CDKN1B V109G Polymorphism a New Prognostic Factor in Sporadic Medullary Thyroid Carcinoma.

Context: CDKN1B codes for the cyclin-dependent kinase inhibitor p27Kip1, a cell-cycle regulatory protein. It is mutated in multiple endocrine neoplasia (MEN)-like syndromes in rats and humans and in several other tumors. The hallmark of MEN2 syndromes is medullary thyroid carcinoma (MTC) that can occur also sporadically. CDKN1B single nucleotide polymorphisms have been detected in several tumors; the T/G variant at codon 109 appears to have a protective effect in breast, hereditary prostate and pancreatic tumors. Objective and Design: We screened germline DNA from eighty-four patients affected by sporadic MTC and ninety matched controls for the CDKN1B V109G polymorphism by PCR amplification and sequencing of the amplicons and correlated with disease progression. We also tested all germline and fifty tumor tissue DNAs for RET proto-oncogene mutations. Computerized tomography, ultrasound scans and serum calcitonin were carried out before surgery and during the follow-up and associated with remission or recurrence. Results: The V109G polymorphism was detected at a frequency of 45.2%, was significantly associated with last post-operative calcitonin levels in the normal range and biochemical remission. Conversely, the wild type allele was associated with post-operative calcitonin levels above normal and a higher risk to develop clinical recurrence and distant metastases. Somatic RET mutations were significantly associated with a more aggressive behaviour especially in wild type allele-bearing patients. Conclusions: Collectively, in sporadic MTC the CDKN1B V109G polymorphism correlates with a more favourable disease progression than the wild type allele and might be considered a new promising prognostic marker.