Progesterone receptor gene variants and risk of endometrial cancer

Prolonged excessive estrogen exposure unopposed by progesterone is widely accepted to be a risk factor for endometrial cancer development. The physiological function of progesterone is dependent upon the presence of its receptor [progesterone receptor (PGR)] and several studies have reported single nucleotide polymorphisms (SNPs) in the PGR gene to be associated with endometrial cancer risk. We sought to confirm the associations with endometrial cancer risk previously reported for four different PGR polymorphisms. A maximum of 2888 endometrial cancer cases and 4483 female control subjects from up to three studies were genotyped for four PGR polymorphisms (rs1042838, rs10895068, rs11224561 and rs471767). Logistic regression with adjustment for age, study, ethnicity and body mass index was performed to calculate odds ratios (ORs) and associated 95% confidence intervals (CIs) and P-values. Of the four SNPs investigated, only rs11224561 in the 3' region of the PGR gene was found to be significantly associated with endometrial cancer risk. The A allele of the rs11224561 SNP was associated with increased risk of endometrial cancer (OR per allele 1.31; 95% CI 1.12-1.53, P = 0.001, adjusted for age and study), an effect of the same magnitude and direction as reported previously. We have validated the endometrial cancer risk association with a tagSNP in the 3' untranslated region of PGR previously reported in an Asian population. Replication studies will be required to refine the risk estimate and to establish if this, or a correlated SNP, is the underlying causative variant.     

Genetic polymorphisms in obesity-related genes and endometrial cancer risk

BACKGROUND:

Obesity is associated with circulating levels of adiponectin and leptin and endometrial cancer risk. Little is known about whether single nucleotide polymorphisms (SNPs) in the genes that encode adiponectin (ADIPOQ), leptin (LEP), adiponectin receptor 1 (ADIPOR1), adiponectin receptor 2 (ADIPOR2), and leptin receptor (LEPR) are associated with endometrial cancer.

METHODS:

The authors selected 87 tagging SNPs to capture common genetic variants in these 5 genes. These SNPs were evaluated in 1028 endometrial cancer cases and 1932 community controls recruited from Chinese women. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs).

RESULTS:

Three of the 10 SNPs evaluated in the ADIPOQ gene were significantly associated with reduced cancer risk. The OR for women homozygous for the minor allele (A/A) for rs3774262 was 0.68 (95% CI, 0.48‐0.97) compared with women homozygous for the major allele (G/G). Similar results were found for SNPs rs1063539 and rs12629945 in ADIPOQ, which were in linkage disequilibrium with rs3774262. These associations became nonsignificant after Bonferroni correction was applied. Controls with the minor allele A at rs3774262 had lower weight, smaller waist and hip circumferences, and lower body mass index than controls with the major allele G (all P < .05). Women homozygous for the minor allele (T/T) of rs2071045 in the LEP gene also had significantly lower risk (OR, 0.70; 95% CI, 0.54‐0.90) than women homozygous for the major allele (C/C). No other SNPs in the LEP, ADIPOR1, ADIPOR2, or LEPR genes were found to be associated with cancer risk.

CONCLUSIONS:

Although a chance finding cannot be ruled out, the consistency of findings for gene‐endometrial cancer risk and gene‐obesity measurements suggests that genetic polymorphisms in the ADIPOQ gene may play a role in endometrial cancer development. Cancer 2011. © 2011 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.     

The modifying effect of C-reactive protein gene polymorphisms on the association between central obesity and endometrial cancer risk

BACKGROUND.

Obesity is a major risk factor for endometrial cancer. Obesity, particularly central obesity, is considered as a systemic inflammatory condition and is related strongly to insulin resistance. C‐reactive protein (CRP) is the most recognized biologic marker of chronic systematic inflammation, and it is conceivable that the CRP gene may work together with obesity in the development of endometrial cancer.

METHODS.

On the basis of a population‐based case–control study in a Chinese population, the authors obtained obesity measurements and data on 6 CRP single‐nucleotide polymorphisms (SNPs) from 1046 patients with newly diagnosed endometrial cancer (cases) and from 1035 age frequency‐matched controls. The association of the CRP SNPs with endometrial cancer risk and their modification on the association between obesity and endometrial cancer risk were evaluated.

RESULTS.

Although CRP SNPs alone were not associated with endometrial cancer, the associations of endometrial cancer with central obesity, measured as the waist‐to‐hip ratio (WHR) and the waist circumference, seemed to be stronger in women who were homozygous for the major allele of reference SNP (rs)1130864 (cytidine [C]/C) than in women who had the C/thymidine (T) and T/T genotypes (interaction test: P = .013 for WHR; P = .083 for waist circumference). When the women were stratified further by menopausal status, the observed interactions persisted mainly in premenopausal women (interaction test: P < .001 for WHR; P = .002 for waist circumference).

CONCLUSIONS.

The current results suggested that, in the Chinese population that was studied, obesity‐related insulin resistance and proinflammatory effects may play an important role in endometrial cancer risk, and these effects were modified significantly by the CRP SNP rs1130864. Cancer 2008. © 2008 American Cancer Society.     

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.     

Comprehensive pathway-based interrogation of genetic variations in the nucleotide excision DNA repair pathway and risk of bladder cancer

BACKGROUND:

Growing evidence suggests that single nucleotide polymorphisms (SNPs) in nucleotide excision repair (NER) pathway genes play an important role in bladder cancer etiology. However, only a limited number of genes and variations in this pathway have been evaluated to date.

METHODS:

In this study, the authors applied a comprehensive pathway‐based approach to assess the effects of 207 tagging and potentially functional SNPs in 26 NER genes on bladder cancer risk using a large case‐control study that included 803 bladder cancer cases and 803 controls.

RESULTS:

In total, 17 SNPs were associated significantly with altered bladder cancer risk (P < .05), of which, 7 SNPs retained noteworthiness after they were assessed with a Bayesian approach for the probability of false discovery. The most noteworthy SNP was reference SNP 11132186 (rs11132186) in the inhibitor of growth family, member 2 (ING2) gene. Compared with the major allele‐containing genotypes, the odds ratio was 0.52 (95% confidence interval, 0.32‐0.83; P = .005) for the homozygous variant genotype. Three additional ING2 variants also exhibited significant associations with bladder cancer risk. Significant gene‐smoking interactions were observed for 3 of the top 17 SNPs. Furthermore, through an exploratory classification and regression tree (CART) analysis, potential gene‐gene interactions were identified.

CONCLUSIONS:

In this a large association study of the NER pathway and the risk of bladder cancer, several novel predisposition variants were identified along with potential gene‐gene and gene‐environment interactions in modulating bladder cancer risk. The results reinforce the importance of a comprehensive, pathway‐focused, and tagging SNP‐based candidate gene approach to identify low‐penetrance cancer susceptibility loci. Cancer 2012;. © 2011 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.     

Genetic variation in innate immunity and inflammation pathways associated with lung cancer risk

BACKGROUND:

Pulmonary inflammation may contribute to lung cancer etiology. The authors conducted a broad evaluation of the association of single nucleotide polymorphisms (SNPs) in innate immunity and inflammation pathways with lung cancer risk and conducted comparisons with a lung cancer genome‐wide association study (GWAS).

METHODS:

In total, 378 patients with lung cancer (cases) and a group of 450 controls from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were included. A proprietary oligonucleotide pool assay was used to genotype 1429 SNPs. Odds ratios and 95% confidence intervals were estimated for each SNP, and P values for trend (P_trend) were calculated. For statistically significant SNPs (P_trend < .05), the results were replicated with genotyped or imputed SNPs in the GWAS, and P values were adjusted for multiple testing.

RESULTS:

In the PLCO analysis, a significant association was observed between lung cancer and 81 SNPs located in 44 genes (P_trend < .05). Of these 81 SNPS, there was evidence for confirmation in the GWAS for 10 SNPs. However, after adjusting for multiple comparisons, the only SNP that retained a significant association with lung cancer in the replication phase was reference SNP rs4648127 (nuclear factor of kappa light polypeptide gene enhancer of B‐cells 1 [NFKB1]) (multiple testing‐adjusted P_trend = .02). The cytosine‐thymine (CT)/TT genotype of NFKB1 was associated with reduced odds of lung cancer in the PLCO study (odds ratio, 0.56; 95% confidence interval, 0.37‐0.86) and the in the GWAS (odds ratio, 0.79; 95% confidence interval, 0.69‐0.90).

CONCLUSIONS:

A significant association was observed between a variant in the NFKB1 gene and the risk of lung cancer. The current findings add to evidence implicating inflammation and immunity in lung cancer etiology. Cancer 2012. Published 2012 by the American Cancer Society.     

Identification of novel germline polymorphisms governing capecitabine sensitivity

BACKGROUND:

Capecitabine, an oral 5‐fluorouracil (5‐FU) prodrug, is widely used in the treatment of breast, colorectal, and gastric cancers. To guide the selection of patients with potentially the greatest benefit of experiencing antitumor efficacy, or, alternatively, of developing toxicities, identifying genomic predictors of capecitabine sensitivity could permit its more informed use.

METHODS:

The objective of this study was to perform capecitabine sensitivity genome‐wide association studies (GWAS) using 503 well genotyped human cell lines from individuals representing multiple different world populations. A meta‐analysis that included all ethnic populations then enabled the identification of novel germline determinants (single nucleotide polymorphisms [SNPs]) of capecitabine susceptibility.

RESULTS:

First, an intrapopulation GWAS of Caucasian individuals identified reference SNP 4702484 (rs4702484) (within adenylate cyclase 2 [ADCY2]) at a level reaching genome‐wide significance (P = 5.2 × 10^?8). This SNP is located upstream of the 5 methyltetrahydrofolate‐homocysteine methyltransferase reductase (MTRR) gene, and it is known that the enzyme for MTRR is involved in the methionine‐folate biosynthesis and metabolism pathway, which is the primary target of 5‐FU‐related compounds, although the authors were unable to identify a direct relation between rs4702484 and MTRR expression in a tested subset of cells. In the meta‐analysis, 4 SNPs comprised the top hits, which, again, included rs4702484 and 3 additional SNPs (rs8101143, rs576523, and rs361433) that approached genome‐wide significance (P values from 1.9 × 10^?7 to 8.8 × 10^?7). The meta‐analysis also identified 1 missense variant (rs11722476; serine to asparagine) within switch/sucrose nonfermentable‐related, matrix‐associated, actin‐dependent regulator of chromatin (SMARCAD1), a novel gene for association with capecitabine/5‐FU susceptibility.

CONCLUSIONS:

Toward the goal of individualizing cancer chemotherapy, the current study identified novel SNPs and genes associated with capecitabine sensitivity that are potentially informative and testable in any patient regardless of ethnicity. Cancer 2011. © 2011 American Cancer Society.     

SNP-SNP interactions between DNA repair genes were associated with breast cancer risk in a Korean population

BACKGROUND:

Single nucleotide polymorphisms (SNPs) in nucleotide excision repair (NER) pathway genes may modulate DNA repair capacity and increase susceptibility to breast cancer (BC). A case‐control study was conducted by evaluating genes involved in DNA repair to identify polymorphisms associated with BC.

METHODS:

The 384 SNPs of 38 candidate genes were genotyped using the Illumina GoldenGate method. Genotypes were determined in a case‐control study that consisted of 346 BC patients and 361 controls. Odds ratios and 95% confidence intervals were computed using logistic regression models. Multiple logistic regression models adjusted for age, family history of BC, and body mass index were used.

RESULTS:

Gene–gene interaction analysis among the DNA repair pathway genes showed significant effects on BC risk. ERCC2 rs50872 (TC genotype) in combination with XPA rs2808668 (TC genotype) and rs1800975 (AG genotype) was strongly associated with an increased risk of BC (P = .0004 and .0002, P_Bonferroni = .023 and .014, respectively). Moreover, the T‐G (including rs2808668 and rs1800975) haplotype in XPA combined with the ERCC2 T allele in rs50872 carriers was also associated with additive risk effect of BC (odds ratios: 2.58, 2.62, and 3.49, respectively).

CONCLUSION:

Genetic variation in DNA repair genes involved in NER mechanisms increased the risk of BC development. These results suggested that a stronger combined effect of SNPs via gene–gene interaction may help to predict BC risk. Cancer 2012;. © 2011 American Cancer Society.     

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.     

Polymorphic markers associated with severe oxaliplatin-induced, chronic peripheral neuropathy in colon cancer patients

BACKGROUND:

To identify potential genetic markers for severe oxaliplatin‐induced chronic peripheral neuropathy (OXCPN), the authors performed a genome‐wide association analysis of patients with colon cancer who received oxaliplatin‐based chemotherapy.

METHODS:

This was a prospective study in which DNA was purified in peripheral blood from patients with colon cancer who received oxaliplatin. The primary endpoint was the development of severe (grade 2 lasting for >7 days or grade 3) OXCPN. For the discovery set, genotyping was done for 96 patients who received adjuvant fluorouracil and oxaliplatin using the a genome‐wide human single‐nucleotide polymorphism (SNP) array. An association between polymorphisms and severe OXCPN was investigated. At the same time, 247 patients who received oxaliplatin‐based, first‐line chemotherapy for advanced disease were enrolled as a validation set.

RESULTS:

Among the 32 genotyped candidate SNPs selected from the discovery set, 9 SNPs in 8 genes (tachykinin, precursor 1[TAC1]; forkhead box C1 [FOXC1]; integrin, alpha 1 [ITGA1]; acylphosphatase 2, muscle type [ACYP2]; deleted in lymphocytic leukemia, 7 [DLEU7]; B‐cell translocation gene 4 [BTG4]; calcium/calmodulin‐dependent protein kinase II inhibitor 1 [CAMK2N1]; and phenylalanyl‐tRNA synthase 2 [FARS2]) had nominal replication (P < .05). The most significant association was observed at reference SNP number (rs)10486003 in TAC1 (P = 4.84 × 10^?7) in combined data from 2 sets. Five SNPs (rs10486003, rs2338, rs830884, rs843748, and rs797519) were significant in a multiple regression analysis (P < .05). Overall prediction accuracy calculated by the regression model was 72.8% (95% confidence interval, 65.8%‐79.9%) in the model development and 75.9% (95% confidence interval, 66.9%‐84.9%) in the model evaluation.

CONCLUSIONS:

The current results indicated that a genome‐wide pharmacogenomic approach is useful for identifying novel polymorphism predictors of severe OXCPN that may be used in personalized chemotherapy. Cancer 2011;. © 2011 American Cancer Society.     

Identification of polymorphisms in ultraconserved elements associated with clinical outcomes in locally advanced colorectal adenocarcinoma

BACKGROUND:

Ultraconserved elements (UCEs) are noncoding genomic sequences that completely identical among human, mouse, and rat species and harbor critical biologic functions. The authors hypothesized that single nucleotide polymorphisms (SNPs) within UCEs are associated with clinical outcomes in patients with colorectal cancer (CRC).

METHODS:

Forty‐eight SNPs within UCEs were genotyped in 662 patients with stage I through III CRC. The associations between genotypes and recurrence and survival were analyzed in patients with stage II or III CRC who received fluoropyrimidine‐based adjuvant chemotherapy using a training and validation design. The training set included 115 patients with stage II disease and 170 patients with stage III disease, and the validation set included 88 patients with stage II disease and 112 patients with stage III disease.

RESULTS:

Eight SNPs were associated with clinical outcomes stratified by disease stage. In particular, for patients with stage II CRC who had at least 1 variant allele of reference SNP sequence 7849 (rs7849), a consistent association with increased recurrence risk was observed in the training set (hazard ratio [HR], 2.39; 95% confidence interval [CI], 1.04‐5.52), in the replication set (HR, 3.70; 95% CI, 1.42‐9.64), and in a meta‐analysis (HR, 2.89; 95% CI, 1.54‐5.41). Several other SNPs were significant in the training set but not in the validation set. These included rs2421099, rs16983007, and rs10211390 for recurrence and rs6590611 for survival in patients with stage II disease; and SNPs rs6124509 and rs11195893 for recurrence in patients with stage III disease. In addition, a significant cumulative effect was observed of multiple risk genotypes and potential gene‐gene interactions on recurrence risk.

CONCLUSIONS:

To the authors' knowledge, this is the first study to evaluate the association between SNPs within UCEs and clinical outcome in patients with CRC. The results suggested that SNPs within UCEs may be valuable prognostic biomarkers for patients with locally advanced CRC who receive 5‐fluorouracil–based chemotherapy. Cancer 2012. © 2012 American Cancer Society.     

The adiponectin gene single-nucleotide polymorphism rs1501299 is associated with hepatocellular carcinoma risk

Purpose

Increasing lines of evidence have suggested that adiponectin, an adipocyte-derived hormone, plays an important role in the development of hepatocellular carcinoma (HCC). However, the relationship between genetic variants of the adiponectin gene (ADIPOQ) and HCC has not been previously explored. Therefore, we performed a case–control study to examine the association of haplotype-tagging single-nucleotide polymorphisms (SNPs) in ADIPOQ with HCC risk.

Methods

Five haplotype-tagging SNPs of ADIPOQ (rs266729, rs822395, rs822396, rs2241766 and rs1501299) were genotyped in 200 HCC patients and 200 non-HCC controls by PCR amplification and direct sequencing. Logistic regression was used to estimate the risk of HCC associated with each individual SNP and we adjusted for multiple testing by the Bonferroni correction.

Results

Of the five tested SNPs, rs1501299 showed a strong and significant association with HCC risk even after the Bonferroni correction. After adjusting for the serological status of the hepatitis virus B core antibody and for other SNPs, the odds ratios were 4.33 [95 % confidence interval (CI) 2.07–9.05; corrected P < 0.005] and 3.71 (95 % CI 1.84–7.48; corrected P < 0.005) for the GG genotype and GG/GT combined genotype, respectively, versus the TT genotype.

Conclusions

This is the first report, demonstrating an association of ADIPOQ polymorphisms with HCC risk. Our results implicate the ADIPOQ SNP rs1501299 as a susceptibility locus for HCC.     

Association of <Emphasis Type="Italic">TP53</Emphasis>codon 72 polymorphism and the outcome of adjuvant therapy in breast cancer patients

Introduction  

Single-nucleotide polymorphisms (SNPs) in codon 72 of the TP53 (also known as p53) gene (rs1042522) and in the promoter region of the MDM2 gene (SNP309; rs2279744) have been suggested to play roles in many cancers. We investigated whether these SNPs were associated with patient outcome and the effect of adjuvant systemic therapy.     

Caspase‐8 polymorphisms and risk of gallbladder cancer in a Northern Indian population

Caspase‐8 (CASP8) is a key controller of apoptosis, and its deregulation plays an important role in carcinogenesis. To evaluate the role of CASP8 polymorphisms in gallbladder cancer (GBC), we examined the risk associated with three single‐nucleotide polymorphisms (SNPs) in a case–control study in North Indian population. Genotypes and haplotypes of the CASP8 polymorphisms (?652 6N ins/del; rs3834129, Ex13 + 51G > C; rs1045485 and IVS12‐19 G > A; rs3769818) were determined for 230 GBC patients and 230 cancer‐free controls randomly selected from the population. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated in multivariate logistic regression analysis for the association of individual SNPs and haplotypes with GBC. Carriers for the “del” allele of rs3834129 SNP were associated with a 0.60‐fold decreased risk for GBC (95% CI = 0.42–0.88; P_trend = 0.005). In the combined analysis of the three CASP8 variants, we found that the individuals with the diplotypes carrying two copies of the common CASP8 del‐G‐G haplotype had 0.35‐fold reduced risk (95% CI = 0.14–0.85) when compared with the diplotype containing 0–1 copy. The false‐positive report probability (FPRP) approach advocated that these results were noteworthy (FPRP < 0.5). The molecular modeling results of rs1045485 polymorphism indicated that the overall configuration of both wild‐type and polymorphic CASP8 protein were similar, with negligible deviation at the site of the polymorphism itself. In summary, low penetrance variants in CASP8 gene may alter the susceptibility toward GBC. © 2010 Wiley‐Liss, Inc.     

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.     

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.