Allelic variant at -79 (C>T) in CDKN1B (p27Kip1) confers an increased risk of thyroid cancer and alters mRNA levels.
The aim of this study is to assess if common genetic variants located in the CDKN1B locus, coding for the cell cycle inhibitor p27(Kip1), are involved in thyroid cancer susceptibility. Based on the literature and functional predictions, we selected three polymorphisms within the CDKN1B gene (rs2066827 (T326G, V109G), rs34330 (-79C>T) and rs36228499 (-838C>A)) to perform the first case-control study in thyroid cancer involving this locus. We had 649 Spanish patients with sporadic thyroid cancer and 385 healthy representative controls available. Luciferase reporter gene assays, real-time quantitative reverse transcription-PCR and immunoblot experiments were carried out to demonstrate the putative effect of the associated variant. The polymorphism rs34330 (-79C>T) was identified as a risk factor for developing the follicular variant of papillary thyroid carcinoma (FVPTC), fitting a recessive model (odds ratio=2.12; 95% confidence interval=1.09-4.15; P value=0.023). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27(Kip1) promoter (P value <0.001). This effect was observed in -79TT genotype control carriers, who showed a tendency towards lower CDKN1B mRNA levels in lymphocytes, as well as at the protein level. This is the first study that identifies CDKN1B as a low-penetrance gene in thyroid cancer, and specifically in FVPTC subtype. We propose a reduced CDKN1B gene transcription depending on the genotype of the -79C>T (rs34330) variant as a novel mechanism underlying p27(Kip1) downregulation.
Landa
Iñigo
I
Spanish National Cancer Centre, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
Montero-Conde
Cristina
C
Malanga
Donatella
D
De Gisi
Silvia
S
Pita
Guillermo
G
Leandro-García
Luis-Javier
LJ
Inglada-Pérez
Lucía
L
Letón
Rocío
R
De Marco
Carmela
C
Rodríguez-Antona
Cristina
C
Viglietto
Giuseppe
G
Robledo
Mercedes
M
D018263:Adenocarcinoma, Follicular / Q000235:genetics*; D000483:Alleles; D018265:Carcinoma, Papillary, Follicular / Q000235:genetics*; D016022:Case-Control Studies; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics*; D012307:Risk Factors; D013030:Spain; D013964:Thyroid Neoplasms / Q000235:genetics*
D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27