Risk Of Cervical Squamous Cell Carcinoma Research Articles

Association between the rs3733846 in the flanking region of miR-143/145 and risk of cervical squamous cell carcinoma.

Aim: To investigate the effect of rs3733846 in the flanking region of miR-143/145 on susceptibility to cervical squamous cell carcinoma (CSCC). Materials & methods: We collected venous blood samples from 242 CSCC patients and 250 healthy controls. The rs3733846 polymorphism was genotyped by SnaPshot and Sanger sequencing. The expression of miR-143/145 in CSCC tissues was detected by quantitative real-time PCR. Results: The rs3733846 AG genotype was associated with a decreased risk of CSCC in genetic model (AGvs.AA: adjustedodds ratio [OR]: 0.44;95% CI: 0.30-0.66;p < 0.001). Patients with the rs3733846 AG/GG genotypes had a reduced risk of developing poorly differential status (OR: 0.57;95% CI: 0.33-0.98;p < 0.04) and lymph node metastasis (OR: 0.49;95% CI: 0.26-0.92;p < 0.03). Conclusion: The rs3733846 in the flanking region of miR-143/145 was related to the susceptibility of CSCC.

A Functional Variant rs2072915 is Associated with the Susceptibility and Mortality of Cervical Squamous Cell Carcinoma.

PurposeGenetic variant has been demonstrated to be a risk factor for the occurrence and outcome of cervical squamous cell carcinoma (CSCC). From previous genome wide association studies, 6p21.32 has been identified as a susceptibility locus of CSCC. The purpose of this study was to investigate the association of a polymorphism rs2072915 located in 6p21.32 with the risk of CSCC and examine the potential mechanism of the rs2072915 in CSCC pathogenesis.Patients and MethodsThe rs2072915 was genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism. miR-637 and RXRB mRNA expression levels in CSCC patients were examined using quantitative PCR. miR-637 target site was determined using the dual-luciferase reporter assay.ResultsThe rs2072915 was associated with a significantly increased risk (AA vs TT: adjusted OR = 2.48, 95% CI, 1.57–3.94, P < 0.001; AT/AA vs TT: adjusted OR = 1.38, 95% CI, 1.06–1.80, P = 0.018; A vs T: adjusted OR = 1.49, 95% CI, 1.21–1.84, P < 0.001, respectively) and shorter survival time of CSCC (P = 0.03). Patients with the rs2072915 AA genotype displayed lower levels of RXRB that is a target of miR-637.ConclusionThese findings suggest that the rs2072915 T > A change might augment the binding energy of miR-637 to RXRB, result in lower levels of RXRB, and thus contribute to the risk of CSCC.

Polymorphisms and haplotypes of TLR4, TLR9 and CYP1A1 genes possibly interfere with high-risk human papillomavirus infection and cervical cancer susceptibility in Jharkhand, India

BackgroundExpression and single nucleotide polymorphisms (SNPs) of TLR4/9 and CYP1A1 genes are vital for cervical squamous cell carcinoma (CSCC) but considerably vary in different populations. MethodsA total of 255-subjects from Jharkhand (130-cases, 125-controls) were utilized to obtain the expression/SNP status of TLR4/9, CYP1A1, and E6 (HPV16/18) by RT-PCR, WB, and allele-specific-PCR followed by sequencing. ResultsOver-expression of TLR4/9 and high infection of HPV16/18(78.5%) were found to be associated with CSCC. Among the seven SNPs(p1-p7) tested, the CT-genotype (p3:rs1927911; OR = 2.142; p = 0.004) and ‘T’-allele (p3; OR = 1.694; p = 0.0061) of TLR4; CC-genotype (p4:rs5743836; OR = 3.307; p = 0.0018), ‘C’-allele (p4; OR = 1.895; p = 0.0009), GA-genotype (p5:rs352140; OR = 2.064; p = 0.0172), AA-genotype (p5; OR = 2.602; p = 0.0021) and ‘A’-allele (p5; OR = 1.939; p = 0.0002) of TLR9; and the TC-genotype (p6:rs4646903; OR = 1.967; p = 0.0452) and GG-genotype (p7:rs1048943; OR = 2.336; p = 0.0287) and ‘G’-allele (p7; OR = 1.685; p = 0.0082) of CYP1A1 were associated with an increased-risk of CSCC. Similarly, the p3:CT-genotype (OR = 1.993; p = 0.0134); p4:CC-genotype (OR = 3.071; p = 0.0057) and ‘C’-allele (OR = 1.838; p = 0.0029); p5:AA-genotype (OR = 2.231; p = 0.0147) and ‘A’-allele (OR = 1.756; p = 0.0032); p6:TC-genotype (OR = 2.370; p = 0.02); and the p7:GG-genotype (OR = 2.255; p = 0.0488) and ‘G’-allele (OR = 1.691; p = 0.0118) showed an association with HPV16/18 infection. Conversely, TLR4 (p1-p2-p3:A-G-T; OR = 3.361; p = 0.029), TLR9 (p4-p5:C-A; OR = 1.786; p = 0.032) and CYP1A1 (p6-p7:C-G; OR = 1.783; p = 0.033) haplotypes with CSCC susceptibility was observed, whereas the TLR4 (p1-p2-p3:A-C-C; OR = 0.4675; p = 8.E-3) and TLR9 (p4-p5:T-G; OR = 0.3937; p = 0.00) haplotypes showed protection against the development of CSCC. Further, though p1:rs10759931 and p2:rs11536889 were found to be insignificant, the p3:CT-genotype, p5:GA/AA-genotype, and p7:GG-genotype were associated with elevated protein; the p4:CC-genotype and p6:TC-genotype were associated with increased mRNA compared to their respective-wild-type-groups. ConclusionThe present study revealed an association between TLR4/9 and CYP1A1 polymorphisms with increased HPV16/18 infection susceptibility and CSCC risk among the women of Jharkhand state.

A Functional Polymorphism in the Promoter of miR-17-92 is Associated with a Reduced Risk of Cervical Squamous Cell Carcinoma.

miR-17-92 cluster was differentially expressed in cervical cancer, playing an important role in regulating cell proliferation, apoptosis, migration, and invasion. The purpose of this study was to investigate the association between polymorphisms (i.e., rs9588884, rs982873, and rs1813389) in the promoter of miR-17-92 and the risk of cervical squamous cell carcinoma (CSCC). The rs9588884 polymorphism was genotyped using a Taqman assay and the rs982873 and rs1813389 polymorphisms were genotyped using a polymerase chain reaction-restriction fragment length polymorphism method. The expression levels of miR-17-92 were determined using a quantitative PCR analysis. The rs9588884 GG genotype was associated with a reduced risk of CSCC in homozygote comparison (adjusted OR = 0.47, 95% CI, 0.30-0.75, P = 0.001), dominant model (adjusted OR = 0.67, 95% CI, 0.50-0.91, P = 0.01), and recessive model (adjusted OR = 0.57, 95% CI, 0.38-0.85, P = 0.01). The rs9588884 G allele was also associated with a reduced risk of CSCC in allele comparison (adjusted OR = 0.71, 95% CI, 0.58-0.88, P = 0.002). Moreover, patients with the rs9588884 GG genotype had lower levels of miR-20a compared with the rs9588884 CC genotype (P = 0.03). These findings indicate that the rs9588884 GG genotype was associated with lower levels of miR-20a and eventually related to the risk of CSCC in Chinese women.

Long Noncoding RNA HULC Promoter Polymorphism rs1041279 Is Associated with an Increased Risk of Cervical Squamous Cell Carcinoma.

Hepatocellular carcinoma upregulated long noncoding RNA (HULC), identified as an oncogene in cervical cancer, is involved in not only the clinical stage, lymph node metastasis, and depth of cervical invasion but also outcome. In this study, we aimed to investigate the association between 3 polymorphisms (i.e., rs1041279, rs3005167, and rs7770772) in the promoter of HULC and the risk of cervical squamous cell carcinoma (CSCC). The polymorphisms were genotyped using the multiplex ligase detection reaction assay. The promoter activity was measured using the dual-luciferase reporter assay kit. The rs1041279 GG genotype and G allele revealed a significantly higher risk of CSCC compared with the rs1041279 CC genotype and C allele (GG vs. CC, adjusted OR = 1.79, 95% CI, 1.17-2.73, P = 0.007; G vs. C, adjusted OR = 1.36, 95% CI, 1.09-1.69, P = 0.006). Haplotype analysis revealed that the rs3005167C-rs7770772G-rs1041279C or rs3005167C-rs7770772G-rs1041279G haplotype had a significantly higher risk of CSCC compared to the rs3005167G-rs7770772G-rs1041279C haplotype (CGC vs. GGC, OR = 2.38, 95% CI, 1.53-3.75, P < 0.001; CGG vs. GGC, OR = 3.76, 95% CI, 2.12-6.68, P < 0.001). Dual-luciferase reporter assay showed that the rs1041279 G promoter resulted in higher transcriptional activity compared with the rs1041279 C (P < 0.01). Additionally, the rs1041279 GG genotype carriers had an increased level of HULC expression (P = 0.03). These findings suggest that the HULC rs1041279 may be a useful marker for the etiology of CSCC.

Association of the MUTYH Gln324His (CAG/CAC) variant with cervical carcinoma and HR-HPV infection in a Chinese population.

This study was performed to investigate the relationship between the MUTYH Gln324His (CAG/CAC) genotype and risk of cervical squamous cell carcinoma (CSCC) in a case-control setting. Mismatch amplification-polymerase chain reaction (MA-PCR) was applied to detect the polymorphism in 400 CSCC, 400 CIN III and 1200 control participants. The homozygous His324His (CAC/CAC) genotype of MUTYH was associated with significantly increased risk of CIN III (OR = 1.94) and CSCC (OR = 3.83). Increased risk of CIN III (OR = 1.34) and CSCC (OR = 1.97) was additionally observed with the heterozygous CAG/CAC genotype. Overall, individuals in both CAC/CAC and CAG/CAC genotype groups were at higher risk of cervical carcinoma (CINIII (OR = 1.46) and CSCC (OR = 2.34)). Within the HR-HPV infection-positive group, CAC/CAC and CAG/CAC genotypes were significantly enriched in relation to CIN III and CSCC. Moreover, we observed a positive correlation between the proportion of homozygous CAC/CAC MUTYH genotype and malignant prognostic factors of CSCC, such as cell differentiation grade and lymph node metastasis. These findings clearly highlight associations between the MUTYH Gln324His (CAG/CAC) polymorphism and susceptibility to CSCC, HR-HPV infection and specific prognostic factors, supporting the utility of this variant as an early indicator for patients at high risk of cervical carcinoma.

Genetic variants of the dUTPase-encoding gene DUT increase HR-HPV infection rate and cervical squamous cell carcinoma risk

Deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is involved in the repair and prevention of uracil misincorporations into DNA. Maintenance of DNA integrity is critical for cancer prevention. Many studies have identified susceptibility loci and genetic variants in cervical cancer. The aim of this study was to explore the distribution frequency of six single nucleotide polymorphisms (SNPs) in the dUTPase-encoding gene DUT in a case-control study to identify the relationship between DUT genetic variants and cervical cancer susceptibility. Six DUT intronic SNPs (rs28381106, rs3784619, rs10851465, rs28381126, rs3784621 and rs11637235) were genotyped by mismatch amplification-PCR in 400 cervical squamous cell carcinomas (CSCCs), 400 precursor cervical intraepithelial neoplasia (CIN) III lesions and 1,200 normal controls. No correlations were found between four DUT SNPs (rs3784621, rs10851465, rs28381106 and rs28381126) and CIN III and CSCC risk. However, the homozygous GG allele of rs3784619 and TT allele of rs11637235 correlated significantly with increased risk of CIN III and CSCC (OR = 2.29, 2.05; OR = 3.15, 3.15, respectively). Individuals with the G allele or G carrier allele (AG + GG) at rs3784619 and with the T allele or T carrier allele (CT + TT) at rs11637235 were at higher risk for CIN III and CSCC (OR = 1.26, 1.30; OR = 1.41, 1.65, respectively). Similarly, in the human papillomavirus (HPV)-positive groups, we found that the homozygous GG alleles of rs3784619 and TT alleles of rs11637235 markedly increased the risk of CIN III and CSCC (OR = 2.44, 2.71; OR = 3.32, 4.04, respectively). When performing a stratified analysis of sexual and reproductive histories, we found that the GG genotype of rs3784619 had a particularly high level of enrichment in the group of patients with > one sexual partner in CIN III (P = 0.043) and CSCC (P = 0.007). Meanwhile, the TT genotype of rs11637235 was enriched for in the high risk HPV (HR-HPV)-positive cases of CIN III (P = 0.033) and CSCC (P = 0.022). Analysis of the haplotype between rs3784619 (A/G) and rs11637235 (C/T) revealed that the genotypes with AA-TT (OR = 2.59), AG-TT (OR = 2.29), GG-CC (OR = 2.72), GG-CT (OR = 3.01 (1.83–4.96)) were significantly associated with increased risk of CIN III. More notably, this risk was much greater for CSCC (AA-TT (OR = 3.62), AG-TT (OR = 5.08), GG-CC (OR = 5.28), and GG-CT (OR = 4.23). Additionally, most GG genotypes of rs3784619 were linkage GG-CT, while most TT genotypes of rs11637235 were linkage AA-TT. In conclusion, these findings suggested that the homozygous GG allele of rs3784619 and the TT allele of rs11637235 in the DUT gene significantly increased the risk of CIN III and CSCC. Most GG genotypes of rs3784619 and TT genotypes of rs11637235 were linkage GG-CT and AA-TT, respectively. The TT genotype of rs11637235 was enriched in the HR-HPV-positive cases. These two SNPs of the DUT gene can be early predictive biomarkers of CIN III and CSCC, and may be involved in HR HPV infection.

Association of Base Excision Repair Gene hOGG1 Ser326Cys Polymorphism with Susceptibility to Cervical Squamous Cell Carcinoma and High-Risk Human Papilloma Virus Infection in a Chinese Population.

This study investigated the association of the human 8-oxoguanine glycosylase 1 (hOGG1) Ser326Cys polymorphism with risk of cervical squamous cell carcinoma (CSCC) and high-risk human papilloma virus (HR-HPV) infection. The hOGG1 Ser326Cys polymorphism is reported to be correlated with the risk of several cancers. However, there are reports that have found no significant differences in the frequency of the hOGG1 Ser326Cys between cervical carcinoma patients and controls. hOGG1 Ser326Cys was genotyped through modified allele mismatch amplification polymerase chain reaction in 1200 healthy controls, 400 cervical intraepithelial neoplasia (CIN) grade III cases, and 400 CSCC cases. The homozygous genotype of hOGG1 Cys326Cys (GG) was associated with increased risk of CIN III (odds ratio, OR = 1.81 [1.31-2.49], p < 0.001) and CSCC (OR = 3.05 [2.2-4.20], p < 0.001). The G allele or G carrier (GG + CG) genotype was a highly-significant risk factor for CSCC (OR = 1.49 [1.14-1.97], p = 0.004). In the HR-HPV-positive group, the homozygous genotype of hOGG1 GG was associated with increased risk of CSCC (OR = 3.66 [2.02-6.62], p < 0.001) and risk of CIN III (OR = 1.82 [1.08-3.06], p = 0.024). The proportion of G allele carriers was significantly increased in CIN III (51.9%, [322/620], OR = 1.33 [1.03-1.72], p = 0.028) and CSCC (62.1% [221/356], OR = 2.02 [1.51-2.71], p < 0.001). The GG and GC genotypes were consistently identified as significant risk factors for CSCC (OR = 1.73 [1.06-2.83], p = 0.029) in the HR-HPV infected group. We further observed enrichment of the hOGG1 Ser326Cys polymorphism in the CIN III (p = 0.021) and CSCC (p < 0.001) stratified by age at first intercourse, with more significant enrichment (p = 0.036) in the HR-HPV infection group. Our findings support associations of the hOGG1 Ser326Cys polymorphism with CSCC carcinogenesis and susceptibility to HR-HPV infection. The hOGG1 Ser326Cys polymorphism may serve as a potential genetic biomarker of susceptibility to cervical cancer and HR-HPV infection.

HLA-DQB1*03 and DRB1*07 alleles increase the risk of cervical cancer among Uighur and Han women in Xinjiang, China.

To explore the association between the determinant factors including HLA-DQB1*03, DRB1-*07, -*13 and high-risk HPV infection, the cervical squamous cell carcinoma (CSCC) pathogenesis among Chinese Uighur and Han population. HLA alleles were genotyped by PCR sequence-specific primers. HPV16 infection rate was significantly higher among the Uighurs and Hans with CSCC as compared with healthy controls, respectively. HLA-DQB1*03 significantly increased among Uighurs with CSCC, while HLA-DRB1*07 significantly increased among Hans with CSCC. Similar tendencies were observed for DQB1*03 with HPV16-positive Uighurs CSCC and DRB1*07 with HPV16-positive Hans CSCC. This study suggests that HLA-DQB1*03 and DRB1*07 alleles may influence the immune response to HPV16 infection and increase the risk of CSCC among the Uighurs and Hans in China.

Association between genetic polymorphisms in the promoters of let-7 and risk of cervical squamous cell carcinoma

Numerous reports showed low levels of let-7 family in cervical cancer, acting as tumor suppressors by regulating multiple target genes. Genetic variants in the promoter of miRNA have been reported to influence individuals' susceptibility to human diseases. We aimed to investigate the association of rs10877887 and rs13293512 polymorphisms in the promoters of let-7 with risk of cervical squamous cell carcinoma (CSCC). A total of 331 patients with CSCC and 358 controls were included. Genotyping of rs10877887 was done using polymerase chain reaction-restriction fragment length polymorphism analysis. Genotyping of rs13293512 was performed using Taqman allelic discrimination. Relative expression of let-7 family was determined using quantitative real-time polymerase chain reaction. The rs10877887CC genotype was significantly associated with an increased risk of CSCC compared with the rs10877887TT (adjusted OR=2.11, 95% CI, 1.31–3.40, p-value=0.002) or rs10877887 TT/CT genotypes (adjusted OR=2.11, 95% CI, 1.34–3.31, p-value<0.001). Similarly increased risk of CSCC was observed when compared rs10877887T with rs10877887C allele (adjusted OR=1.35, 95% CI, 1.08–1.69, p-value=0.008). Combined analysis showed that individuals carrying the genotypes of rs10877887CC+rs13293512CC had a 4.78-fold higher risk to develop CSCC compared with those carrying the genotypes of rs10877887CT/TT+rs13293512CT/TT (OR=4.78, 95% CI, 1.78–12.84, p-value=0.001). Additionally, patients harboring rs10877887CC genotype had a lower level of let-7i in CSCC tissues (p-value=0.02). This observation indicates that rs10877887 may be a useful biomarker for the etiology of CSCC.

A novel functional indel polymorphism within long non-coding RNAs growth arrest specific 5 conferred risk for cervical squamous cell carcinoma in Chinese Han populations

Background: Growth arrest specific 5 (GAS5) has been reported as a tumor repressor in multiple cancers, but the role of the indel polymorphism rs145204276 within GAS5 in cervical squamous cell carcinoma (CSCC) susceptibility has not been well established yet. Methods: A hospital based case-control study in Shehong and Xuzhou centers was performed to evaluate the potential association of the indel polymorphism rs145204276 within GAS5 with CSCC risk, and further in vivo and in vitro assays were applied to confirm the plausible association. Results: When taking ins/ins genotype as reference in codominant model, ins/del genotype confers a slightly increased risk for CSCC [odds ratio (OR) =1.27, 95% confidence interval (CI): 1.04–1.52, P=0.02], the homozygous del/del genotype shows an increased risk for CSCC (OR =2.24, 95% CI: 1.60–2.97, P trend in vivo and in vitro , and stratified analysis has revealed that the relation is more marked in subjects with postmenopausal status, tobacco consumption, or senior age (>49 years). Furthermore, the association of the polymorphism with CSCC risk is salient in cases with tumor stage IV (P=0.001). Conclusions: We have found that the novel functional indel polymorphism rs145204276 is associated with CSCC risk. Replication investigations and further functional assays are required for the current investigation.

ITPR3 gene haplotype is associated with cervical squamous cell carcinoma risk in Taiwanese women.

Host immunogenetic background plays an important role in human papillomavirus (HPV) infection and cervical cancer development. Inositol 1,4,5-triphosphate receptor type 3 (ITPR3) is essential for both immune activation and cancer pathogenesis. We aim to investigate if ITPR3 genetic polymorphisms are associated with the risk of cervical cancer in Taiwanese women. ITPR3 rs3748079 A/G and rs2229634 C/T polymorphisms were genotyped in a hospital-based study of 462 women with cervical squamous cell carcinoma (CSCC) and 921 age-matched healthy control women. The presence and genotypes of HPV in CSCC was determined. No significant association of individual ITPR3 variants were found among controls, CSCC, and HPV-16 positive CSCC. However, we found a significant association of haplotype AT between CSCC and controls (OR = 2.28, 95% CI 1.31–3.97, P = 2.83 × 10−3) and the OR increased further in CSCC patients infected with HPV-16 (OR = 2.89, 95% CI 1.55–5.37, P = 4.54 × 10−4). The linkage disequilibrium analysis demonstrated that ITPR3 association with CSCC was independent of HLA-DRB1 alleles. In conclusion, these findings suggest that AT haplotype in the ITPR3 gene may serve as a potential marker for genetic susceptibility to CSCC.

A Functional Polymorphism in the Promoter of MiR-143/145 Is Associated With the Risk of Cervical Squamous Cell Carcinoma in Chinese Women: A Case-Control Study.

MiR-143/145 is down-regulated in cervical cancer, which may serve as a tumor suppressor by targeting KRAS and Ras-responsive element-binding protein (RREB1). Activated KRAS leads to down-regulation of miR-143/145 transcription in a RREB1-dependent manner, establishing a miR-143/145-KRAS-RREB1 feedback loop. A polymorphism rs4705343C/T in the promoter of miR-143/145 might influence the binding of TATA-binding protein. We hypothesized that the miR-143/145 rs4705343 and KRAS rs712 may be related to the occurrence of cervical squamous cell carcinoma (CSCC). In this study, we genotyped the 2 polymorphisms in 415 patients with CSCC and 504 controls using polymerase chain reaction–restriction fragment length polymorphism. The promoter activities were measured by the Dual-Luciferase Reporter Assay System. We found that the rs4705343TC genotype was associated with an increased risk of CSCC (adjusted odds ratio [OR] = 1.37; 95% confidence interval [CI], 1.05–1.80). The significantly increased association was also observed in a dominant genetic model (adjusted OR = 1.32; 95% CI, 1.01–1.72). Combined analysis showed that individuals carrying the genotypes of rs4705343 TC/CC and rs712GT/TT had a 1.47-fold increased risk of CSCC (adjusted OR = 1.47; 95% CI, 1.01–2.15). By using multifactor dimensionality reduction software method, we identified a significant interaction between the miR-143/145 rs4705343 and KRAS rs712. Dual-Luciferase Reporter Assay showed that the luciferase activity was significantly lower in cells transfected with the rs4705343C allele than that of the rs4705343T allele. These findings indicate that miR-143/145 rs4705343 and KRAS rs712 may contribute to the etiology of CSCC in Chinese women.

Genetic susceptibility to cervical squamous cell carcinoma is associated with HLA-DPB1 polymorphisms in Taiwanese women.

Cervical cancer is a multifactorial disease, and increasing evidence suggests that host immunogenetic background may contribute to its pathogenesis. Genetic variations in human leukocyte antigen (HLA) genes may alter the efficiency of immune response to human papillomavirus (HPV) antigens and have been implicated in the risk of cervical cancer. We investigated whether polymorphisms in the HLA-DPB1 gene were associated with cervical cancer risk in a Taiwanese population. HLA-DPB1 alleles and +550 G/A polymorphism were genotyped in a case-control study of 473 women with cervical squamous cell carcinoma (CSCC) and 676 healthy controls. The presence and genotypes of HPV in CSCC were determined. We found that the DPB1*05:01 and +550 A alleles were associated with decreased and increased risk of CSCC, respectively [odds ratio (OR) = 0.72, Pc = 0.001; OR = 1.25, Pc = 0.03]. In subgroup analysis based on HPV type 16 positivity, significant associations were shown in the DPB1*05:01 and *13:01 alleles (OR = 0.65, Pc = 0.0007; OR = 1.83, Pc = 0.004). Furthermore, the DPB1*05:01-G and *13:01-G haplotypes conferred decreased and increased risk of both CSCC and HPV-16 positive CSCC women, respectively (OR = 0.72, Pc = 0.0009; OR = 0.63, Pc = 0.0004 for DPB1*05:01-G; OR = 1.55, Pc = 0.03; OR = 1.84, Pc = 0.004 for DPB1*13:01-G). A risk haplotype DPB1*02:01-A was also observed in the HPV-16 positive CSCC women (OR = 1.51, Pc = 0.05). These findings suggest that HLA-DPB1 gene is involved in the CSCC development.

Tagging Snps in the Excision Repair Cross-Complementing Group 4 (ERCC4)Gene Increased Risk of Cervical Squamous Cell Carcinoma (CSCC) and Modulate the Disease Outcome

Background: Given the important role of ERCC4 gene in multiple DNA repair systems, we hypothesized that genetic variations within this gene may be a cervical squamous cell carcinoma (CSCC) risk and disease modulatory factor.Methods: In population-based, case-control association study including 143 CSCC patients and 207 healthy women, two ERCC4tagSNPs were studied.Results: A significant protective effect against CSCC was observed assuming a dominant model in case of ERCC4rs3136176 ([AA]+[AT]vs.[TT]: p=0.04,OR=0.43), and genotype [AA] strongly protects against poorly (G3) differentiated CSCC (pcorreced=0.008,OR=0.15) and significantly increased the disease remission rate (p=0.05,OR=0.48).A statistically significant increase frequency of ERCC4rs1799798 [A] allele was seen in patients with well differentiated (G1) CSCC (p=0.02, OR=2.40). Contrary, an opposite trend was observed when G1 was compared with G2 (moderately differentiated) CSCC (p=0.06). Furthermore, ERCC4rs1799798 [A] allele tended to be increased in patients with carcinoma planoepitheliale keratodes (Cpk) (p=0.07).Haplotype ERCC4rs3136176[A]/ERCC4rs1799798[G] significantly decreased risk of G1 as well as G3 CSCC (p=0.02,OR=0.50, and p=0.017,OR=0.42, respectively) and only tended to decrease risk of CSCC (p=0.07,OR=0.758) as well as carcinoma planoepitheliale akeratodes (Cpa) (p=0.059,OR=0.71).In contrast haplotype AA significantly increased risk of G1 CSCC and risk of Cpk (p=0.01, OR=2.51, and p=0.049, OR=1.96, respectively), whereas haplotype TG increased risk of G3 CSCC (p=0.037, OR=2.17).The overall survival rates showed similar mean survival rates according to patients' genotypes at both studied SNPs.Conclusion: The above findings consistently suggested that genetic variants in ERCC4 gene may play significant role in CSCC pathophysiology.

Human leucocyte antigen-G polymorphisms are associated with cervical squamous cell carcinoma risk in Taiwanese women

BackgroundThe mere presence of human papillomavirus (HPV) is not enough for cervical cancer development and immunogenetic background may play an important role. Human leucocyte antigen (HLA)-G acts as a negative regulator of immune responses and its expression in tumour cells may enable them to avoid immune attack. We aim to study if polymorphisms in the HLA-G gene are associated with cervical cancer risk in Taiwanese women. Methods+1537 A/C, 14-bp deletion/insertion (Del/Ins), and +3142 G/C polymorphisms were genotyped in a hospital-based study of 317 women with cervical squamous cell carcinoma (CSCC) and 400 healthy control women frequency matched by age. The presence and genotypes of HPV in CSCC were determined. ResultsWe found the +3142 C/C genotype and C allele were associated with increased risk for CSCC (adjusted odds ratio [OR]=1.78, P=0.004; adjusted OR=1.31, P=0.014, respectively). In subgroup analysis based on HPV type 16 positivity, significant associations with higher adjusted ORs were found in +3142 C/C genotype and C allele (adjusted OR=2.19, P=0.001; adjusted OR=1.48, P=0.003, respectively) and +1537 C/C genotype and C allele frequencies increased significantly (adjusted OR=2.88, P=0.004; adjusted OR=1.69, P=0.0005, respectively). Furthermore, the C-Del-C haplotype conferred increased risk of both CSCC and HPV-16 positive CSCC women (adjusted OR=1.41, P=0.009; adjusted OR=1.94, P=0.0001, respectively). ConclusionThese findings suggest that HLA-G gene is involved in the susceptibility to CSCC.

Nucleotide variation in IL‐10 and IL‐12 and their receptors and cervical and vulvar cancer risk: A hybrid case–parent triad and case–control study

Given the important role of cell mediated immunity in viral clearance and control of premalignant lesions, we hypothesize that variation in the IL-12/IL-10 cytokine and cytokine receptor genes may influence cervical and vulvar cancer risk. We evaluated 76 tagSNPs from seven candidate genes (IL-10, IL-12A, IL-12B, IL-10RA, IL-10RB, IL-12RB1, and IL12RB2) in case-parent sets (n=43 cervical squamous cell carcinoma (SCC), n=96 cervical adenocarcinoma, n=53 vulvar SCC), additional cases (n=356 cervical SCC, n=406 cervical adenocarcinoma, and n=473 vulvar SCC) and population based controls (1,111). We calculated log-additive odds ratios (ORs) and 95% confidence intervals (CIs) for the association between tagSNP and cancer risk using a pseudo-likelihood based method which combined genotype information on cases, parents, and population controls. After correction for multiple comparisons, we identified several statistically significant SNP associations. Cervical SCC risk was associated with the minor alleles of the IL10RA rs9610 3' UTR SNP (OR=1.76, 95% CI=1.15-2.68) and two synonymous IL12RB2 SNPs (rs4297265, OR=0.46, 95% CI=0.26-0.82; rs2229546, OR=0.43, 95% CI=0.21-0.87). Cervical adenocarcinoma risk was associated with the minor alleles of the IL10RA rs4252314 intronic SNP (OR=2.23, 95% CI=1.26-3.96) and IL12RB1 rs11575934 non-synonymous SNP (OR=1.51, 95% CI=1.12-2.05). Finally, the minor allele of the IL12B rs3181224 3' UTR SNP was associated with a reduced risk of vulvar SCC (OR=0.30, 95% CI=0.12-0.74). These results raise the possibility that a shift in the balance of the immune response due to genetic variants in key cytokine genes could influence the development of cervical and vulvar cancer.

Genetic variation in DNA repair genes: ERCC4 and XRCC3 and cervical squamous cell carcinoma risk

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Association between two genetic variants of CD226 gene and Cervical Squamous Cell Carcinoma: A case–control study

Cervical carcinoma is a common gynecologic tumor severely influencing the health and life quality of women worldwide. CD226, a costimulatory molecule, is mainly participated in the activation and differentiation of T cells. Recent studies have investigated the association between two genetic variants (rs763361 and rs727088) of CD226 gene and many diseases. In order to evaluate whether these two variants are associated with Cervical Squamous Cell Carcinoma (CSCC), a case–control study including 349 CSCC patients and 380 unrelated healthy controls was carried out to determine the genotypes of these two variants by using the methods of polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing methods. Significantly increased CSCC risk was observed to be associated with G allele of rs727088 locus (OR=1.422, 95% CI=1.129–1.792). We have also observed that increased CSCC risk was statistically associated with rs727088 polymorphism in a dominant model (OR=1.41, 95% CI=1.05–1.89). Results of stratified analysis revealed that both rs763361 and rs727088 polymorphisms were not associated with clinical characters. Collectively, this study supports that rs727088 polymorphism may contribute to increased CSCC susceptibility.

Genetic polymorphisms in the ITPKC gene and cervical squamous cell carcinoma risk.

Cervical cancer is caused primarily by infection with oncogenic types of human papillomavirus (HPV). However, HPV infection alone is not sufficient for the progression to cervical cancer. Host immunogenetic factors may involve in the development of this disease. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is recently shown to act as a negative regulator of T-cell activation. We aim to study if polymorphisms in the ITPKC gene are associated with the risk of cervical cancer in Taiwanese women. ITPKC rs28493229 C/G, rs890934 G/T, rs2303723 C/T, and rs10420685 A/G polymorphisms were genotyped in a hospital-based study of 465 women with cervical squamous cell carcinoma (CSCC) and 800 age-matched healthy control women. The presence and genotypes of HPV in CSCC were determined. The frequency of G/G genotype and G allele of the ITPKC rs28493229 polymorphism was significantly higher in patients with CSCC compared with controls (OR = 1.81, 95 % CI 1.20-2.73, P = 0.005, P (c) = 0.02; OR = 1.70, 95 % CI 1.14-2.54, P = 0.008, P (c) = 0.03, respectively). No significant associations were found for other 3 polymorphisms. Haplotype analysis revealed the distribution of haplotype CGTA was significantly reduced in women with CSCC (OR = 0.59, 95 % CI 0.40-0.89, P = 0.01, P (c) = 0.04). In conclusion, we found the G/G genotype and G allele of the ITPKC rs28493229 polymorphism may contribute to the risk of CSCC in Taiwanese women. This finding provides new insights into the mechanisms of immune activation in cervical cancer.