The TP53 codon 72 polymorphism and predisposition to adrenocortical cancer in Polish patients

Abstract

Abstract. The TP53 polymorphism occurs at codon 72 of exon 4 with two alleles encoding either arginine or proline. The association between this common polymorphism and risk of different cancers has been extensive studied, however various reports are controversial. We have analyzed the 72Pro polymorphic variant in patients with adrenocortical tumors to evaluate whether 72G➝C substitution at codon 72 of TP53 gene may be associated with increased risk for malignancy in adrenal cortex in comparison to the control group. DNA extracted from peripheral leucocytes of 46 Polish patients with adrenocortical tumors (17 malignant and 29 benign) and 50 controls was examined by PCR-HD method followed by direct sequencing. TP53 polymorphism in codon 72 was found in 47% of ACC cases, in 28% of patients with adenomas and in 24% of controls. The genotype Arg/Arg, Arg/Pro and Pro/Pro distribution was respectively 53%/ 35%/12% for cancers, 72%/28%/0% for benign tumors and 76%/24%/0% for controls. High frequency of 72Pro allele in patients with carcinoma (29%) in comparison to the benign tumors (14%) and controls (12%) was statistically analyzed. We found that 72Pro variant of TP53 gene was associated with a significantly increased risk of ACC (OR = 3.05; 95% CI = 1.17-7.91, p=0.03). Our results suggest that the TP53 codon 72 polymorphism could be associated with susceptibility for adrenocortical cancer in the examined Polish patients. IntroductionThe TP53 tumor suppressor gene, located on chromosome 17p13, is one of the most important protectors of genomic integrity. It controls cell growth and division, detects DNA damage and is involved in the process of transcription of genes that are responsible for DNA repair and apoptosis (1,2). The alterations in TP53 sequence which are associated with p53 protein inactivation are considered to play an important role in the process of carcinogenesis. Somatic mutations in TP53 gene are frequent genetic events observed in various human neoplasms with the frequencies varying from 10% to 60% (3,4). Germ-line mutations in TP53 are found in 70% families affected by Li-Fraumeni syndrome (LFS) and some of them are associated with familial predisposition to early onset cancers development in mutation carriers (5-7).The polymorphisms in TP53 gene, defined as DNA sequence variations, are localized mainly in introns. The functional consequence of intronic variations are speculated. It has been suggested that mutations in intron sequences may initiate aberrant mRNA splicing, influence coding region mutations or affect DNA-protein interactions (8-10). Only five polymorphisms were found in coding regions (exons) at codons 21, 36, 47, 72 and 213. Three of them (21, 36 and 213) are silent and do not change amino acid sequence (11-13). The codon 47 polymorphism is rare (14), while polymorphism in codon 72 is common. In various reports, the codon 72 polymorphism was considered as a potential risk factor for different neoplasms, particularly in lung, skin and head and neck carcinomas, but results are controvers...

Less common genotype variants of TP53 polymorphisms are associated with poor outcome in adult patients with adrenocortical carcinoma

“…The only previously described polymorphism in ACC patients is located in exon 4, codon 72 (R72P) (19). The more frequent genotype (G/G) was found in our collective in 51 patients (70.8%) and the less frequent genotypes (G/C nZ17, C/C nZ4) in 21 patients (29.2%).…”

“…For example, while Murata et al (18) reported lung cancer to be associated with the arginine variant of the R72P polymorphism, others observed a higher prevalence of the proline variant compared with controls in such patients (17). Similarly, in the only previous study on TP53 polymorphims in ACC patients, a threefold higher prevalence of the proline variant of the R72P polymorphism compared with controls was observed (19), although in our study no such difference of TP53 R72P alleles was observed using both a larger patient sample and a larger control group. However, although our patient sample is large for a rare cancer like ACC, it is still small in comparison with studies in other malignancies (7,16,37,38).…”

“…Murata et al (18) reported lung cancer to be associated with the arginine variant of the R72P polymorphism, whereas others observed a higher prevalence of the proline variant compared with controls in such patients (17). In the only previous study on TP53 polymorphisms in ACC patients, a threefold higher prevalence of the proline variant of the R72P polymorphism compared with controls was observed (19).…”

“…This assumption is supported by a small study from Poland that determined the sequence variants of the R72P polymorphism in a cohort (nZ17) of patients with ACC in comparison with a healthy control group and identified a threefold higher prevalence of the proline allele in codon 72 in patients with ACC. They concluded that the proline genotype may represent a possible risk factor for the development of ACC (19).…”

Expression of the zinc-finger transcription factor Snail in adrenocortical carcinoma is associated with decreased survival

“…Germline mutations of the tumour supressor p53 and overexpression of insulin-like growth factor 1 are well known to promote the development of ACC (Edgren et al, 1997;Ignaszak-Szczepaniak et al, 2006;Slater et al, 2006).…”