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 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.     

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.     

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.     

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.     

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.     

The Relationship Between Eight GWAS‐Identified Single‐Nucleotide Polymorphisms and Primary Breast Cancer Outcomes

Background.

Several single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome-wide association studies (GWAS). We investigated whether eight risk SNPs identified in GWAS were associated with breast cancer disease-free survival (DFS) and overall survival (OS) rates.

Patients and Methods.

A cohort of 739 white women with early-stage breast cancer was genotyped for eight GWAS-identified SNPs (rs2981582, rs1219648 [FGFR2], rs3803662, rs12443621, rs8051542 [TOX3], rs999737 [RAD51L1], rs6504950 [17q23], and rs4973768 [3p24]). Relationships between SNPs and breast cancer outcomes were evaluated using Cox proportional hazard regression models. The cumulative effects of SNPs on breast cancer outcomes were assessed by computing the number of at-risk genotypes.

Results.

At a median follow-up of 121 months (range: 188–231 months) for survivors, 237 deaths (32%) and 186 breast cancer events (25%) were identified among the 739 patients. After adjusting for age, clinical stage, and treatment, rs12443621 (16q12; p = .03) and rs6504950 (17q23; p = .008) were prognostic for OS but not DFS. A higher risk for death was also found in the multivariable analysis of patients harboring three or four at-risk genotypes of the GWAS SNPs compared to patients carrying two or less at-risk genotypes (hazard ratio: 1.60, 95% confidence interval: 1.23–2.24; p = .0008).

Conclusion.

The study results suggest that previously identified breast cancer risk susceptibility loci, rs12443621 (16q12) and rs6504950 (17q23), may influence breast cancer prognosis or comorbid conditions associated with overall survival. The precise molecular mechanisms through which these risk SNPs, as well as others that were not included in the analysis, influence clinical outcomes remain to be determined.     

Variant TP53BP1 rs560191 G>C is associated with risk of gastric cardia adenocarcinoma in a Chinese Han population

Objective:To investigate the association between gastric cardia adenocarcinoma（GCA） and ten functional single nucleotide polymorphisms（SNPs）,including TP53BP1 rs560191 G>C,CASP8 rsl035142 G>T,CASP7 rs3127075 G>C,CASP7 rs7907S19 C>A,and six C1orf10/CRNN variants.We performed a hospitalbased case-control study to evaluate the genetic effects of these SNPs.Methods:Two hundred and forty-three GCA cases and 476 controls were enrolled in this study.A customby-design 48-Plex SNPscan^TM Kit was used to determine their genotypes.Results:When the TP53BP1 rs560191 GG homozygote genotype was used as the reference group,the GC genotype was associated with a significantly increased risk of GCA.The CC genotype was not associated with the risk of GCA compared with the GG genotype.None of the CASP8 rs1035142 G>T,CASP7rs3127075 G>C,CASP7 rs7907519 C>A or the six C1orf10/CRNN polymorphisms showed a significant difference in genotype distributions between the cases and the controls.Conclusions:The results demonstrated that the functional polymorphism TP53BP1 rs560191 G>C might contribute to GCA susceptibility.However,the statistical power of our study was limited.Large,welldesigned stuthes and further functional investigations are needed to confirm our findings.     

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.     

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.     

<Emphasis Type="Italic">TP53</Emphasis>mutation status and gene expression profiles are powerful prognostic markers of breast cancer

Introduction  

Gene expression profiling of breast carcinomas has increased our understanding of the heterogeneous biology of this disease and promises to impact clinical care. The aim of this study was to evaluate the prognostic value of gene expression-based classification along with established prognostic markers and mutation status of the TP53 gene (tumour protein p53) in a group of breast cancer patients with long-term (12 to 16 years) follow-up.     

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.     

Genetic variants in <Emphasis Type="Italic">MMP9</Emphasis> and <Emphasis Type="Italic">TCF2</Emphasis> contribute to susceptibility to lung cancer

Objective|  

The Wnt signaling pathway is crucial for pulmonary development and differentiation; dysregulation of the Wnt signaling pathway may impair lung function. Indeed, single nucleotide polymorphisms (SNPs) of Wnt pathway-related genes have been suggested as risk factors for certain types of cancers. In this study, we aimed to evaluate the influence of SNPs in Wnt-related genes (TCF2, MMP9) on susceptibility to lung cancer.     

rs15869 at miRNA binding site in <Emphasis Type="Italic">BRCA2</Emphasis> is associated with breast cancer susceptibility

BRCA1 and BRCA2 mutations confer an increased lifetime risk of breast cancer; however, the associations of microRNA (miRNA) binding site single nucleotide polymorphisms (SNPs) in 3′ untranslated region (3′-UTR) of BRCA1 and BRCA2 with breast cancer (BC) risk were rarely reported. In this case–control study (498 BC patients and 498 matched controls), three SNPs (rs8176318, rs12516 and rs15869) were selected in the 3′-UTR of BRCA1 and BRCA2 genes, which were within miRNA-binding seed regions and might have potential function to regulate the expression of BRCA1/BRCA2. Unconditional logistic regression model was used to analyze the association between three SNPs and BC risk with adjustment of reproductive factors, and Student’s t test was performed to assess relative expression of BRCA2 in human breast cancer cell lines. Multifactor dimensionality reduction method was applied to calculate gene–reproductive factors interactions. A novel finding showed that AC [odds ratio (OR) 1.524; 95% confidence interval (CI) 1.141–2.035] genotype of rs15869 in BRCA2 could increase the risk of BC and recombinant plasmid-pGenesil-1-miR-627 could negatively regulate the expression of BRCA2 in MCF-7 and MDA-MB-231 cells. Gene–reproductive factors interactions analysis revealed that rs15869 together with age at menarche and number of pregnancy could increase the risk of BC by 2.39-fold and TT genotype (OR 0.316; 95% CI 0.130–0.767) of rs8176318 had a significant association with progesterone receptor status in BC patients. Our findings suggest that the miRNA-binding SNPs in BRCA1/BRCA2 and their interaction with reproductive factors might contribute to BC risk, and miR-627 might down-regulate BRCA2 expression in MCF-7 and MDA-MB-231 cells.     

Two-stage case-control study of common <Emphasis Type="Italic">ATM</Emphasis> gene variants in relation to breast cancer risk

The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene that plays a critical role in cell cycle arrest, apoptosis, and DNA repair. We evaluated two reported nonsynonymous SNPs (rs1800054 and rs1800058) and three additional common gene variants (rs664143, rs228589, rs1003623) in the ATM gene in relation to breast cancer risk. A two-stage case-control study, using data from the Shanghai Breast Cancer Study, was conducted in which all SNPs were screened in the stage I study, including 1,123 cases and 1,232 controls. Any promising associations were re-evaluated in the stage II study, including 2,003 cases and 1,918 controls. In the stage I study, with the exception of rs1003623, no apparent association was found for any other SNPs with breast cancer risk. For the rs1003623, the T allele was associated with an increased breast cancer risk among postmenopausal women with odds ratios (ORs) of 1.4 (95% Confidence Intervals (CIs) = 1.0−1.9) for the CT and 1.6 (95% CIs = 1.0−2.4) for the TT, (P for trend = 0.03). This association, however, was not replicated in the stage II study, suggesting that the positive association identified in stage I for rs1003623 may be due to chance. Our study reveals no apparent association of common ATM variants with breast cancer risk and underscores the importance of replication using independent samples to reduce type I errors in association studies of low-penetrance genetic factors.     

<Emphasis Type="Italic">PTTG</Emphasis>/securin activates expression of <Emphasis Type="Italic">p53</Emphasis> and modulates its function

Background  

Pituitary tumor transforming gene (PTTG) is a novel oncogene that is expressed abundantly in most tumors. Overexpression of PTTG induces cellular transformation and promotes tumor formation in nude mice. PTTG has been implicated in various cellular processes including sister chromatid separation during cell division as well as induction of apoptosis through p53-dependent and p53-independent mechanisms. The relationship between PTTG and p53 remains unclear, however.     

Tobacco,alcohol, and <Emphasis Type="Italic">p53</Emphasis> overexpression in early colorectal neoplasia

Background  

The p53 tumor suppressor gene is commonly mutated in colorectal cancer. While the effect of p53 mutations on colorectal cancer prognosis has been heavily studied, less is known about how epidemiologic risk factors relate to p53 status, particularly in early colorectal neoplasia prior to clinically invasive colorectal cancer (including adenomas, carcinoma in situ (CIS), and intramucosal carcinoma).     

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.     

Pharmacogenetic association between <Emphasis Type="Italic">GSTP1</Emphasis> genetic polymorphism and febrile neutropenia in Japanese patients with early breast cancer

Background

Genetic risk factors for febrile neutropenia (FN), the major adverse event of perioperative chemotherapy for early breast cancer, remain unclear.

Methods

This study retrospectively explored pharmacogenetic associations of single nucleotide polymorphisms (SNPs) of the uridine glucuronosyltransferase 2B7 (UGT2B7, rs7668258), glutathione-S-transferase pi 1 (GSTP1, rs1695), and microcephalin 1 (MCPH1, rs2916733) genes with chemotherapy-related adverse events in 102 Japanese women who received epirubicin and cyclophosphamide as perioperative chemotherapy for early breast cancer.

Results

The allele frequencies for all of the SNPs were in concordance with the Hap-Map data of Japanese individuals. Among the 24 patients who had FN at least once during all courses of chemotherapy, 23 had the A/A genotype, and 1 had the A/G genotype of the GSTP1 polymorphism (rs1695, P = 0.001); 23 of the 70 patients with the A/A genotype had FN, as compared with only 1 of the 32 patients with the A/G and G/G genotypes. The genotype distributions of the UGT2B7 and MCPH1 polymorphisms did not differ between the patients who had FN or grade 3/4 neutropenia and those who did not.

Conclusion

Among Japanese women who received epirubicin and cyclophosphamide as perioperative chemotherapy for early breast cancer, those with the A/A genotype of the GSTP1 polymorphism (rs1695) were more likely to have FN.

     

Functional polymorphisms of circadian positive feedback regulation genes and clinical outcome of Chinese patients with resected colorectal cancer

BACKGROUND:

Previous studies have demonstrated that circadian genes play a role in the development and progression of many cancers. This study aims to assess the effects of single nucleotide polymorphisms (SNPs) in circadian genes on recurrence and survival of colorectal cancer (CRC) patients.

METHODS:

Nine functional SNPs in 3 genes (CLOCK, NPAS2, and BMAL1) on the circadian positive feedback loop were selected and genotyped using the Sequenom iPLEX genotyping system in a cohort of 411 resected Chinese CRC patients. Multivariate Cox proportional hazards model and Kaplan‐Meier curve were used for the prognosis analysis.

RESULTS:

The authors identified 2 SNPs in the CLOCK gene to be significantly associated with CRC overall survival. SNP rs3749474 exhibited a significant association with survival of CRC patients in the additive model (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.37‐0.81; P = .003). In addition, patients carrying the heterozygous variant of rs1801260 had significantly increased overall survival compared with those carrying homozygous wild‐type genotype (HR, 0.31; 95% CI, 0.11‐0.88; P = .03). Findings from functional assay provided further biological support for these significant associations. Stratified analysis found no modifying effect of chemotherapy on the prognostic significance of both SNPs. Moreover, we observed cumulative effects of these 2 SNPs on CRC overall survival (P for trend = .01). Compared with patients carrying no unfavorable genotypes, those carrying 2 unfavorable genotypes had a 2.92‐fold increased risk of death (P = .03).

CONCLUSIONS:

The results suggest for the first time that CLOCK gene polymorphisms may serve as an independent prognostic marker for CRC patients. Cancer 2012;. © 2011 American Cancer Society.