DNA polymorphisms of several genes and predisposition to breast cancer

Background

Breast cancer is one of the major cancers around the world but its etiology is still not well understood. Only about 50% of the disease is associated with known risk factors including high-penetrance genes and lifestyle factors. Candidate low-penetrance genes are involved in a variety of pathways; for example, DNA damage by free radicals. The enzymes involved in this mechanism are N-acetyltransferase2 (NAT2) and manganese superoxide dismutase (MnSOD). NAT2 catalyzes acetylation of aromatic amines and hydrasines and forms of free radicals, and MnSOD catalyzes their dismutation. Genes TGFBR1 and RGS19IP1 encode proteins that take part in transforming growth factor beta signaling, mainly resulting in inhibition of cell proliferation. The first exon of TGFBR1 contains a polymorphic GCG repeat; (GCG)₆ was previously reported as the tumor susceptibility allele associated with some types of cancer. The 5'-untranslated region of RGS19IP1 contains a CGG repeat, the polymorphism of which had not been studied before.

Methods

SNPs of NAT2 and MnSOD were detected by the PCR-RFLP method, alleles of TGFBR1 were detected by electrophoresis and RGS19IP1 alleles were detected by fragment analysis on 123 breast cancer cases and 121 controls.

Results

We have assessed the frequency of frequent allelic variants of NAT2 (NAT2*4 [wild type], NAT2*5 [T341C], NAT2*6 [G590A], NAT2*7 [G857A]). The NAT2*11 allele in the Russian sample was found as well. Our breast cancer cases had statistically significant positive association with NAT2*6/*6 or NAT2*11 (33.4% vs 11.0%; P = 0.0005; OR = 3.06 [95% CI = 1.62-5.77], cases vs controls). The frequency of the NAT2*5 and NAT2*7 alleles was not significantly elevated in our breast cancer sample compared with controls. The MnSOD gene was studied for polymorphism of valine (V) versus alanine (A) in the leader peptide at position 16. The V/V genotype (MroNI^-/-) was associated with decreased risk of breast cancer (24.4% vs 38.0%; P = 0.0268; OR = 0.53 [95% CI = 0.03-0.91]). The risk of breast cancer decreased in a combination of NAT2*4, NAT2*5 or NAT2*7 alleles and V/V genotype MnSOD (20.3% vs 36.1%; P = 0.0068; OR = 0.45 [95% CI 0.25-0.79]).

Our breast cancer cases had statistically significant positive association with the (GCG)₆ allele of TGFBR1 (13.8% vs 6.1%, P = 0.016, OR = 2.47 [95% CI = 1.21-5.07]). Statistically significant positive association with the genotype 6A/9A (20.2% vs 11.6%, α = 0.05, OR = 1.92 [95% CI = 1.05-3.49]) was also revealed. Genotype 6A/9A can be used as a predisposition marker, the relative risk for this genotype carrier being increased 1.7-fold. We have identified a polymorphism of the CGG repeat in RGS19IP1 with at least eight alleles: four major (CGG₁₀–CGG₁₃), with frequencies 20.4%, 41.6%, 27.6% and 10.4%, respectively; the rest of the alleles are rare with overall frequency of 1% in control; heterozygosity, 0.729. Our breast cancer cases had statistically significant positive association with the rare alleles (4.7% vs 1%, P = 0.01, OR = 4.92 [95%, CI = 1.42-17.1]).

Conclusion

All polymorphisms tested could be used as a panel of markers for detecting families and individuals of high breast cancer risk.