Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
1.
Genet Test Mol Biomarkers ; 20(12): 771-776, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27617348

ABSTRACT

AIMS: von Hippel-Lindau (VHL) disease is caused by mutations in the VHL tumor suppressor gene. As tumors that develop in the context of VHL also occur in a sporadic context, the frequency of this syndrome may be underestimated. Our aim was to identify VHL gene mutations in Argentinian patients who fulfilled the clinical criteria for type 1 VHL disease and in patients with VHL-associated manifestations that did not meet these criteria. METHODS: We performed a retrospective cohort study, including patients who met current diagnostic criteria for type 1 VHL (Group 1, n = 19) and patients with VHL-associated manifestations that did not meet these criteria (Group 2, n = 21). Genomic DNA was extracted from peripheral blood leukocytes. Mutation analysis involved DNA sequencing, while large deletions were determined by universal primer quantitative fluorescent multiplex polymerase chain reaction (UPQFM-PCR) and multiplex ligation-dependent probe amplification (MLPA) analysis. RESULTS: VHL mutations were detected in 16/19 (84.2%) patients in Group 1 and included: gross deletions (4/16); nonsense mutations (6/16); frameshift mutations (4/16); missense mutations (1/16); and splicing mutations (1/16). Three of these mutations were novel. No alterations were found in 3 of 19 VHL patients. In Group 2, one nonsense VHL mutation was detected in a young patient with a solitary central nervous system hemangioblastoma without familial history. A study of 30 first-degree relatives revealed four carriers with VHL mutations. CONCLUSIONS: We found three novel mutations in the VHL gene in our population. Our results emphasize the importance of a complete genetic study of VHL to confirm type 1 VHL disease, not only in patients with clinical diagnostic criteria but also in those presenting a single typical manifestation.


Subject(s)
Germ-Line Mutation , Von Hippel-Lindau Tumor Suppressor Protein/genetics , von Hippel-Lindau Disease/genetics , Adolescent , Adult , Aged , Argentina , Asian People/genetics , Child , Child, Preschool , Codon, Nonsense/genetics , Cohort Studies , DNA Mutational Analysis , Female , Frameshift Mutation/genetics , Hemangioblastoma/genetics , Humans , Male , Middle Aged , Multiplex Polymerase Chain Reaction , Mutation, Missense/genetics , Pedigree , Retrospective Studies , Sequence Deletion , Von Hippel-Lindau Tumor Suppressor Protein/blood , Von Hippel-Lindau Tumor Suppressor Protein/metabolism
2.
Cancer Chemother Pharmacol ; 74(4): 739-50, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25100134

ABSTRACT

PURPOSE: Sunitinib is a first-line advanced renal cell carcinoma (RCC) standard of care. In a randomized phase II trial comparing sunitinib treatment schedules, separate exploratory biomarker analyses investigated the correlations of efficacy with selected serum, germ line single-nucleotide polymorphism (SNP), or tumor markers. METHODS: Advanced RCC patients received first-line sunitinib 50 mg/day on the approved 4-week-on-2-week-off schedule (n = 146) or 37.5 mg/day continuous dosing (n = 146). The following correlation analyses were performed: (1) response evaluation criteria in solid tumors-defined tumor response with serum soluble protein levels via two distinct multiplex (n < 1,000) platforms; (2) response and time-to-event outcomes with germ line SNPs in vascular endothelial growth factor (VEGF)-A and VEGF receptor (VEGFR)3 genes; and (3) response and time-to-event outcomes with tumor immunohistochemistry status for hypoxia-inducible factor 1-alpha (HIF-1α) and carbonic anhydrase-IX or tumor Von Hippel-Lindau (VHL) gene inactivation status. RESULTS: Lower baseline angiopoietin-2 (Ang-2) and higher baseline matrix metalloproteinase-2 (MMP-2) levels were identified by both platforms as statistically significantly associated with tumor response. There were no significant correlations between VEGF-A or VEGFR3 SNPs and outcomes. Progression-free survival was longer for HIF-1α percent of tumor expression groups 0-2 (HIF-1α low) versus 3-4 (HIF-1α high; p = 0.034). There were no significant correlations between outcomes and each VHL inactivation mechanism [mutation (86% of VHL-inactive patients), methylation (14%), and large deletion (7%)] or mechanisms combined. CONCLUSIONS: Serum Ang-2 and MMP-2 and tumor HIF-1α were identified as relevant baseline biomarkers of sunitinib activity in advanced RCC, warranting further research into their prognostic versus predictive value.


Subject(s)
Angiopoietin-2/blood , Carcinoma, Renal Cell , Indoles , Kidney Neoplasms , Matrix Metalloproteinase 2/blood , Pyrroles , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor Receptor-3/genetics , Von Hippel-Lindau Tumor Suppressor Protein , Adult , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/pharmacokinetics , Antigens, Neoplasm/blood , Antigens, Neoplasm/genetics , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Carbonic Anhydrase IX , Carbonic Anhydrases/blood , Carbonic Anhydrases/genetics , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Disease-Free Survival , Drug Administration Schedule , Drug Monitoring/methods , Drug Screening Assays, Antitumor , Female , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/blood , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Indoles/administration & dosage , Indoles/adverse effects , Indoles/pharmacokinetics , Kidney Neoplasms/drug therapy , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Male , Polymorphism, Single Nucleotide , Prognosis , Pyrroles/administration & dosage , Pyrroles/adverse effects , Pyrroles/pharmacokinetics , Sunitinib , Treatment Outcome , Von Hippel-Lindau Tumor Suppressor Protein/blood , Von Hippel-Lindau Tumor Suppressor Protein/genetics
4.
Am J Physiol Renal Physiol ; 299(1): F1-13, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20444740

ABSTRACT

The kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood cell production. Efforts to understand the molecular basis of oxygen-regulated erythropoiesis have led to the identification of erythropoietin (EPO), which is essential for normal erythropoiesis and to the purification of hypoxia-inducible factor (HIF), the transcription factor that regulates EPO synthesis and mediates cellular adaptation to hypoxia. Recent insights into the molecular mechanisms that control and integrate cellular and systemic erythropoiesis-promoting hypoxia responses and their potential as a therapeutic target for the treatment of renal anemia are discussed in this review.


Subject(s)
Erythrocytes/metabolism , Erythropoiesis , Erythropoietin/blood , Hypoxia/blood , Iron/blood , Oxygen/blood , Anemia/blood , Anemia/drug therapy , Anemia/genetics , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Bone Marrow/metabolism , Erythrocytes/drug effects , Erythropoiesis/drug effects , Erythropoiesis/genetics , Erythropoietin/biosynthesis , Erythropoietin/genetics , Gene Expression Regulation , Hematinics/therapeutic use , Homeostasis , Humans , Hypoxia/genetics , Kidney/metabolism , Polycythemia/blood , Polycythemia/genetics , Procollagen-Proline Dioxygenase/genetics , Procollagen-Proline Dioxygenase/metabolism , Protein Processing, Post-Translational , Von Hippel-Lindau Tumor Suppressor Protein/blood , Von Hippel-Lindau Tumor Suppressor Protein/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...