Association of p21 SNPs and risk of cervical cancer among Chinese women
BMC Cancer
Association of p21 SNPs and risk of cervical cancer among Chinese women
Ning Wang 0
Shizhuo Wang 0
Qiao Zhang 0
Yanming Lu 0
Heng Wei 0
Wei Li 0
Shulan Zhang 0
Duo Yin 0
Yangling Ou 0
0 Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University , Shenyang , China
Background: The p21 codon 31 single nucleotide polymorphism (SNP), rs1801270, has been linked to cervical cancer but with controversial results. The aims of this study were to investigate the role of p21 SNP-rs1801270 and other untested p21 SNPs in the risk of cervical cancer in a Chinese population. Methods: We genotyped five p21 SNPs (rs762623, rs2395655, rs1801270, rs3176352, and rs1059234) using peripheral blood DNA from 393 cervical cancer patients and 434 controls. Results: The frequency of the rs1801270 A allele in patients (0.421) was significantly lower than that in controls (0.494, p = 0.003). The frequency of the rs3176352 C allele in cases (0.319) was significantly lower than that in controls (0.417, p < 0.001).The allele frequency of other three p21 SNPs showed not statistically significantly different between patients and controls. The rs1801270 AA genotype was associated with a decreased risk for the development of cervical cancer (OR = 0.583, 95%CI: 0.399 - 0.853, P = 0.005). We observed that the three p21 SNPs (rs1801270, rs3176352, and rs1059234) was in linkage disequilibrium (LD) and thus haplotype analysis was performed. The AGT haplotype (which includes the rs1801270A allele) was the most frequent haplotype among all subjects, and both homozygosity and heterozygosity for the AGT haplotype provided a protective effect from development of cervical cancer. Conclusions: We show an association between the p21 SNP rs1801270A allele and a decreased risk for cervical cancer in a population of Chinese women. The AGT haplotype formed by three p21 SNPs in LD (rs1801270, rs3176352 and rs1059234) also provided a protective effect in development of cervical cancer in this population.
P21; Single nucleotide polymorphism; Cervical cancer; Haplotype
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Background
Cervical cancer is the second most common cancer in
women worldwide [1,2]. The human papilloma virus
(HPV) appears to be a necessary factor in the
development of almost all cases (> 90%) of cervical cancer [3].
The HPV E6 and E7 proteins are viral genes expressed
in virtually all HPV-positive cervical carcinomas, and
many experiments have shown that these are cooperative
viral oncoproteins [4] that inactivate p53 and
retinoblastoma (pRb) tumor suppressors, promoting
carcinogenesis [4,5].
HPV infection is relatively common while only a small
fraction of those infected develop cancer, suggesting that
additional environmental, genetic, or immunological
factors contribute to the progression to cervical cancer
[6,7]. Cell cycle progression is regulated by
cyclindependent kinases, crucial for normal growth and
differentiation. Disruption of cell cycle control is common in
cancer cells and is believed to play an essential role in
cancer initiation and development. The
cyclindependent kinase inhibitor p21 (also known as WAF1or
CIP1) is encoded by the CDKN1A gene located on
chromosome 6p21.2 [8,9]. The p21 protein binds to and
inhibits the activity of cyclin-CDK2 or -CDK4
complexes, and disrupts cell cycle progression at G1 phase
[10,11]. The expression of p21 is induced by the binding
of tumor suppressor protein p53 to the p21 promoter
[12-14]. The p21 protein can also interact with
proliferating cell nuclear antigen (PCNA), a DNA polymerase
accessory factor, and plays a regulatory role in S phase
DNA replication and DNA damage repair [15].
Therefore, alteration in the p21 functional and/or
promoter regions may adversely affect the regulation of
cellular proliferation and increase susceptibility to cancer.
Identification of several genetic variants in p21 have
been associated with cervical cancer [16,17]. The p21
single nucleotide polymorphism (SNP) rs1801270C/A,
which occurs in codon 31, results in an amino acid
substitution of arginine for serine. This polymorphism is
located in a highly conserved region of p21 and is
expected to affect its molecular function [18]. Prior
studies have linked the p21 codon 31 SNP (rs1801270) to
cervical cancer, with conflicting results [19,20]. In this
study, we genotyped five p21 SNPs (rs1801270 at codon
31, rs762623 and rs2395655 in the promoter region,
rs3176352 in an intron, and rs1059234 in the 3
noncoding region) in 393 cervical cancer patients and 434
cancer-free controls to look for any associations
between SNP alleles or genotypes and cervical cancer in a
Chinese population.
Methods
Before beginning this study, the study protocol was
approved by the Ethics Committee of our hospital
(Shengjing Hospital of China Medical University,
Shenyang, China).
Subjects
We ascertained 393 patients with cervical cancer between
October, 2008 and September, 2011 at the Shengjing
Hospital of China Medical University. Di (...truncated)