Association of Single Nucleotide Polymorphisms in Wnt Signaling Pathway Genes with Breast Cancer in Saudi Patients

Breast cancer is a complex heterogeneous disease involving genetic and epigenetic alterations in genes encoding proteins that are components of various signaling pathways. Candidate gene approach have identified association of genetic variants in the Wnt signaling pathway genes and increased susceptibility to several diseases including breast cancer. Due to the rarity of somatic mutations in key genes of Wnt pathway, we investigated the association of genetic variants in these genes with predisposition to breast cancers. We performed a case-control study to identify risk variants by examining 15 SNPs located in 8 genes associated with Wnt signaling. Genotypic analysis of individual locus showed statistically significant association of five SNPs located in β-catenin, AXIN2, DKK3, SFRP3 and TCF7L2 with breast cancers. Increased risk was observed only with the SNP in β-catenin while the other four SNPs conferred protection against breast cancers. Majority of these associations persisted after stratification of the cases based on estrogen receptor status and age of on-set of breast cancer. The rs7775 SNP in exon 6 of SFRP3 gene that codes for either arginine or glycine exhibited very strong association with breast cancer, even after Bonferroni''s correction. Apart from these five variants, rs3923086 in AXIN2 and rs3763511 in DKK4 that did not show any association in the overall population were significantly associated with early on-set and estrogen receptor negative breast cancers, respectively. This is the first study to utilize pathway based approach to identify association of risk variants in the Wnt signaling pathway genes with breast cancers. Confirmation of our findings in larger populations of different ethnicities would provide evidence for the role of Wnt pathway as well as screening markers for early detection of breast carcinomas.     

Genetic variants in the WNT signaling pathway are protectively associated with colorectal cancer in a Saudi population

The Wnt/β-catenin signaling pathway has been etiologically implicated in the development and progression of colorectal cancer. We studied thirteen single nucleotide polymorphisms (SNPs) located in SFRP3 (rs7775), CTNNB1 (β-catenin) [rs4135385, rs13072632], APC (rs454886, rs459552), LRP6 (rs2075241, rs2284396), DKK4 (rs3763511), DKK3 (rs6485350), TCF4 (rs12255372) and AXIN2 (rs3923086, rs3923087, rs4791171) in patients with colorectal cancer (n?=?122) and controls (n?=?110). Evaluation of WNT pathway SNPs showed protective association for rs4135385, located in β-catenin. Additionally, variants in SFRP3 (rs7775) and LRP6 (rs2284396) which did not show any association in the overall analysis were significantly associated with female and old aged colorectal cancer patients, respectively.     

Laryngeal cancer risk and common single nucleotide polymorphisms in nucleotide excision repair pathway genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5 and XPA

Because the molecular mechanisms underlying the development of laryngeal cancer are not well understood, we conducted a case–control study to determine the association between eight common SNPs in NER pathway genes and risk of laryngeal cancer, and the association between genetic polymorphisms and environmental factors. A 1:1 matched case–control study of 176 cases and 176 controls was conducted. Laryngeal cancer cases were more likely to smoke and drink (all P values < 0.05). Subjects with the ERCC1 rs11615 CC genotype and C allele had an increased risk of laryngeal cancer. Similarly, individuals with the ERCC5 rs17655 GG genotype and G allele had an increased risk of laryngeal cancer. Gene–gene interaction analysis showed that subjects carrying ERCC1 rs11615 C allele and XPG/ERCC5 rs17655 G allele had a greatly increased risk of breast cancer. Stratified analysis revealed that the interaction between polymorphisms of ERCC1 rs11615 and ERCC5 rs17655 and smoking on cancer risk was statistically significant, and ERCC1 rs11615 polymorphisms also had a significant interaction with drinking habit. In conclusion, our study suggests that ERCC1 rs11615 and ERCC5 rs17655 polymorphisms are associated with increased risk of laryngeal cancer, and that they confer more risk among smokers and drinkers.     

Selected polymorphisms in sex hormone-related genes, circulating sex hormones and risk of endometrial cancer

Background: The role of estrogen and progesterone in the development of endometrial cancer is well documented. Few studies have examined the association of genetic variants in sex hormone-related genes with endometrial cancer risk. Methods: We conducted a case-control study nested within three cohorts to examine the association of endometrial cancer risk with polymorphisms in hormone-related genes among 391 cases (92% postmenopausal at diagnosis) and 712 individually-matched controls. We also examined the association of these polymorphisms with circulating levels of sex hormones and SHBG in a cross-sectional analysis including 596 healthy postmenopausal women at blood donation (controls from this nested case-control study and from a nested case-control study of breast cancer in one of the three cohorts). Results: Adjusting for endometrial cancer risk factors, the A allele of rs4775936 in CYP19 was significantly associated (OR(per allele)=1.22, 95% CI=1.01-1.47, p(trend)=0.04), while the T allele of rs10046 was marginally associated with increased risk of endometrial cancer (OR(per allele)=1.20, 95% CI=0.99-1.45, p(trend)=0.06). PGR rs1042838 was also marginally associated with risk (OR(per allele)=1.25, 95% CI=0.96-1.61, p(trend)=0.09). No significant association was found for the other polymorphisms, i.e. CYP1B1 rs1800440 and rs1056836, UGT1A1 rs8175347, SHBG rs6259 and ESR1 rs2234693. Rs8175347 was significantly associated with postmenopausal levels of estradiol, free estradiol and estrone and rs6259 with SHBG and estradiol. Conclusion: Our findings support an association between genetic variants in CYP19, and possibly PGR, and risk of endometrial cancer.     

Genetic predisposition of six well‐defined polymorphisms in HMGB1/RAGE pathway to breast cancer in a large Han Chinese population

Breast cancer constitutes an enormous burden in China. A strong familial clustering of breast cancer suggests a genetic component in its carcinogenesis. To examine the genetic predisposition of high mobility group box‐1/receptor for advanced glycation end products (HMGB1/RAGE) pathway to breast cancer, we genotyped six well‐defined polymorphisms in this pathway among 524 breast cancer patients and 518 cancer‐free controls from Heilongjiang province, China. There were no deviations from Hardy–Weinberg equilibrium for all polymorphisms. In single‐locus analysis, the frequency of rs1800624 polymorphism mutant A allele in RAGE gene was significantly higher in patients than in controls (24.52% versus 19.50%, P = 0.006), with the carriers of rs1800624‐A allele being 1.51 times more likely to develop breast cancer relative to those with rs1800624‐GG genotype after adjustment (95% confidence interval or CI: 1.17–1.94, P = 0.001). In HMGB1 gene, haplotype analysis did not reveal any significance, while in RAGE gene, haplotypes C‐T‐A and C‐A‐G (alleles in order of rs1800625, rs18006024, rs2070600) were significantly associated with an increased risk of breast cancer (adjusted OR = 2.72 and 10.35; 95% CI: 1.20–6.18 and 1.58–67.80; P = 0.017 and 0.015 respectively). In further genetic score analysis, per unit and quartile increments of unfavourable alleles were significantly associated with an increased risk of breast cancer after adjustment (odds ratio or OR = 1.20 and 1.26; 95% CI: 1.09–1.32 and 1.12–1.42; P < 0.001 and <0.001 respectively). Our findings altogether demonstrate a significant association between RAGE gene rs1800624 polymorphism and breast cancer risk, and more importantly a cumulative impact of multiple risk associated polymorphisms in HMGB1/RAGE pathway on breast carcinogenesis.     

Association of single nucleotide polymorphisms of ERCC1 and XPF with colorectal cancer risk and interaction with tobacco use

We investigated the association between polymorphisms in excision repair cross-complementation group 1 (ERCC1) (rs3212986, rs2298881 and rs11615) and xeroderma pigmentosum-complementation group F (XPF) (rs2276466 and rs6498486) and risk of colorectal cancer. A 1:1 matched case–control study was conducted. Conditional regression analysis indicated that individuals carrying the ERCC1 rs3212986 TT genotype and T allele had a marginally increased risk of colorectal cancer when compared with subjects with the GG genotype. Similarly, subjects carrying the rs11615 TT genotype and T allele had a marginally increased risk of colorectal cancer when compared with those with the CC genotype. Stratified analysis revealed that individuals with rs3212986 TT who were current or former smokers had a significantly increased risk of colorectal cancer, and a significant interaction was found between this SNP and cigarette smoking. In conclusion, our study suggests that rs3212986 and rs11615 polymorphisms are associated with risk of colorectal cancer in a Chinese population, particularly in smokers. This finding could be useful in revealing the genetic characteristics of colorectal cancer, and suggests more effective strategies for prevention and treatment.     

Association of Polymorphisms and Haplotypes in the Insulin-Like Growth Factor 1 Receptor (IGF1R) Gene with the Risk of Breast Cancer in Korean Women

The insulin-like growth factor (IGF) signaling pathway plays an important role in cancer biology. The IGF 1 receptor (IGF1R) overexpression has been associated with a number of hematological neoplasias and solid tumors including breast cancer. However, molecular mechanism involving IGF1R in carcinogenic developments is clearly not known. We investigated the genetic variations across the IGF1R polymorphism and the risk of breast cancer risk in Korean women. A total of 1418 individuals comprising 1026 breast cancer cases and 392 age-matched controls of Korean were included for the analysis. Genomic DNA was extracted from whole blood and single nucleotide polymorphisms (SNPs) were analyzed on the GoldenGate Assay system by Illumina’s Custom Genetic Analysis service. SNPs were selected for linkage disequilibrium (LD) analysis by Haploview. We genotyped total 51 SNPs in the IGF1R gene and examined for association with breast cancer. All the SNPs investigated were in Hardy-Weinberg equilibrium. These SNPs tested were significantly associated with breast cancer risk, after correction for multiple comparisons by adjusting for age at diagnosis, BMI, age at menarche, and age at first parturition. Among 51 IGF1R SNPs, five intron located SNPs (rs8032477, rs7175052, rs12439557, rs11635251 and rs12916884) with homozygous genotype (variant genotype) were associated with decreased risk of breast cancer. Fisher’s combined p-value for the five SNPs was 0.00032. Three intron located SNPs with heterozygous genotypes also had decreased risk of breast cancer. Seven of the 51 IGF1R SNPs were in LD and in one haplotype block, and were likely to be associated with breast cancer risk. Overall, this case-control study demonstrates statistically significant associations between breast cancer risk and polymorphisms in IGF1R gene.     

Genetic variants in the microRNA machinery gene GEMIN4 are associated with risk of prostate cancer: a case-control study of the Chinese Han population

Single-nucleotide polymorphisms located in the microRNA biogenesis pathway could alter the risk for developing prostate cancer. The present study was intended to identify common genetic variants responsible for prostate cancer susceptibility in the GEMIN4 gene. The high-resolution melting method was used to genotype seven polymorphisms (rs7813, rs4968104, rs3744741, rs2740348, rs1062923, rs910925, and rs910924) in the GEMIN4 gene in 300 prostate cancer patients and 244 matched controls. The encouraging discovery in this study was in the rs2740348. Patients carrying the variant heterozygote GC genotype in the rs2740348 were at a 36% decreased risk of prostate cancer (odds ratio [OR] = 0.64; 95% confidence interval [CI] = 0.42, 0.99). Similarly, this variant allele carrier showed significant risk for prostate cancer (OR = 0.64). In addition, subjects carrying the homozygote TT genotype in the rs7813 had a significantly increased risk of prostate cancer (OR = 2.53, 95% CI = 1.07, 6.28). Two common haplotypes were found to be associated with decreased risk of prostate cancer. In the subgroup analysis, higher risk of more severity of prostate cancer (clinical stage III and IV) was observed in individuals with the rs7813 TT genotype (OR = 2.64, 95% CI = 1.02, 7.64), while lower risk of more severity of prostate cancer was observed in individuals with the rs3744741 T allele (OR = 0.69, 95% CI = 0.50, 0.96). Overall, our study provides substantial support for the association between the GEMIN4 gene and the risk of prostate cancer.     

Association between SIRT1 Gene Polymorphisms and Breast Cancer in Egyptians

Background

Breast cancer is reported to cause the highest mortality among female cancer patients. Previous studies have explored the association of silent mating-type information regulator 2 homolog 1 (SIRT1) gene expression with prognosis in breast cancer. However, no studies exist, so far, on the role of SIRT1 gene polymorphism in breast cancer risk or prognosis. The present study aimed to assess the association between SIRT1 gene polymorphisms and breast cancer in Egyptians.

Methods

The study comprised 980 Egyptian females divided into a breast cancer group (541 patients) and a healthy control group (439 subjects). SIRT1 gene single nucleotide polymorphisms (SNPs) rs3758391, rs3740051 and rs12778366 were genotyped using real-time polymerase chain reaction (RT-PCR). Allelic and genotypic frequencies were determined in both groups and association with breast cancer and clinicopathological characteristics was assessed.

Results

Breast cancer patients exhibited elevated serum SIRT1 levels which varied among different tumor grades. SIRT1 rs3758391 and rs12778366 TT genotypes were more frequent, exhibited higher SIRT1 levels than CC and CT genotypes and were associated with histologic grade and lymph node status. SIRT1 rs12778366 TT genotype also correlated with negative estrogen receptor (ER) and progesterone receptor (PR) statuses. The T allele frequency for both SNPs was higher in breast cancer patients than in normal subjects. Combined GG and AG genotypes of rs3740051 were more frequent, showed higher serum SIRT1 levels than the AA genotype, and were associated with ER and PR expression. Furthermore, inheritance of the G allele was associated with breast cancer.

Conclusions

Our findings reveal that rs3758391 and rs12778366 polymorphisms of SIRT1 gene are associated with breast cancer risk and prognosis in the Egyptian population.     

Estrogen receptor alpha regulates the Wnt/β-catenin signaling pathway in colon cancer by targeting the NOD-like receptors

It has been reported that estrogen receptors (ERs) participate in carcinogenesis by directly regulating NOD-like receptors (NLRs). However, the expression profiles of ERs and NLRs in tumor and the ER-NLR regulated signaling pathway are not clear. In this study, we summarized gene expression profiles of ERs and NLRs across normal and tumor tissue by comprehensive data mining. Then we explored the ER-NLR regulated signaling pathway by RNA sequencing (RNA-seq). The results showed that the NLRs and ERs were differentially expressed in different neoplasm tissues. Such expression discrepancies might influence inflammatory regulation and tumorigenesis. Importantly, we identified that ER-NLR regulate Wnt/β-catenin pathway in colon cancer. Taking colon adenocarcinoma (COAD) as example, we found that Wnt2b/LRP8/Dvl1/Axin2/GSK3a/APC/β-catenin genes were differentially expressed in ER^−/− mouse colon tissue and colon cancer cells. The selective ERα antagonist could significantly decrease Wnt2b/LRP8/Dvl1 expression, increase destruction complex (Axin2/GSK3a/APC) expression, and promote degradation of β-catenin in colon carcinoma cell by inhibited NLRP3 expression. In short, the research demonstrates that NLRs are potential biomarkers for cancer, and ERs can regulate the Wnt/β-catenin signaling pathway in cancer by targeting the NLRs. Our results provide a possible signaling pathway in which ER-NLR is correlated with Wnt/β-catenin.     

GPR30 gene polymorphisms are associated with progesterone receptor status and histopathological characteristics of breast cancer patients

G-protein coupled receptor GPR30 has been demonstrated to mediate estrogenic effects on essential features of human breast cancer cells. Polymorphisms in GPR30 gene might therefore affect breast cancer susceptibility or tumor characteristics. This is the first study examining allele and genotype frequencies of GPR30 single nucleotide polymorphisms (SNPs) in breast cancer patients. A total of 257 sporadic breast cancer cases and 247 age-matched controls were genotyped for three GPR30 polymorphisms by means of allele-specific tetra-primer PCR. Comparison of the breast cancer case and the control group with regard to the SNP allele, genotype and haplotype frequencies did not show significant differences. In contrast, the GPR30 SNPs tested were significantly associated with tumor size, histological grading, nodal status and progesterone receptor (PR) status. The A allele of SNP rs3808351 was significantly less frequent in patients with large or G3 tumors, T allele of SNP rs11544331 less frequently occurred in patients with positive nodal status, suggesting that both SNPs might exert protective effects regarding aggressive breast cancer entities. Both homozygous GG genotype of promoter SNP rs3808350 and T allele of missense SNP rs11544331 were inversely associated with PR-negativity, suggesting that they might exert protective effects regarding development of PR-negative cancer. In conclusion, the results of this study support the important role of GPR30 in breast cancer and encourage functional studies on the molecular mechanisms underlying the association of GPR30 polymorphisms with PR status and tumor growth.     

Genetic Variations in MicroRNA Processing Genes Are Associated with Susceptibility in Depression

MicroRNAs (miRNAs) are new prominent gene expression regulators that have critical roles in neural development by regulating synaptic functions, and miRNA biogenesis may play an important role in psychiatric disorders. Despite emerging evidences demonstrating that single-nucleotide polymorphisms in the miRNA processing genes were associated with cancer and cardiovascular disorders, evidences about association between variants of the genes and depression are lacking. This study aims to find the association between miRNA processing gene variants and depression. We genotyped three polymorphisms from three miRNA processing genes in a case-control study including 314 patients and 252 matched healthy controls. The high-resolution melting method was used to genotype the three loci. Frequencies of genotypes and alleles showed significant difference between patients with depression and healthy controls in DGCR8 rs3757 and AGO1 rs636832. An allele frequency was significantly higher in rs3757 and lower in rs636832, respectively. Variant allele of DGCR8 rs3757 was associated with increased risk of suicidal tendency and improvement response to antidepressant treatment, whereas the variant of AGO1 rs636832 showed decreased risk of suicidal tendency, suicidal behavior, and recurrence. Besides allele frequency showed significant difference when compared patients with remission to controls, no significant differences were found in GEMIN4 rs7813 between patients and healthy controls. DGCR8 rs3757 and AGO1 rs636832 were found to have significant association with depression, and GEMIN4 rs7813 did not affect susceptibility to depression. These observations suggested that miRNA processing polymorphisms may affect depression risk and treatment.     

Genetic variants of fibroblast growth factor receptor 2 (<Emphasis Type="Italic">FGFR2</Emphasis>) are associated with breast cancer risk in Chinese women of the Han nationality

Fibroblast growth factor receptor 2 (FGFR2), a recently described risk factor for breast cancer, plays important roles in cell growth, invasiveness, motility, and angiogenesis. In attempt to investigate whether FGFR2 polymorphisms are associated with a risk of breast cancer in Chinese women of the Han nationality, we genotyped single-nucleotide polymorphisms (SNPs) of seven FGFR2 sites (rs2981582, rs17102287, rs17542768, rs10510097, rs11200012, rs3750817, rs2981578) in 816 women including 388 breast cancer patients and 428 healthy controls via the polymerase chain reaction single-strand conformation polymorphism procedure as well as sequence detection. Our results suggest that the A allele and AA genotype of SNP rs2981578 appear to be protective factors associated with breast cancer, while the CT genotype of SNP rs3750817 is a putative risk factor.     

Association of rs11801299 and rs1380576 polymorphisms at MDM4 with risk,clinicopathological features and prognosis in patients with retinoblastoma

Backgroundrs11801299 and rs1380576, two novel polymorphisms in MDM4 gene, have been investigated in several different cancer types. However, the role of these two polymorphisms in retinoblastoma (RB) remains unclear.MethodsA total of 126 patients with primary RB and 148 age-/gender-matched controls were included in this retrospective study. The frequency of rs11801299 and rs1380576 were determined between RB patients and controls. The association of these two polymorphisms with clinicopathological characteristics, prognosis were further evaluated.ResultsAA genotype at rs11801299 was significantly associated with an increased risk of developing RB (OR = 2.06, 95%CI 1.09–3.90). The possibility of developing RB was also significantly increased in individuals with A allele at rs11801299 (OR = 1.49, 95%CI 1.06–2.08). RB patients carrying AA genotype and A allele at rs11801299 were more likely to have tumor invasion and poor differentiation. As for rs1380576, a significantly lower risk of developing RB was observed in patients with G allele (CG + GG) compared with wild-type CC genotype (OR = 0.59, 95%CI 0.36–3.95). RB patients with GG genotype or G allele had a lower risk of developing highly aggressive cancer. Kaplan-Meier curves and log-rank results revealed that RB patients carrying AA genotype or A allele (AA + GA) at rs11801299 had significantly poorer prognosis. Multivariate COX analysis showed that the rs11801299 G allele was associated with decreased survival but was not an independent prognostic factor.Conclusionrs11801299 was significantly associated with RB risk, pathological differentiation, tumor aggressiveness and poor prognosis.     

Association of Single Nucleotide Polymorphisms in VDR and DBP Genes with HBV-Related Hepatocellular Carcinoma Risk in a Chinese Population

Background

Polymorphisms of genes encoding components of the vitamin D pathway including vitamin D receptor (VDR) and vitamin D binding protein (DBP) have been widely investigated because of the complex role played by vitamin D in cancer tumorogenesis. In this study, we investigated the association between VDR and DBP gene polymorphisms and HBV-related HCC risk in a Chinese population.

Methods

Study subjects were divided into three groups: 184 HBV patients with HCC, 296 HBV patients without HCC, and 180 healthy controls. The VDR rs2228570, and rs3782905 and the DBP rs7041 polymorphisms were genotyped using PCR-RFLP and the VDR rs11568820 polymorphism was genotyped by PCR-SSP, respectively. DNA sequencing was performed to validate the genotype results.

Results

We found that there were significant differences in the genotype and allele frequencies of the VDR rs2228570 and DBP rs7041 polymorphisms between HBV patients with HCC and healthy controls. The rs2228570 T allele was associated with a significant increased HBV-related HCC risk as compared with the C allele. The rs2228570 TT and TT/TC genotypes were correlated with a significant increased HBV-related HCC risk when compared with the wild-type CC homozygote. Similarly, the rs7041 G allele was associated with a significant increased HBV-related HCC risk as compared with the T allele. The rs7041 GG and GG/TG genotypes were correlated with a significant increased HBV-related HCC risk when compared with the wild-type TT homozygote. However, we did not observe any significant effect of VDR rs11568820, and rs3782905 polymorphisms on HBV-related HCC risk in this population. In haplotype analysis, we also did not find any significant differences in haplotype frequencies of the VDR gene between HBV patients with HCC and the healthy controls.

Conclusions

We conclude that the VDR rs2228570 and DBP rs7041 polymorphisms may contribute to increased susceptibility to HBV-related HCC in the Chinese population. Due to the marginal significance, further large and well-designed studies in diverse ethnic populations are needed to confirm our results.     

Association between the c.*229C>T polymorphism of the topoisomerase IIβ binding protein 1 (TopBP1) gene and breast cancer

Topoisomerase IIβ binding protein 1 (TopBP1) is involved in cell survival, DNA replication, DNA damage repair and cell cycle checkpoint control. The biological function of TopBP1 and its close relation with BRCA1 prompted us to investigate whether alterations in the TopBP1 gene can influence the risk of breast cancer. The aim of this study was to examine the association between five polymorphisms (rs185903567, rs116645643, rs115160714, rs116195487, and rs112843513) located in the 3′UTR region of the TopBP1 gene and breast cancer risk as well as allele-specific gene expression. Five hundred thirty-four breast cancer patients and 556 population controls were genotyped for these SNPs. Allele-specific TopBP1 mRNA and protein expressions were determined by using real time PCR and western blotting methods, respectively. Only one SNP (rs115160714) showed an association with breast cancer. Compared to homozygous common allele carriers, heterozygous and homozygous for the T variant had significantly increased risk of breast cancer (adjusted odds ratio = 3.81, 95 % confidence interval: 1.63–8.34, p = 0.001). Mean TopBP1 mRNA and protein expression were higher in the individuals with the CT or TT genotype. There was a significant association between the rs115160714 and tumor grade and stage. Most carriers of minor allele had a high grade (G3) tumors classified as T2-T4N1M0. Our study raises a possibility that a genetic variation of TopBP1 may be implicated in the etiology of breast cancer.