HVEM Gene Polymorphisms Are Associated with Sporadic Breast Cancer in Chinese Women

<div><p>As a costimulatory molecule, Herpesvirus entry mediator (HVEM) can bind with several costimulatory members, thus HVEM plays different roles in T cell immunity. HVEM and its ligands have been involved in the pathogenesis of various autoimmune, inflammatory diseases and tumors. In the current study, we conducted a case-control study comparing polymorphisms of HVEM and breast cancer. Subjects included 575 females with breast cancer and 604 age-matched healthy controls. Six HVEM SNPs (rs2281852, rs1886730, rs2234163, rs11573979, rs2234165, and rs2234167) were genotyped by PCR-RFLP. The results showed significant differences in genotypes and alleles between rs1886730 and rs2234167 (<i>P</i><0.05). One haplotype (CTGCGG) that was associated with breast cancer was found via haplotype analysis. Our research also indicated an association between polymorphisms of HVEM and clinicopathologic features, including lymph node metastasis, estrogen receptor, progesterone receptor and P53. Our results primarily indicate that polymorphisms of the HVEM gene were associated with the risk of sporadic breast cancer in northeast Chinese females.</p></div

Primers and PCR programs for HVEM PCR-RFLP genotyping.

<p>Primers and PCR programs for HVEM PCR-RFLP genotyping.</p

Haplotypes of HVEM gene.

<p>S1 = rs2281852, S2 = rs1886730, S3 = rs2234163, S4 = rs11573979, S5 = rs2234165, S6 = rs2234167.</p>*<p>correcting the P value for multiple testing by Haploview program using 10,000 permutations.</p

Clinicopathologic information of breast cancer patients.

<p>IDC infiltrative ductal carcinoma, MC medullary carcinoma, LN lymph node, TZ tumor size, ER estrogen receptor, PR progesterone receptor.</p

Allele frequencies of HVEM polymorphisms and their associations with breast cancer risk.

*<p>P<0.01 after correcting the P value for multiple testing by Haploview program using 10,000 permutations.</p><p>Rs2281852: cases n = 575, missing n = 0; controls n = 604, missing n = 0.</p><p>Rs1886730: cases n = 564, missing n = 11; controls n = 600, missing n = 4.</p><p>Rs2234163: cases n = 570, missing n = 5; controls n = 602, missing n = 2.</p><p>Rs11573979: cases n = 571, missing n = 4; controls n = 601, missing n = 3.</p><p>Rs2234165: cases n = 574, missing n = 1; controls n = 601, missing n = 3.</p><p>Rs2234167: cases n = 574, missing n = 1; controls n = 603, missing n = 1.</p

Investigation of CD28 Gene Polymorphisms in Patients with Sporadic Breast Cancer in a Chinese Han Population in Northeast China

<div><h3>Background</h3><p>CD28 is one of a number of costimulatory molecules that play crucial roles in immune regulation and homeostasis. Accumulating evidence indicates that immune factors influence breast carcinogenesis. To clarify the relationships between polymorphisms in the CD28 gene and breast carcinogenesis, a case-control study was conducted in women from Heilongjiang Province in northeast of China.</p> <h3>Methodology/Principal Findings</h3><p>Our research subjects consisted of 565 female patients with sporadic breast cancer and 605 age- and sex-matched healthy controls. In total, 12 single nucleotide polymorphisms (SNPs) in the CD28 gene were successfully determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The relationship between the CD28 variants and clinical features, including histological grade, tumor size, lymph node metastasis, human epidermal growth factor receptor 2 (C-erbB2), estrogen receptor (ER), progesterone receptor (PR), and tumor protein 53 (P53) status were analyzed. A statistically significant association was observed between rs3116496 and breast cancer risk under different genetic models (additive P = 0.0164, dominant P = 0.0042). Different distributions of the rs3116496 ‘T’ allele were found in patients and controls, which remained significant after correcting the P value for multiple testing using Haploview with 10,000 permutations (corrected P = 0.0384). In addition, significant associations were observed between rs3116487/rs3116494 (D’ = 1, r² = 0.99) and clinicopathological features such as C-erbB2 and ER status, in breast cancer patients.</p> <h3>Conclusions/Significance</h3><p>Our findings indicate that CD28 gene polymorphisms contribute to sporadic breast cancer risk and have a significant association with clinicopathological features in a northeast Chinese Han population.</p> </div

Genotype distribution of TNF-α, TNFRSF1A and TNFRSF1B gene polymorphisms.

<p>*The dominant model: comparing the combination of heterozygotes and minor allele homozygotes with the major allele homozygotes.</p>#<p>The recessive model: comparing minor allele homozygotes with the combination of heterozygotes and major allele homozygotes.</p><p>Abbreviations: OR = odds ratio; CI = confidence interval.</p

Alleles of the genotyped SNPs in CD28 gene.

1<p>Allele data was analyzed using Haploview 4.1. Significant values (<i>p</i><0.05) are in bold.</p>2<p><i>P</i> = 0.0384 after correcting <i>P</i> value for multiple testing by Haploview 4.1 program using 10,000 permutations.</p

Haplotypes distributions of TNF-α, TNFRSF1A and TNFRSF1B.

#<p>The order of SNPs in TNF-α is rs1800629 and rs361525.</p><p>*The order of SNPs in TNFRSF1A is rs767455, rs4149577 and rs1800693.</p>&<p>The order of SNPs in TNFRSF1A is rs1061622 and rs1061624.</p>a<p>P = 0.0065, ^bP = 0.0009 and ^cP = 0.0008 after correction for multiple testing.</p

Allele distribution of TNF-α, TNFRSF1A and TNFRSF1B SNPs.

a<p>P = 0.004 and ^bP = 0.003 after correction for multiple testing.</p><p>Abbreviations: OR = odds ratio; CI = confidence interval.</p