Germline polymorphisms of the VEGF pathway predict recurrence in nonadvanced differentiated thyroid cancer

Vincenzo Marotta, Concetta Sciammarella, Mario Capasso, Alessandro Testori, Claudia Pivonello, Maria Grazia Chiofalo, Claudio Ambardella, Marica Grasso, Antonio Antonino, Annamaria Annunziata, Paolo Emidio Macchia, Rosario Pivonello, Luigi Santini, Gerardo Botti, Simona Losito, Luciano Pezzullo, Annamaria Colao, Antongiulio Faggiano

Research output: Contribution to journalArticlepeer-review


Context: 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. Objectives: 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). Design: Multicenter, retrospective, observational study. Setting: Four referral centers. Patients: Blood samples were obtained from consecutive DTC patients. Genotyping was performed according to the TaqMan protocol, including 4 VEGF-A (22578C>A, 2460T>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. Outcome Measures: Rate of recurrent structural disease/disease-free survival (DFS). Difference in MVD between tumors from patients with different genotype. Results: 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 6 60 months) were enrolled. Two "risk" genotypes were identified by combining VEGF-A SNPs 22578 C>A, 2460 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) andwas slightly deleterious in lowto 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). Conclusions: Analysis of germline VEGF-A SNPs could empower a prognostic approach to DTC.

Original languageEnglish
Pages (from-to)661-671
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Issue number2
Publication statusPublished - Feb 1 2017

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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