Aims: We have studied whether TP53 rs1042522, rs17878362, and rs1625895 alleles having a protective effect against breast cancer (BC) will be lost in tumors, whereas those allowing disease development will be retained. Methods: Analysis of TP53 polymorphisms was performed in blood leukocytes and tumors from 80 Caucasian BC patients. In addition, TP53 loss of heterozygosity (LOH), methylation, and mutations were studied in tumor DNA of BC individuals with loss of alleles of TP53 polymorphisms. Results: In breast tumors of patients heterozygous for TP53 polymorphisms, we detected loss of rs1042522 C and G and rs17878362 A2 alleles; however, the loss of the C allele was preferential. We found that loss of TP53 alleles, namely rs1042522 C, has been caused by an LOH mechanism, namely TP53 deletions, whereas TP53 point mutations frequently occurred in the retained G allele (p=0.03). In addition, we showed that BC patients with rs1042522 CC genotype were characterized by only unifocal tumors and decreased frequency of lymph node metastases (p=0.03). Conclusions: Taken together, we showed the preferential loss of the rs1042522 C allele, which is protective against BC progression, in breast tumors. Also, the loss of the C allele, which encodes p53 protein with the best DNA repair cupability according to literature data, may create prerequisites for mutations, but not for methylation in a retained G variant, as we found here. However, these results need to be confirmed because of the limited statistical power of the present study and the small sampling.
To evaluate the potential for gene-gene interaction effects in sporadic breast cancer (BC) risk, we studied combinations of the fibroblast growth factor receptor 2 (FGFR2) rs1219648 and tumor protein 53 (TP53) rs1042522, rs1625895, and rs17878362 polymorphisms in BC patients (n=388) and healthy persons (n=275). In addition to a single-locus effect manifested by the association of FGFR2 rs1219648 and TP53 rs1042522 polymorphisms with high BC risk, depending on menopause status (0.001
d-Glucuronyl C5-epimerase (GLCE) is one of key enzymes in heparan sulfate biosynthesis and possesses tumour-suppressor function in breast carcinogenesis. Here, we investigated a potential involvement of GLCE polymorphism(s) in breast cancer development in Siberian women population. Comprehensive analysis of SNP databases revealed GLCE rs3865014 (Val597Ile) missense polymorphism as the main significantly present in human populations. According the TaqMan-based SNP assay, allele distributions for the rs3865014 (A>G) were similar in healthy Siberian women (n=136) and cancer patients (n=129) (A0,73:G0,27) and intermediate between the European and Asian populations, while genotype distributions were different, with the increase of AG rate in breast cancer patients (OR=1.76; 95% CI=1.04-1.90; P(Y)=0.035 ?(2)=4.44). Heterozygous AG genotype was associated with tumour size (OR=3.67, P(Y)=0.004), ER-negative tumours (OR=3.25, P(Y)=0.0028), triple-negative tumours (OR=4.94, P(Y)=0.015) but not menopausal status, PR and HER-2 status, local or distant metastasis. Homozygous GLCE genotypes (AA/GG) were more common for ER+PR+ luminal A breast cancer (OR=0.25, P(Y)=0.031). Loss-of-heterozigosity was identified in 5 of 51 breast tumours and the loss of G allele was associated with the decreased GLCE expression. Epidemiologic data for the GLCE SNP in different racial/ethnic groups demonstrated high AG genotype rates as a risk factor not for breast cancer incidence but for poor prognosis of the disease. The obtained data suggest an involvement of GLCE rs3865014 in breast cancer development. Heterozygous AG genotype might be a risk factor for breast cancer susceptibility in Siberian women and is associated with aggressive ER-negative and triple-negative cancer subtypes.
There are two regulatory single nucleotide polymorphisms (rSNPs) at the beginning of the second intron of the mouse K-ras gene that are strongly associated with lung cancer susceptibility. We performed functional analysis of three SNPs (rs12228277: T greater than A, rs12226937: G greater than A, and rs61761074: T greater than G) located in the same region of human KRAS. We found that rs12228277 and rs61761074 result in differential binding patterns of lung nuclear proteins to oligonucleotide probes corresponding two alternative alleles; in both cases, the transcription factor NF-Y is involved. G greater than A substitution (rs12226937) had no effect on the binding of lung nuclear proteins. However, all the nucleotide substitutions under study showed functional effects in a luciferase reporter assay. Among them, rs61761074 demonstrated a significant correlation with allele frequency in non-small-cell lung cancer (NSCLC). Taken together, the results of our study suggest that a T greater than G substitution at nucleotide position 615 in the second intron of the KRAS gene (rs61761074) may represent a promising genetic marker of NSCLC.