title: Germline Polymorphisms of the VEGF Pathway Predict Recurrence in Nonadvanced Differentiated Thyroid Cancer.
abstract: Tumor angiogenesis is determined by host genetic background rather than environment. Germline single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) pathway have demonstrated prognostic value in different tumors.
  
  
  
  Our main objective was to test the prognostic value of germline SNPs of the VEGF pathway in nonadvanced differentiated thyroid cancer (DTC). Secondarily, we sought to correlate analyzed SNPs with microvessel density (MVD).
  
  
  
  Multicenter, retrospective, observational study.
  
  
  
  Four referral centers.
  
  
  
  Blood samples were obtained from consecutive DTC patients. Genotyping was performed according to the TaqMan protocol, including 4 VEGF-A (-2578C>A, -460T>C, +405G>C, and +936C>T) and 2 VEGFR-2 (+1192 C>T and +1719 T>A) SNPs. MVD was estimated by means of CD34 staining.
  
  
  
  Rate of recurrent structural disease/disease-free survival (DFS). Difference in MVD between tumors from patients with different genotype.
  
  
  
  Two hundred four patients with stage I-II DTC (mean follow-up, 73 ± 64 months) and 240 patients with low- to intermediate-risk DTC (mean follow-up, 70 ± 60 months) were enrolled. Two "risk" genotypes were identified by combining VEGF-A SNPs -2578 C>A, -460 T>C, and +405 G>C. The ACG homozygous genotype was protective in both stage I-II (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.01 to 1.43; P = 0.018) and low- to intermediate-risk (OR, 0.14; 95% CI, 0.01 to 1.13; P = 0.035) patients. The CTG homozygous genotype was significantly associated with recurrence in stage I-II (OR, 5.47; 95% CI, 1.15 to 26.04; P = 0.018) and was slightly deleterious in low- to intermediate-risk (OR, 3.39; 95% CI, 0.8 to 14.33; P = 0.079) patients. MVD of primary tumors from patients harboring a protective genotype was significantly lower (median MVD, 76.5 ± 12.7 and 86.7 ± 27.9, respectively; P = 0.024).
  
  
  
  Analysis of germline VEGF-A SNPs could empower a prognostic approach to DTC.
authors.affiliation: IOS & COLEMAN Srl, 80143, Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Marotta
authors.affiliation: IOS & COLEMAN Srl, 80143, Naples, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Sciammarella
authors.affiliation: CEINGE Biotecnologie Avanzate and.
authors.forename: Mario
authors.initials: M
authors.lastname: Capasso
authors.affiliation: CEINGE Biotecnologie Avanzate and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Testori
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University, 80131, Naples, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pivonello
authors.affiliation: Thyroid and Parathyroid Surgery Unit and.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Chiofalo
authors.affiliation: Department of Anesthesiologic, Surgical and Emergency Sciences, Division of General and Oncologic Surgery, Second University of Naples, 80131, Naples, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Gambardella
authors.affiliation: San Giovanni di Dio e Ruggi D'Aragona, Universitary Hospital, and Division of General Surgery, University of Salerno, 84131, Salerno, Italy; and.
authors.forename: Marica
authors.initials: M
authors.lastname: Grasso
authors.affiliation: Division of General Surgery, Sant' Ottone Frangipane Hospital, 83031, Ariano Irpino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Antonino
authors.affiliation: Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS "Fondazione G. Pascale," 80131, Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Annunziata
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University, 80131, Naples, Italy.
authors.forename: Paolo Emidio
authors.initials: PE
authors.lastname: Macchia
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University, 80131, Naples, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Pivonello
authors.affiliation: Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS "Fondazione G. Pascale," 80131, Naples, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Santini
authors.affiliation: Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS "Fondazione G. Pascale," 80131, Naples, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.affiliation: Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori-IRCCS "Fondazione G. Pascale," 80131, Naples, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Losito
authors.affiliation: Thyroid and Parathyroid Surgery Unit and.
authors.forename: Luciano
authors.initials: L
authors.lastname: Pezzullo
authors.affiliation: Department of Clinical Medicine and Surgery, Federico II University, 80131, Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
authors.affiliation: Thyroid and Parathyroid Surgery Unit and.
authors.forename: Antongiulio
authors.initials: A
authors.lastname: Faggiano
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D055806:Microvessels / Q000473:pathology*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012189:Retrospective Studies; D013964:Thyroid Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2