TP53 codon 72 polymorphism in radiation-associated human papillary thyroid cancer

Abstract

The study investigated an association between the germline polymorphism at TP53 codon 72 and the development of papillary thyroid cancer (PTC) following exposure to radiation from the Chernobyl accident. TP53 genotype was examined in 48 pediatric/adolescent (age at diagnosis <18 years) and 68 adult post-Chernobyl patient with PTC, 53 adult patients with sporadic PTC and 313 healthy individuals from Russian-Ukrainian population. In addition, we evaluated loss of heterozygosity for TP53 and the allele expression ratio. The genotype of the patients was correlated with clinicopathological data. Arg TP53 homozygotes were found to be significantly underrepresented among adults with post-Chernobyl PTC, but not in children and adolescents when compared with sporadic PTC cases and the general population. In the tumors, cell transformation did not lead to allelic loss or biased TP53 allele expression in heterozygous individuals. None of TP53 genotypes specifically associated with tumor stage and morphology, however there were particular correlations with lymph node status in certain age groups of radiation-associated cases not seen in sporadic PTCs. The findings suggest TP53 allele combinations other than Arg/Arg may contribute to the risk of development of PTC in individuals exposed to radiation during their late childhood, adolescence or in young adulthood.

Genome-wide gene expression profiling suggests distinct radiation susceptibilities in sporadic and post-Chernobyl papillary thyroid cancers

“…This and the longlasting presence of these signatures support the susceptibility signature model. The recent finding that different TP53 alleles are associated with radiation exposure in adult PTC from Russian-Ukrainian patients (Rogounovitch et al, 2006) also supports this view. The susceptibility model, and the corollary that radiation susceptibility varies among individuals, may partly explain why only a minority of the population most exposed to radiation in Ukraine and Belarus developed PTC.…”

Polymorphisms of DNA damage response genes in radiation-related and sporadic papillary thyroid carcinoma

“…www.endocrinology-journals.org Rogounovitch et al (2006) in Russian healthy controls is also 0.28. Thus, the effect of population admixtures in the controls in our investigation could not be completely ruled out.…”

“…The study of codon 72 polymorphism in thyroid tumors from Russian and Ukrainian patients demonstrated a significantly lower frequency of wild-type homozygotes (i.e. Arg/Arg) among adults with IR-induced PTC when compared with sporadic PTC cases and general population (Rogounovitch et al 2006). Data obtained in the present work, using an independent set of samples, confirm these findings suggesting the modifying role (or as of a marker) of the TP53 Arg72Pro polymorphism in PTC developed after exposure to IR which is further supported by the absence of significant difference in genotype distributions among our two control groups.…”

“…All restriction endonucleases for PCR/RFLP were from New England BioLabs (Ipswich, MA, USA). TaqMan allelic discrimination assay for TP53 variants was done essentially as described previously (Rogounovitch et al 2006). Melting curve T m -shift assay for MTF1 genotyping was designed according to the described technology (Wang et al 2005) and done in a Thermal Cycler Dice Real Time System TP800 (TaKaRa, Ohtsu, Japan).…”

“…Data on the TP53 and XRCC3 polymorphisms associations are quite limited (Hillebrandt et al 1997, Boltze et al 2002, Granja et al 2004, Sturgis et al 2005, Rogounovitch et al 2006. Therefore, in this study, we addressed the relation of SNPs in aforementioned DNA damage response genes to the risk of PTCs of different etiology.…”