Common genetic polymorphisms in pre-microRNAs and risk of cervical squamous cell carcinoma

MicroRNAs (miRNAs) function as gene regulator and they participate in diverse biological pathways. Common single nucleotide polymorphisms (SNPs) in pre‐microRNAs may change their property through altering miRNAs expression and/or maturation. We conducted a pilot study to test whether SNPs in pre‐microRNAs were associated with cervical squamous cell carcinoma (CSCC). Genotypes of three SNPs in pre‐miRNAs (hsa‐miR‐196a2 rs11614913 C/T, hsa‐miR‐499 rs3746444 A/G, and hsa‐miR‐146a rs2910164 G/C) in 226 CSCC patients and 309 control subjects were determined with the use of PCR‐restriction fragment length polymorphism (RFLP) assay. Significantly increased CSCC risks were found to be associated with G allele of rs3746444 and G allele of rs2910164 (P = 0.017, OR = 1.454, and P = 0.016, OR = 1.355, respectively). Increased CSCC risks were associated with them in different genetic model (P = 0.0004, OR = 1.98 for rs3746444 in an overdominant model, and P = 0.024, OR = 2.10 for rs2910164 in a codominant model, respectively). Results of stratified analyses revealed that rs2910164 is associated with tumor differentiation and lymph node status (P = 0.043, OR = 2.08, and a borderline P = 0.057, OR = 0.41, respectively). No association between rs11614913 and CSCC risk was observed. The present study provides evidence that rs3746444 and rs2910164 are associated with CSCC, indicating that common genetic polymorphisms in pre‐microRNAs contribute to the pathogenesis of CSCC. Mol. Carcinog. © 2011 Wiley‐Liss, Inc.     

p14ARF genetic polymorphisms and susceptibility to second primary malignancy in patients with index squamous cell carcinoma of the head and neck

BACKGROUND:

p14^ARF, an alternate reading frame (ARF) product of the cyclin‐dependent kinase inhibitor 2A locus, plays a critical role in crosstalk between the tumor protein 53 (p53) and retinoblastoma (Rb) pathways and in cellular anticancer mechanisms. Therefore, the authors of this report investigated the association between single nucleotide polymorphisms (SNPs) of the p14^ARF gene and the risk of developing a second primary malignancy (SPM) after an index squamous cell carcinoma of the head and neck (SCCHN).

METHODS:

The log‐rank test and Cox proportional hazards models were used to assess the association of 2 p14^ARF SNPs (reference SNP [rs]3731217 and rs3088440) with SPM‐free survival and with the risk of developing an SPM among 1287 patients who had SCCHN.

RESULTS:

Patients with either p14^ARF variant genotypes of the 2 polymorphisms had a significantly reduced SPM‐free survival compared with patients with no variant genotypes (log‐rank test; P = .006). Compared with the p14^ARF thymine‐thymine (TT) and guanine‐guanine (GG) genotypes, the variant genotypes of p14^ARF TG/GG and guanine‐adenine (GA)/AA were associated with a significantly moderately increased risk of developing an SPM (p14^ARF rs3731217: adjusted hazard ratio [aHR], 1.48; 95% confidence interval [CI], 1.00‐2.19; p14^ARF rs3088440: aHR, 1.61; 95% CI, 1.07‐2.43). Moreover, after combining the variant genotypes of the 2 SNPs, patients who had variant genotypes were at significantly greater risk of developing an SPM compared with patients who had no variant genotypes (aHR, 3.07; 95% CI, 1.54‐6.12), and the risk was particularly pronounced in several subgroups.

CONCLUSIONS:

The current results suggested that there is a modestly increased risk of developing an SPM after an index SCCHN with each p14^ARF polymorphism, and there is an even greater risk of developing an SPM for patients with combined variant genotypes of the 2 SNPs. Therefore, p14^ARF polymorphisms may be susceptible markers of the risk of developing an SPM in patients with SCCHN. Cancer 2011. © 2010 American Cancer Society.     

A single nucleotide polymorphism in the alcohol dehydrogenase 7 gene (alanine to glycine substitution at amino acid 92) is associated with the risk of squamous cell carcinoma of the head and neck

BACKGROUND:

The authors conducted a hospital‐based study of 1110 patients with squamous cell carcinoma of the head and neck (SCCHN) and a control group of 1129 patients to replicate the associations reported by a recent, large European study between 2 potentially functional single nucleotide polymorphisms (SNPs) of the alcohol dehydrogenase (ADH) genes, a substitution in ADH1B at amino acid 48 from arginine to histidine (R48H) (reference SNP number [rs]1229984; guanine to adenine [G→A]) and a substitution in ADH7 at amino acid 92 from alanine to glycine (A92G) (rs1573496; cytosine to guanine [C→G]), and the risk of squamous cell carcinoma of the head and neck (SCCHN).

METHODS:

Multivariate logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). False‐positive report probabilities (FPRPs) also were calculated for significant findings.

RESULTS:

The ADH7 A92G GG and combined CG + GG genotypes were associated with a decreased risk of SCCHN (GG: adjusted OR, 0.32; 95% CI, 0.13‐0.82; CG + GG: adjusted OR, 0.74; 95% CI, 0.59‐0.94; FPRP, .098) compared with the CC genotype. This association was also evident in subgroups of older patients (aged >57 years), men, former smokers, patients with oral cancer, and patients with N) lymph node status (P < .05 for all); however, such associations were not observed for the ADH1B R48H SNP.

CONCLUSIONS:

The current results support the ADH7 A92G SNP as a marker for the risk of SCCHN in non‐Hispanic white populations. Cancer 2010. © 2010 American Cancer Society.     

Genetic variants of the nonhomologous end joining gene LIG4 and severe radiation pneumonitis in nonsmall cell lung cancer patients treated with definitive radiotherapy

BACKGROUND:

Nonhomologous end joining (NHEJ) is a pathway that repairs DNA double‐strand breaks (DSBs) to maintain genomic stability in response to irradiation. The authors hypothesized that single nucleotide polymorphisms (SNPs) in NHEJ repair genes may affect clinical outcomes in patients with nonsmall cell lung cancer (NSCLC) who receive definitive radio(chemo)therapy.

METHODS:

The authors genotyped 5 potentially functional SNPs—x‐ray repair complementing defective repair in Chinese hamster cells 4 (XRCC4) reference SNP (rs) number rs6869366 (?1394 guanine to thymine [?1394G→T] change) and rs28360071 (intron 3, deletion/insertion), XRCC5 rs3835 (guanine to adenine [G→A] change at nucleotide 2408), XRCC6 rs2267437 (?1310 cytosine to guanine [C→G) change], and DNA ligase IV (LIG4) rs1805388 (threonine‐to‐isoleucine change at codon 9 [T9I])—and estimated their associations with severe radiation pneumonitis (RP) (grade ≥3) in 195 patients with NSCLC.

RESULTS:

A predictive role in radiation pneumonitis (RP) development was observed for the LIG4 SNP rs1805388 (adjusted hazard ratio, 2.08; 95% confidence interval, 1.04‐4.12; P = .037 for the CT/TT genotype vs the CC genotype). In addition, men with the TT genotype of the XRCC4 rs6869366 SNP and women with AG + AA genotypes of the XRCC5 rs3835 SNP also were at increased risk of developing severe RP.

CONCLUSIONS:

The current results indicated that NHEJ genetic polymorphisms, particularly LIG4 rs1805388, may modulate the risk of RP in patients with NSCLC who receive definitive radio(chemo)therapy. Large studies will be needed to confirm these findings. Cancer 2011;. © 2011 American Cancer Society.     

An integrated analysis of germline and somatic, genetic and epigenetic alterations at 9p21.3 in glioblastoma

BACKGROUND:

Glioblastoma multiforme (GBM) is the most prevalent and deadly brain tumor. A variety of germline and somatic, genetic and epigenetic alterations at 9p21.3, which encode CDKN2A/CDKN2B tumor suppressor genes, have been isolatedly reported to be associated with GBM risk and prognosis.

METHODS:

To obtain a comprehensive view of these events, we leveraged the wide‐spectrum GBM data available from The Cancer Genome Atlas project and performed an integrated analysis by systematically evaluating 9p21.3‐related germline single‐nucleotide polymorphisms, somatic copy number alterations (CNAs), DNA methylation, and microRNAs (miRNAs) with regard to CDKN2A/CDKN2B expression and patient prognosis in GBM.

RESULTS:

Our multivariate analysis indicated that expression of CDKN2A and CDKN2B was both strongly affected by CNAs (P = 1.00 × 10^?4 and 2.37 × 10^?14). The miRNAs hsa‐mir‐126, hsa‐mir‐517a, and hsa‐mir‐125b exhibited significant negative correlations with CDKN2A expression (P = 0.003, 0.041, and 0.050). Survival analysis showed that complete 9p21.3 loss and low CDKN2B expression were associated with worse prognosis for both tumor progression/recurrence‐free survival (P = .041 and .019) and patient overall survival (P = .043 and .021) after adjustment for age and treatment, and that higher methylation at cg17449661 predicted poorer overall survival (P = .048).

CONCLUSION:

Representing one of the first attempts to systematically integrate various levels of alterations associated with the often complex cancer genomes and phenotypes, our study provided a holistic view and a mechanistic explanation over the functional connections of multiple 9p21.3‐related events in GBM, as well as clinically useful biomarker information for predicting disease outcomes. Cancer 2012;. © 2011 American Cancer Society.     

Polymorphisms in MicroRNA‐Related Genes Are Associated With Survival of Patients With T‐Cell Lymphoma

Objective

Elaborate evaluation of prognosis of T-cell lymphoma (TCL) is vital for current therapy and future stratified and individualized therapy. MicroRNAs (miRNAs) play important roles in cancer development and prognosis. We aimed to assess the effects of single nucleotide polymorphisms (SNPs) in miRNA-related genes on the survival of patients with TCL.

Patients and Methods

We genotyped 13 SNPs selected from 12 miRNA-related genes in 220 TCL patients and explored the association of SNPs with survival.

Results

Among the 13 SNPs, four (DROSHA rs6877842, DICER rs3742330, mir149 rs2292832, and mir499 rs3746444) were significantly associated with TCL survival after adjusting for subtype and International Prognostic Index score. In stratified analyses, all four SNPs remained significantly associated with survival in patients with mature T type. Of the four SNPs, only mir149 rs2292832 was not significantly associated with survival in patients with an International Prognostic Index score of 0–1. Furthermore, a dose-dependent cumulative effect of the four SNPs on TCL survival was observed by counting the number of unfavorable genotypes. Survival tree analysis also showed higher order interactions between these SNPs.

Conclusion

The results suggested that miRNA-related polymorphisms are associated with survival of TCL patients; thus, they may be used individually and jointly to predict survival of patients with TCL.     

Genetic variations in regulator of G‐protein signaling (RGS) confer risk of bladder cancer

BACKGROUND:

Alterations in the regulator of G‐protein signaling (RGS) pathway have been implicated in several cancers; therefore, the authors investigated the role of such alterations in overall bladder cancer risk, recurrence, progression, and survival.

METHODS:

In this case‐control series, 803 patients with bladder cancer were frequency‐matched with a control cohort of 803 healthy individuals. Ninety‐five single‐nucleotide polymorphisms (SNPs) in 17 RGS genes were investigated for an association with overall bladder cancer risk, recurrence, and progression in patients who had nonmuscle‐invasive bladder cancer (NMIBC) and for an association with death in patients who had muscle‐invasive bladder cancer (MIBC). Cumulative effects and classification and regression tree analyses were performed for SNPs that were associated with overall bladder cancer risk. Kaplan‐Meier plots were created to evaluate differences in the survival of patients with MIBC.

RESULTS:

Reference SNP 10759 (rs10759) on the RGS4 gene demonstrated the greatest association with overall bladder cancer risk, conferring a 0.77‐fold reduced risk with an increasing number of variant alleles (P < .001). A cumulative effects analysis that included all 5 significant SNPs demonstrated an increasing risk with the number of unfavorable genotypes (odds ratio, 4.13; 95% confidence interval, 2.14‐7.98). In patients with NMIBC, 11 SNPs were identified that had an association with disease recurrence, and 13 SNPs were associated with disease progression. Of the 10 SNPs that were associated with death in patients with MIBC, rs2344673 in an additive model was the most significant and was associated with a decreased median survival of 13.3 months compared with 81.9 months in individuals without a variant allele.

CONCLUSIONS:

Genetic variations in the RGS pathway were associated with the overall risk of bladder cancer, recurrence, and progression in patients with NMIBC and with the risk of death in patients with MIBC. Cancer 2013. © 2013 American Cancer Society.     

Genetic variants of the p53 and p73 genes jointly increase risk of second primary malignancies in patients after index squamous cell carcinoma of the head and neck

BACKGROUND:

Because of the structural and biochemical similarities between the antitumor p53 and p73 proteins, the authors hypothesized that individuals who carry high‐risk genotypes of p53 codon 72 and p73 G4C14‐to‐A4T14 polymorphisms have a higher risk of developing second primary malignancy (SPM) after index squamous cell carcinoma of the head and neck (SCCHN).

METHODS:

A cohort of 1269 patients with index cases of SCCHN was recruited between May 1995 and January 2007 at The University of Texas MD Anderson Cancer Center and followed for SPM development. Patients were genotyped for p53 codon 72 and p73 G4C14‐to‐A4T14 polymorphisms. A log‐rank test and Cox proportional hazard models were used to compare SPM‐free survival and SPM risk among different risk groups with the combined risk genotypes of the 2 polymorphisms.

RESULTS:

The data demonstrated that patients with p53 WP + PP and p73 GC/GC genotypes had a worse SPM‐free survival and an increased SPM risk compared with the corresponding p53 WW and p73 GC/AT + AT/AT genotypes. After combining the 2 polymorphisms, a borderline significantly or significantly reduced SPM‐free survival and increased SPM risk were observed in the medium‐risk group (p53 WW and p73 GC/GC or p53 P carriers and p73 AT carriers) and high‐risk group (p53 P carriers and p73 GC/GC) compared with low‐risk group (p53 WW and p73 AT carriers), respectively.

CONCLUSIONS:

The results suggest an increased risk of SPM after index SCCHN with both p53 and p73 polymorphisms individually and in combination. Cancer 2011;. © 2011 American Cancer Society.     

Wnt antagonist gene polymorphisms and renal cancer

BACKGROUND:

Epigenetic silencing of several wingless‐type mouse mammary tumor virus integration site (Wnt) pathway‐related genes has been reported in renal cancer. Except for the T‐cell factor 4 gene TCF4, there are no reports regarding Wnt pathway gene polymorphisms in renal cancer. Therefore, the authors of this report hypothesized that the polymorphisms in Wnt signaling genes may be risk factors for renal cancer.

METHODS:

In total, 210 patients (145 men and 65 women) with pathologically confirmed renal cell carcinoma (RCC) and 200 age‐matched and sex‐matched control individuals were enrolled in this study. We genotyped 14 single nucleotide polymorphisms (SNPs) in 6 genes. including Dickkopf 2 (DKK2) (reference SNP identification number 17037102 [rs17037102], rs419558, and rs447372), DKK3 (rs3206824, rs11022095, rs1472189, rs7396187, and rs2291599), DKK4 (rs2073664), secreted frizzled‐related protein 4 (sFRP4) (rs1802073 and rs1802074), mothers against decapentaplegic homolog (SMAD) family member 7 or SMAD7 (rs12953717), and disheveled associated activator of morphogenesis 2 or DAAM2 (rs6937133 and rs2504106) using polymerase chain reaction‐restriction fragment length polymorphism analysis and direct sequencing in the patients with RCC and in the healthy, age‐matched control group. The relations also were tested between these polymorphisms and clinicopathologic data, including sex, tumor grade, tumor stage, lymph node involvement, distant metastasis, and overall survival.

RESULTS:

A significant decrease in the frequency of the guanine/adenine (G/A) + A/A genotypes in the DKK3 codon 335 rs3206824 was observed in the patients with RCC compared with the control group. The frequency of the rs3206824 (G/A) A‐rs7396187 (guanine/cytosine [G/C]) C haplotype was significantly lower in patients with RCC compared with other haplotypes. In addition, DKK3 rs1472189 cytosine/thymine (C/T) was associated with distant metastasis, and, DKK2 rs17037102 G‐homozygous patients had a decreased risk for death in multivariate Cox regression analysis.

CONCLUSIONS:

To the authors' knowledge, this is the first report documenting that DKK3 polymorphisms are associated with RCC and that the DKK2 rs17037102 polymorphism may be a predictor for survival in patients with RCC after radical nephrectomy. Cancer 2009. © 2009 American Cancer Society.     

Association of the progesterone receptor gene with endometrial cancer risk in a Chinese population

BACKGROUND:

Single nucleotide polymorphisms (SNPs) in the progesterone receptor (PGR) gene have been associated with the risk of endometrial cancer. However, to the authors' knowledge, no study to date has systematically evaluated the role of the PGR gene in endometrial carcinogenesis.

METHODS:

Exposure information and DNA samples collected in the Shanghai Endometrial Cancer Study, a population‐based case‐control study of 1204 incident cases and 1212 age‐ and frequency‐matched population controls, were used in this study. Seven tag SNPs were identified for the PGR gene plus the 5‐kilobase (kb) flanking regions using the Han Chinese data from the HapMap project with a pairwise correlation coefficient (r²) ≥ 0.90. These 7 SNPs captured 92% of SNPs in the region with a pairwise r² ≥ 0.90 or 100% of SNPs with a pairwise r² ≥ 0.80. Genotyping of polymorphisms was performed by using the Affymetrix MegAllele Targeted Genotyping System. A logistic regression model was used to compute adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs).

RESULTS:

Of 7 tag SNPs that were assessed, 2 polymorphisms in the 3′ flanking region of the PGR gene, reference SNP identification number (rs) 11224561 (rs11224561) and rs471767, were associated with the risk of endometrial cancer. The cytosine/cytosine (CC) genotype of SNP rs11224561 was associated with decreased risk (OR, 0.68; 95% CI, 0.50‐0.92) compared with the thymine/thymine (TT) genotype. Carrying the guanine (G) allele of the rs471767 SNP also was associated with decreased risk, although the association was not statistically significant (OR, 0.78, 95%CI, 0.59‐1.04 and OR, 0.32, 95%CI, 0.03‐3.05 for the adenine [A]G and GG genotypes, respectively, compared with the homozygote AA).

CONCLUSIONS:

The current findings suggested that polymorphisms in the 3′ flanking region of the PGR gene may be associated with the risk of endometrial cancer. Cancer 2009. © 2009 American Cancer Society.     

Cyclooxygenase‐2 gene polymorphisms reduce the risk of oral premalignant lesions

BACKGROUND:

Oral premalignant lesions (OPLs) have the potential to transform into malignant oral cancers. Overexpression of the cyclooxygenase‐2 gene (COX‐2) is observed frequently in OPLs and oral cancers, suggesting that this gene may play an important role in the progression of oral cancer. Single‐nucleotide polymorphisms of COX‐2 have been associated with the risk of multiple cancers; however, to date, their effects on OPL susceptibility have not been evaluated sufficiently.

METHODS:

The authors conducted a case‐control study that included 147 patients with OPL and a group of 147 healthy, matched controls. The effects of 3 potentially functional COX‐2 polymorphisms on the risk of OPL were evaluated: the ?765 G→C polymorphism (rs20417), the exon 10 +837 T→C polymorphism (rs5275), and the exon 10 ?90 C→T polymorphism (rs689470).

RESULTS:

The variant‐containing genotypes of COX‐2 exon 10 +837T→C variant were associated with a significantly reduced risk of OPL (odds ratio [OR], 0.48; 95% confidence interval [95% CI], 0.28‐0.80). This protective effect also was significant in men, younger individuals, ever smokers, and ever drinkers. Consistently, a common halotype WMW (in the following order: ?765G→C, exon 10 +837T→C, and exon 10 ?90C→T; w, widetype; M, variable allele) and a common diplotype (WWW/WMW) that contained the variant allele of exon 10 +837T→C, both were associated with a reduced risk of OPL (WMW: OR, 0.55; 95% CI, 0.33‐0.93; WWW/WMW: OR, 0.44; 95% CI, 0.22‐0.89). In addition, using never smokers with the variant‐containing genotypes as the reference group, interaction effects were observed between specific COX‐2 variants and tobacco smoking in the modulation of OPL risk.

CONCLUSIONS:

Overall, the current results provided the first epidemiologic evidence indicating that potentially functional polymorphisms of the COX‐2 gene may have an impact on individual susceptibility to OPLs. Cancer 2009. © 2009 American Cancer Society.     

Identification of candidate genes carrying polymorphisms associated with the risk of colorectal cancer by analyzing the colorectal mutome and microRNAome

BACKGROUND:

The presence of single‐nucleotide polymorphisms (SNPs) within the 3′‐untranslated regions of genes could affect the binding between a microRNA (miRNA) and its target, with consequences on gene expression regulation. Considering the important role of miRNAs in carcinogenesis, it is hypothesized here that these SNPs could also affect the individual risk of colorectal cancer (CRC).

METHODS:

To test this hypothesis, a list was developed of 140 somatically mutated genes deduced from previous works on the mutome of the CRC. A further selection was conducted of SNPs within target sites for miRNAs that are expressed only in the colorectum (the colorectal microRNAome) and having adequate population frequencies. This yielded 12 SNPs that were genotyped in a case‐control association study on 717 colorectal cases and 1171 controls from the Czech Republic.

RESULTS:

Statistically significant associations were found between the risk of CRC and the variant alleles of KIAA0182 (rs709805) (odds ratio = 1.57; 95% confidence interval = 1.06‐2.78, for the variant homozygotes) and NUP210 genes (rs354476) (odds ratio = 1.36; 95% confidence interval = 1.02‐1.82, for the variant homozygotes).

CONCLUSIONS:

The results support the study hypothesis and highlight the importance of SNPs within miRNA‐dependent regulatory regions. Further studies on the role exerted by NUP210 and KIAA0182 in colorectal carcinogenesis are warranted. Cancer 2012. © 2012 American Cancer Society.     

Interactions between environmental factors and polymorphisms in angiogenesis pathway genes in esophageal adenocarcinoma risk: a case-only study

BACKGROUND:

Gastroesophageal reflux disease (GERD), higher body mass index (BMI), smoking, and genetic variants in angiogenic pathway genes have been individually associated with increased risk of esophageal adenocarcinoma. However, how angiogenic gene polymorphisms and environmental factors jointly affect esophageal adenocarcinoma development remains unclear.

METHODS:

By using a case‐only design (n = 335), the authors examined interactions between 141 functional/tagging angiogenic single nucleotide polymorphisms (SNPs) and environmental factors (GERD, BMI, smoking) in modulating esophageal adenocarcinoma risk. Gene‐environment interactions were assessed by a 2‐step approach. First, the authors applied random forest to screen for important SNPs that had either main or interaction effects. Second, they used case‐only logistic regression to assess the effects of gene‐environment interactions on esophageal adenocarcinoma risk, adjusting for covariates and false‐discovery rate.

RESULTS:

Random forest analyses identified 3 sets of SNPs (17 SNPs‐GERD, 26 SNPs‐smoking, and 34 SNPs‐BMI) that had the highest importance scores. In subsequent logistic regression analyses, interactions between 2 SNPs (rs2295778 of HIF1AN, rs13337626 of TSC2) and GERD, 2 SNPs (rs2295778 of HIF1AN, rs2296188 of VEGFR1) and smoking, and 7 SNPs (rs2114039 of PDGRFA, rs2296188 of VEGFR1, rs11941492 of VEGFR1, rs17708574 of PDGFRB, rs7324547 of VEGFR1, rs17619601 of VEGFR1, and rs17625898 of VEGFR1) and BMI were significantly associated with esophageal adenocarcinoma development (all false‐discovery rates ≤0.10). Moreover, these interactions tended to have SNP dose‐response effects for increased esophageal adenocarcinoma risk with increasing number of combined risk genotypes.

CONCLUSIONS:

These findings suggest that genetic variations in angiogenic genes may modify esophageal adenocarcinoma susceptibility through interactions with environmental factors in an SNP dose‐response manner. Cancer 2012;. © 2011 American Cancer Society.     

Genetic variation in MicroRNA genes and risk of oral premalignant lesions

MicroRNAs (miRNAs) have been reported to play a key role in oncogenesis and, recently, studies have examined the role miRNAs might play in the risk of premalignant lesions. To our knowledge, no study has investigated the association between miRNA polymorphisms and risk of oral premalignant lesions (OPLs). We genotyped 31 single nucleotide polymorphisms (SNPs) among 21 miRNA‐related genes in a case–control study including 136 OPL patients and 136 matched controls. Patients with at least one variant allele of mir26a‐1:rs7372209 had a significantly increased risk of OPL (OR, 2.09; 95% CI, 1.23–3.56). Likewise, patients with at least one variant allele of DICER:rs3742330 had a significantly increased risk of OPL (OR, 2.09; 95% CI, 1.03–4.24). To assess the cumulative effects, we performed a combined unfavorable genotype analysis that included all SNPs showing at least a borderline statistical significance. A significant trend of increased risk of OPL with increasing number of unfavorable genotypes was observed (P for trend <0.0001). This study presents the first epidemiologic evidence supporting that individual as well as combined genotypes of miRNA‐related variants may be used to predict the risk of OPL, and may be useful for identifying patients with OPL at high risk for progression to oral cancer. © 2009 Wiley‐Liss, Inc.     

Statistically significant association of the single nucleotide polymorphism (SNP) rs13181 (ERCC2) with predisposition to Squamous Cell Carcinomas of the Head and Neck (SCCHN) and Breast cancer in the north Indian population

Background

Non-synonymous single nucleotide polymorphisms (SNPs) within vital DNA repair genes may cause reduction of activity leaving the genome unrepaired resulting in genomic instability and cancer.

Materials and methods

The present endeavour involved study on the association of the SNP rs13181 (Lys751Gln/A18911C) in the Nucleotide Excision Repair (NER) pathway gene ERCC2 (excision repair cross-complementing rodent repair deficiency, complementation group 2) with the risks of Squamous Cell Carcinomas of the Head and Neck (SCCHN) and Breast cancer using a case-control based association study among 685 (400 controls and 285 SCCHN-affected cases) and 395 (227 normal healthy female controls and 168 breast cancer cases) ethnically-matched samples, respectively from north India using Polymerase Chain Reaction followed by Restriction Fragment Length Polymorphism (PCR-RFLP) analysis.

Results

Results showed significant association of rs13181 homozygous mutant (CC) [Odds Ratio (OR) 4.412, 95% Confidence Interval (CI) 2.413 to 8.068], heterozygous (AC) (OR 2.086, 95% CI 1.246 to 3.492) and combined mutant (AC + CC) (OR 2.672, 95% CI 1.647 to 4.334) genotypes with predisposition to Breast cancer. Statistically significant increase in SCCHN risk was also associated with the mutant genotypes of rs13181 (ERCC2), viz. homozygous mutant (CC) (OR 1.680, 95% CI 1.014 to 2.784), heterozygous (AC) (OR 1.531, 95% CI 1.092 to 2.149) and combined mutant (AC + CC) (OR 1.560, 95% CI 1.128 to 2.158) genotypes.

Conclusion

The results of this case-control study indicate that the polymorphism rs13181 might be a risk factor for predisposition towards SCCHN and breast cancer among north Indian subpopulations.     

Association between microRNA genetic variants and susceptibility to colorectal cancer in Chinese population

MicroRNAs (miRNAs) play an important role in the pathogenesis of neoplasm. Single nucleotide polymorphisms (SNPs) within miRNAs can change their phenotype and function. We attempted to analyze the relationship between two SNP loci in miRNAs and colorectal cancer (CRC) in Chinese Han population. We genotyped the polymorphism of two common miRNA SNPs, miR-146a (rs2910164 G > C) and miR-499 (rs3746444 T > C), in a case–control study of 276 CRC cases and 373 healthy controls using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). The genotypes and allele frequencies of the two SNP loci were first compared between patients and controls and then further analyzed among subgroups of patients with different clinicopathological profiles. The rs2910164 CG genotype was significantly associated with a decreased risk of CRC [CG versus GG, odds ratio (OR)?=?0.567; 95 % confidence intervals (CIs)?=?0.338–0.952; p?=?0.031]. No significant differences of miR-499 genotype and allele distribution were detected between patients and controls. Comparison between groups divided by clinicopathologic features showed that the polymorphism of miR-146a was associated with the degree of tumor differentiation (p?=?0.014), and the G allele of rs2910164 trended to a mature differentiation (OR?=?0.553; 95 % CI?=?0.315–0.971; p?=?0.038). MiR-146a (rs2910164 G > C) polymorphism is associated with CRC susceptibility and histological differentiation in Chinese Han population.