco, Anna Mandrioli, Maria Giulia Pirini, Giovanni Brandi, Lidia Gatto, Saponara, Maristella, Urbini, Milena, Astolfi, Annalisa, Indio, Valentina, Ercolani, Giorgio, Del Gaudio, Massimo, Santini, Donatella, Pirini, Maria Giulia, Fiorentino, Michelangelo, Nannini, Margherita, Lolli, Cristian, Mandrioli, Anna, Gatto, Lidia, Brandi, Giovanni, Biasco, Guido, Pinna, Antonio Daniele, and Pantaleo, Maria Abbondanza
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Male ,PTEN ,Receptor, Platelet-Derived Growth Factor alpha ,DNA Copy Number Variations ,Genotype ,Gastrointestinal Stromal Tumors ,CCND2 ,CDKN2C ,DMD ,GIST ,NGS ,Copy number analysis ,Gene mutation ,Translocation, Genetic ,NO ,CDKN2A ,Humans ,Genetic Predisposition to Disease ,Hedgehog Proteins ,Neoplasm Metastasis ,Cells, Cultured ,Aged ,Base Sequence ,biology ,GiST ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Exons ,Middle Aged ,Transplantation ,Proto-Oncogene Proteins c-kit ,Oncology ,Chromosomes, Human, Pair 1 ,Tumor progression ,Mutation ,biology.protein ,Cancer research ,Female ,Chromosomes, Human, Pair 4 ,Research Paper ,Signal Transduction - Abstract
// Maristella Saponara 1,* , Milena Urbini 2,* , Annalisa Astolfi 2 , Valentina Indio 2 , Giorgio Ercolani 3 , Massimo Del Gaudio 3 , Donatella Santini 4 , Maria Giulia Pirini 4 , Michelangelo Fiorentino 5 , Margherita Nannini 1 , Cristian Lolli 1 , Anna Mandrioli 1 , Lidia Gatto 1 , Giovanni Brandi 1 , Guido Biasco 1,2 , Antonio Daniele Pinna 3 and Maria Abbondanza Pantaleo 1,2 1 Department of Specialized, Experimental, and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 2 Interdepartmental Centre of Cancer Research “G. Prodi”, University of Bologna, Bologna, Italy 3 Department of General and Emergency Surgery and Organ Transplantation, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 4 Pathology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 5 Laboratory of Molecular Oncologic and Transplantation Pathology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy * These authors have contributed equally to the work Correspondence to: Maria Abbondanza Pantaleo, email: // Keywords : GIST, CCND2, NGS, PTEN, CDKN2C, DMD Received : May 04, 2015 Accepted : October 05, 2015 Published : November 02, 2015 Abstract About 85% of GISTs are associated with KIT and PDGFRα gene mutations, which predict response to tyrosine kinase inhibitors. Although the outcomes in patients affected by GIST have dramatically improved, tumor progression control still remains a challenge. The aim of this study is the genomic characterization of individual metastatic KIT-exon 11-mutant GIST to identify additional aberrations and simultaneous molecular events representing potential therapeutic targets. Seven patients with metastatic GIST were studied with whole transcriptome sequencing and copy number analysis. Somatic single nucleotide variations were called; however, no shared mutated genes were detected except KIT. Almost all patients showed loss of genomic regions containing tumor suppressor genes, sometimes coupled with single nucleotide mutation of the other allele. Additionally, six fusion transcripts were found and three patients showed amplifications involving known oncogenes. Evaluating the concordance between CN status and mRNA expression levels, we detected overexpression of CCND2 and EGFR and silencing of CDKN2A, CDKN2C, SMARCB1, PTEN and DMD. Altered expression of these genes could be responsible for aberrant activation of signaling pathways that support tumor growth. In this work, we assessed the effect of Hedgehog pathway inhibition in GIST882 cells, which causes decrement of cell viability associated with reduction of KIT expression. Additional genomic alterations not previously reported in GIST were found even if not shared by all samples. This contributes to a more detailed molecular understanding of this disease, useful for identification of new targets and novel therapeutics and representing a possible point of departure for a truly individualized clinical approach.
- Published
- 2015
17. miRNA profiling in gastrointestinal stromal tumors: implication as diagnostic and prognostic markers
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Margherita Nannini, Maria Abbondanza Pantaleo, Guido Biasco, Annalisa Astolfi, Gloria Ravegnini, Sabrina Angelini, Nannini, Margherita, Ravegnini, Gloria, Angelini, Sabrina, Astolfi, Annalisa, Biasco, Guido, and Pantaleo, Maria A
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Cancer Research ,medicine.medical_treatment ,Antineoplastic Agents ,PDGFRA ,Biology ,medicine.disease_cause ,Bioinformatics ,gastrointestinal stromal tumor ,NO ,Targeted therapy ,gastrointestinal stromal tumors ,microRNA ,Biomarkers, Tumor ,Genetics ,medicine ,Animals ,Humans ,Epigenetics ,Neoplasm Metastasis ,Protein Kinase Inhibitors ,Neoplasm Staging ,Chromosomes, Human, Pair 14 ,wild-type ,GiST ,Gene Expression Profiling ,KIT ,Prognosis ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,MicroRNAs ,Proto-Oncogene Proteins c-kit ,Imatinib mesylate ,Drug Resistance, Neoplasm ,Mutation ,Imatinib Mesylate ,Chromosome Deletion ,Neoplasm Grading ,Transcriptome ,Carcinogenesis - Abstract
MicroRNAs are a class of short noncoding RNAs, that play a relevant role in multiple biological processes, such as differentiation, proliferation and apoptosis. Gastrointestinal stromal tumors (GIST) are considered as a paradigm of molecular biology in solid tumors worldwide, and after the discovery of specific alterations in the KIT and PDGFRA genes, they have emerged from anonymity to become a model for targeted therapy. Epigenetics have an emerging and relevant role in different steps of GIST biology such as tumorigenesis, disease progression, prognosis and drug resistance. The aim of the present review was to summarize the current evidence about the role of microRNAs in GIST, including their potential application as well as their limits.
- Published
- 2015
18. Polymorphisms in DNA repair genes in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome
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Patrizia Hrelia, Milena Urbini, Maria Abbondanza Pantaleo, Giulia Sammarini, Muriel Assunta Musti, Maristella Saponara, Nicola Venturoli, Lidia Gatto, Gloria Ravegnini, Guido Biasco, Vittorio Simeon, Annalisa Astolfi, Margherita Nannini, Sabrina Angelini, Ravegnini, Gloria, Nannini, Margherita, Simeon, Vittorio, Musti, Muriel, Sammarini, Giulia, Saponara, Maristella, Gatto, Lidia, Urbini, Milena, Astolfi, Annalisa, Biasco, Guido, Pantaleo, Maria A, Venturoli, Nicola, Hrelia, Patrizia, Angelini, Sabrina, and Pantaleo, Maria A.
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0301 basic medicine ,Oncology ,Male ,Candidate gene ,Cancer Research ,DNA Repair ,medicine.disease_cause ,Bioinformatics ,DNA Glycosylases ,0302 clinical medicine ,XRCC3 ,Genotype ,DNA repair pathways ,Gastrointestinal Neoplasms ,Aged, 80 and over ,Mutation ,GiST ,General Medicine ,Middle Aged ,Prognosis ,Xeroderma Pigmentosum Group A Protein ,DNA-Binding Proteins ,Survival Rate ,DNA repair pathway ,030220 oncology & carcinogenesis ,Female ,GIST ,Adult ,medicine.medical_specialty ,DNA repair ,Gastrointestinal Stromal Tumors ,Imatinib ,Polymorphisms ,Biology ,NO ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,Allele ,Polymorphism ,Aged ,Neoplasm Staging ,Xeroderma Pigmentosum Group D Protein ,Polymorphism, Genetic ,Minor allele frequency ,030104 developmental biology ,DNA Repair Enzymes ,Follow-Up Studies - Abstract
DNA repair pathways play an essential role in cancer susceptibility by maintaining genomic integrity. This led us to investigate the influence of polymorphisms in the genes coding repair pathway enzymes on gastrointestinal stromal tumours (GIST) susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 20 polymorphisms in 11 genes in 81 cases and 147 controls. The XPD rs13181 wild-type allele and hOGG1 rs1052133 and XPF rs1800067 minor alleles were significantly associated with disease susceptibility. XPA rs1800975 and rs2808668 were associated with tumour size (P = 0.018), metastatic status at onset (P = 0.035) and mitotic index (P = 0.002). With regards to outcome treatment, the XPD rs50872 minor allele had a significant favourable impact on time to progression (TTP). Similarly, the XPC rs2228000 minor allele was correlated with a longer TTP (P = 0.03). On the contrary, the XPC rs2228001 and hOGG1 rs1052133 minor alleles were associated with a diminished TTP (P = 0.005 and P = 0.01, respectively). Regarding OS, we found the presence of at least one hOGG1 (rs1052133) minor allele that had a 60 % lower risk to die compared to the wild-type carriers (P = 0.04). Furthermore, the XRCC3 rs861539 variant allele is associated with a hazard of early death compared with the wild-type genotype (P = 0.04). To the best of our knowledge, this is the first study on polymorphisms in DNA repair genes, belonging to the different pathways, extensively evaluated in GIST patients. Through this multiple candidate gene approach, we report for the first time the significant associations between polymorphisms in DNA repair genes, susceptibility, clinical pathological features and clinical outcome in GIST.
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- 2016
19. Integrating miRNA and gene expression profiling analysis revealed regulatory networks in gastrointestinal stromal tumors
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Maria Abbondanza Pantaleo, Lidia Gatto, Massimo Negrini, Milena Urbini, Guido Biasco, Margherita Nannini, Sabrina Angelini, Gloria Ravegnini, Patrizia Hrelia, Donatella Santini, Manuela Ferracin, Valentina Indio, Giulia Sammarini, Annalisa Astolfi, Maristella Saponara, Vittorio Simeon, Pantaleo, Maria Abbondanza, Ravegnini, Gloria, Astolfi, Annalisa, Simeon, Vittorio, Nannini, Margherita, Saponara, Maristella, Urbini, Milena, Gatto, Lidia, Indio, Valentina, Sammarini, Giulia, Santini, Donatella, Ferracin, Manuela, Negrini, Massimo, Hrelia, Patrizia, Biasco, Guido, and Angelini, Sabrina
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Male ,0301 basic medicine ,Cancer Research ,Receptor, Platelet-Derived Growth Factor alpha ,Receptor, IGF Type 1 ,0302 clinical medicine ,IGF1R ,Gastrointestinal Neoplasms ,Aged, 80 and over ,Genetics ,let-7b ,GiST ,KIT ,Middle Aged ,GIST ,miR-455-5p ,miR139-5p ,PDGFRA ,WT-SDH deficient ,Gene Expression Regulation, Neoplastic ,Succinate Dehydrogenase ,Proto-Oncogene Proteins c-kit ,030220 oncology & carcinogenesis ,Female ,Adult ,Stromal cell ,Adolescent ,Gastrointestinal Stromal Tumors ,Socio-culturale ,macromolecular substances ,Biology ,Young Adult ,03 medical and health sciences ,microRNA ,Humans ,RNA, Messenger ,Aged ,Insulin-like growth factor 1 receptor ,Gene Expression Profiling ,CD44 ,Receptors, Somatomedin ,Cyclin-Dependent Kinase 6 ,digestive system diseases ,Gene expression profiling ,MicroRNAs ,030104 developmental biology ,biology.protein ,Cancer research ,Cyclin-dependent kinase 6 - Abstract
Aim: Currently, little is known about differences in miRNA expression between KIT/PDGFRA mutant and KIT/PDGFRA wild-type (WT)-SDH deficient gastrointestinal stromal tumors (GIST). This prompted us to perform an integrated multiple expression profile of miRNA and mRNA, constructing an original miRNA–mRNA regulatory network in KIT/PDGFRA WT-SDH deficient GIST patients. Patients & methods: Analyses were carried out on KIT/PDGFRA mutant versus KIT/PDGFRA WT-SDH deficient GIST. Genome-wide miRNA and gene-expression analysis were performed using Agilent Human miRNA microarray and Affimetrix array, respectively. Results: Three potential regulatory networks (IGF1R → miR-139-5p/miR-455/let-7b, cyclin-dependent kinase 6 (CDK6) → miR-139-5p/let-7b and CD44 → miR-330-3p) were identified. Conclusion: The miR-139-5p, 455-5p and let-7b signature, in particular, may represent an important therapeutic target in KIT/PDGFRA WT-SDH deficient GIST, usually characterized by IGF1R overexpression.
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- 2016
20. SDHC methylation in gastrointestinal stromal tumors (GIST): a case report
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Margherita Nannini, Milena Urbini, Maria Abbondanza Pantaleo, Gloria Ravegnini, Annalisa Astolfi, Valentina Indio, Guido Biasco, Christopher L. Corless, Michael Heinrich, Urbini, Milena, Astolfi, Annalisa, Indio, Valentina, Heinrich, Michael C, Corless, Christopher L, Nannini, Margherita, Ravegnini, Gloria, Biasco, Guido, and Pantaleo, Maria A
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Adult ,medicine.medical_specialty ,Stromal cell ,Gastrointestinal Stromal Tumors ,Case Report ,PDGFRA ,macromolecular substances ,Biology ,medicine.disease_cause ,Methylation ,NO ,Epigenesis, Genetic ,medicine ,Genetics ,SDHC, Methylation, Hypermethylation, GIST, dSDH GIST ,Humans ,Genetics(clinical) ,Hypermethylation ,Promoter Regions, Genetic ,neoplasms ,Genetics (clinical) ,Mutation ,SDHC ,GIST ,dSDH GIST ,GiST ,Wild type ,Cytogenetics ,High-Throughput Nucleotide Sequencing ,Membrane Proteins ,DNA Methylation ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,DNA methylation ,Cancer research ,CpG Islands ,Female - Abstract
Background Gastrointestinal stromal tumors (GIST) recently have been recognized as a genetically and biologically heterogeneous disease. In addition to KIT or PDGFRA mutated GIST, mutational inactivation of succinate dehydrogenase (SDH) subunits has been detected in the KIT/PDGFRA wild-type subgroup, referred to as SDH deficient (dSDH). Even though most dSDH GIST harbor mutations in SDHx subunit genes, some are SDHx wild type. Epigenetic regulation by DNA methylation of CpG islands recently has been found to be an alternative mechanism underlying the lack of SDH complex in GIST. Case presentation We report a particular case of dSDH GIST, previously analyzed with microarrays and next-generation sequencing, for which no molecular pathogenetic events have been identified. Gene expression analysis showed remarkable down-modulation of SDHC mRNA with respect to all other GIST samples, both SDHA-mutant and KIT/PDGFRA-mutant GIST. By a bisulfite methylation assay targeted to 2 SDHC CpG islands, we detected hypermethylation of the SDHC promoter. Conclusion Herein we report an additional case of dSDH GIST without SDHx mutation but harboring hypermethylation in the SDHC promoter, thus confirming the complexity of the molecular background of this subtype of GIST. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0233-7) contains supplementary material, which is available to authorized users.
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- 2015
21. Whole exome sequencing (WES) on formalin-fixed, paraffin-embedded (FFPE) tumor tissue in gastrointestinal stromal tumors (GIST)
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Milena Urbini, Maristella Saponara, Chiara Giusy Genovese, Margherita Nannini, Giovanni Brandi, Anna Mandrioli, Guido Biasco, Donatella Santini, Maria Abbondanza Pantaleo, Annalisa Astolfi, Valentina Indio, Giorgio Ercolani, Astolfi, Annalisa, Urbini, Milena, Indio, Valentina, Nannini, Margherita, Genovese, Chiara Giusy, Santini, Donatella, Saponara, Maristella, Mandrioli, Anna, Ercolani, Giorgio, Brandi, Giovanni, Biasco, Guido, and Pantaleo, Maria A
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Gastrointestinal stromal tumors (GIST) ,Formalin-fixed ,paraffin-embedded (FFPE) ,Fresh frozen tissue ,Next generation sequencing (NGS) ,Tissue Fixation ,Stromal cell ,Gastrointestinal Stromal Tumors ,Biology ,DNA sequencing ,NO ,Formaldehyde ,Genetics ,Humans ,Exome ,Formalin-fixed, paraffin-embedded (FFPE) ,Exome sequencing ,Paraffin Embedding ,GiST ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,DNA, Neoplasm ,Tumor tissue ,Molecular biology ,Random Amplified Polymorphic DNA Technique ,Gene expression profiling ,Mutation ,DNA microarray ,Research Article ,Biotechnology - Abstract
Background Next generation sequencing (NGS) technology has been rapidly introduced into basic and translational research in oncology, but the reduced availability of fresh frozen (FF) tumor tissues and the poor quality of DNA extracted from formalin-fixed, paraffin-embedded (FFPE) has significantly impaired this process in the field of solid tumors. To evaluate if data generated from FFPE material can be reliably produced and potentially used in routine clinical settings, we performed whole exome sequencing (WES) from tumor samples of Gastrointestinal stromal tumors (GIST), either extracted FF or FFPE, and from matched normal DNA. Methods We performed whole exome enrichment and sequencing at 100bp in paired end on four GIST samples, either from FFPE or fresh-frozen tissue, and from matched normal DNA. Results The integrity of DNA extracted from FFPE was evaluated by a modified RAPD PCR method, thus identifying high quality (HQ) and low quality (LQ) FFPE. DNA library production and exome capture was feasible for both classes of FFPE, despite the smaller yield and insert size of LQ-FFPE. WES produced data of equal quality from FF and FFPE, while only HQ-FFPE yielded an amount of data comparable to FF samples. Bioinformatic analysis showed that the percentage of variants called both in FF and FFPE samples was very high in HQ-FFPE, reaching 94-96 % of the total number of called variants. Classification of somatic variants by nucleotide substitution type showed that HQ-FFPE and FF had similar mutational profiles, while LQ-FFPE samples carried a much higher number of mutations than the FF counterpart, with a significant enrichment of C > T/G > A substitutions. Focusing on potential disease-related variants allowed the discovery of additional somatic variants in GIST samples, apart from the known oncogenic driver mutation, both from sequencing of FF and FFPE material. False positive and false negative calls were present almost exclusively in the analysis of FFPE of low quality. On the whole this study showed that WES is feasible also on FFPE specimens and that it is possible to easily select FFPE samples of high quality that yield sequencing results comparable to the FF counterpart. Conclusions WES on FFPE material may represent an important and innovative source for GIST research and for other solid tumors, amenable of possible application in clinical practice. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1982-6) contains supplementary material, which is available to authorized users.
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- 2015
22. Personalized Medicine in Gastrointestinal Stromal Tumor (GIST): Clinical Implications of the Somatic and Germline DNA Analysis
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Annalisa Astolfi, Guido Biasco, Margherita Nannini, Gloria Ravegnini, Giulia Sammarini, Maria Abbondanza Pantaleo, Sabrina Angelini, Patrizia Hrelia, Ravegnini, Gloria, Nannini, Margherita, Sammarini, Giulia, Astolfi, Annalisa, Biasco, Guido, Pantaleo, Maria A, Hrelia, Patrizia, and Angelini, Sabrina
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Receptor, Platelet-Derived Growth Factor alpha ,Gastrointestinal Stromal Tumors ,Somatic cell ,WT-GIST ,Review ,Catalysis ,Germline ,NO ,lcsh:Chemistry ,Inorganic Chemistry ,Humans ,Medicine ,Precision Medicine ,Physical and Theoretical Chemistry ,Stromal tumor ,Protein Kinase Inhibitors ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,Gastrointestinal Neoplasms ,personalized therapy ,drug resistance ,GiST ,business.industry ,Organic Chemistry ,biomarkers ,DNA, Neoplasm ,General Medicine ,Precision medicine ,Computer Science Applications ,Proto-Oncogene Proteins c-kit ,Imatinib mesylate ,lcsh:Biology (General) ,lcsh:QD1-999 ,KIT/PDGFRA mutant GIST ,GIST ,polymorphisms ,Immunology ,Imatinib Mesylate ,Cancer research ,biomarker ,Personalized medicine ,business - Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. They are characterized by gain of function mutations in KIT or PDGFRA tyrosine kinase receptors, with their consequent constitutive activation. The gold standard therapy is imatinib that offers a good and stable response for approximately 18–36 months. However, resistance is very common and it is vital to identify new biomarkers. Up until now, there have been two main approaches with focus to characterize novel targets. On the one hand, the focus is on the tumor genome, as the final clinical outcome depends mainly from the cancer specific mutations/alterations patterns. However, the germline DNA is important as well, and it is inconceivable to think the patients response to the drug is not related to it. Therefore the aim of this review is to outline the state of the art of the personalized medicine in GIST taking into account both the tumor DNA (somatic) and the patient DNA (germline).
- Published
- 2015
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