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.     

p73 G4C14‐to‐A4T14 polymorphism and risk of second primary malignancy after index squamous cell carcinoma of head and neck

P73 plays an important role in modulating cell‐cycle control, inducing apoptosis, and inhibiting cell growth. A novel noncoding p73 G4C14‐to‐A4T14 exon 2 polymorphism was associated with risk of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that p73 G4C14‐to‐A4T14 polymorphism modulates risk of second primary malignancies (SPM) in patients after index SCCHN. We followed a cohort of 1,384 patients diagnosed with incident SCCHN between May 1995 and January 2007 for SPM development. Log‐rank test and Cox proportional hazard models were used to compare SPM‐free survival and SPM risk between the different genotype groups. Our results showed that patients carrying the p73 variant AT allele were less likely to develop SPM compared with the patients with p73 GC/GC genotype (Log‐rank test, p = 0.013). Compared with the p73 GC/GC genotype, there was a significantly reduced risk of SPM associated with the p73 GC/AT genotype (HR, 0.61, 95% CI, 0.40–0.93) and the combined p73 GC/AT+AT/AT genotypes (HR, 0.59, 95% CI, 0.39–0.89), but a nonsignificantly reduced risk for p73 AT/AT genotype (HR, 0.44, 95% CI, 0.14–1.41). The p73 AT allele was significantly associated with risk of SPM in an allele dose‐response manner (p = 0.011 for trend). The risk of SPM associated with p73 variant genotypes (GC/AT+AT/AT) was more pronounced in several subgroups (e.g., older patients, men, minorities, ever smokers, and ever drinkers). Our results support that this p73 polymorphism may be a marker for risk of SPM among patients with an incident SCCHN. © 2009 UICC     

A possible primary cause of cancer: deficient cellular interactions in endocrine pancreas

Background

Cell cycle deregulation is common in human cancer, and alterations of p27 and p21, two critical cell cycle regulators, have been implicated in the development of many human malignancies. Therefore, we hypothesize that p27 T109G polymorphism individually or in combination with p21 (C98A and C70T) polymorphisms modifies risk of second primary malignancy (SPM) in patients with index squamous cell carcinoma of head and neck (SCCHN).

Methods

A cohort of 1,292 patients with index SCCHN was recruited between May 1995 and January 2007 at the M.D. Anderson Cancer Center and followed for SPM occurrence. Patients were genotyped for the three polymorphisms. A log-rank test and Cox proportional hazards models were used to compare SPM-free survival and SPM risk.

Results

We found that patients with p27 109 TG/GG, p21 98 CA/AA and p21 70 CT/TT variant genotypes had a worse SPM-free survival and an increased SPM risk than those with the corresponding p27109 TT, p21 98 CC, and p21 70 CC common genotypes, respectively. After combining the three polymorphisms, there was a trend for significantly increased SPM risk with increasing number of the variant genotypes (P _trend = 0.0002). Moreover, patients with the variant genotypes had an approximately 2.4-fold significantly increased risk for SPM compared with those with no variant genotypes (HR, 2.4, 95% CI, 1.6-3.6).

Conclusions

These results suggest that p27 T109G polymorphism individually or in combination with p21 (C98A and C70T) polymorphisms increases risk of SPM in patients with index SCCHN.     

Genetic variants of JNK and p38α pathways and risk of non‐small cell lung cancer in an Eastern Chinese population

The JNK and p38α pathways play an important role in carcinogenesis. Therefore, we hypothesize that single nucleotide polymorphisms (SNPs) of genes involved in these pathways are associated with risk of lung cancer. We first selected and genotyped 11 independent SNPs of the JNK and p38α pathway‐related genes in a discovery set of 1,002 non‐small cell lung cancer (NSCLC) cases and 1,025 cancer‐free controls of Eastern Chinese. Then, we validated those significant SNPs in a replication set of 1,333 NSCLC cases and 1,339 cancer‐free controls of Eastern Chinese. Multifactor dimensionality reduction (MDR) and classification and regression tree (CART) analyses were used to identify interactions between significant SNPs and other covariates. In both discovery and replication as well as their pooled analysis, carriers of GADD45G rs8252T variant genotypes had a significantly lower risk of NSCLC (adjusted OR = 0.81 and 0.79, 95% CI = 0.72–0.92 and 0.64–0.99 and p = 0.001 and 0.040 for dominant and recessive genetic models, respectively) and carriers of MAP2K7 rs3679T variant genotypes had an increased risk of NSCLC (adjusted OR = 1.19 and 1.29, 95% CI = 1.05–1.34 and 1.09–1.54 and p = 0.005 and 0.004 for dominant and recessive genetic models, respectively). Furthermore, rs8252 variant CT/TT carriers showed significantly higher levels of GADD45G mRNA expression than CC carriers in the target tissues. We observed some evidence of interactions between rs8252 genotypes and sex in NSCLC risk. These results indicate that GADD45G rs8252 and MAP2K7 rs3679 SNPs may be susceptibility biomarkers for NSCLC in Eastern Chinese populations.     

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.     

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.     

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.     

p73 G4C14-to-A4T14 polymorphism and risk of human papillomavirus-associated squamous cell carcinoma of the oropharynx in never smokers and never drinkers

BACKGROUND.

The p53 tumor suppressor protein homolog p73 can be inactivated by oncoprotein E6 of human papillomavirus (HPV). Variation in p73 may alter the interaction between the E6 protein and p73 and, thus, alter the risk for HPV‐associated carcinogenesis. It is believed that the p73 G4C14‐to‐A4T14 polymorphism affects p73 function by altering gene expression; however, whether that polymorphism also alters the risk of HPV type 16 (HPV‐16)‐associated squamous cell carcinoma of the oropharynx (SCCOP) is unknown.

METHODS.

The current case‐control study included a case group of 188 non‐Hispanic white patients with newly diagnosed SCCOP and a control group of 349 healthy individuals. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for cases and controls stratified by p73 genotype, age, sex, smoking status, alcohol use, and HPV‐16 status. The effects of p73 genotypes on the risk of HPV‐16‐associated SCCOP were explored with further stratification by smoking and drinking status.

RESULTS.

HPV‐16 seropositivity was associated with an increased risk of SCCOP (adjusted OR, 5.98; 95% CI, 3.89‐9.20), especially among never smokers (adjusted OR, 13.8; 95% CI, 5.91‐32.1), never drinkers (adjusted OR, 14.9; 95% CI, 5.24‐42.4), and individuals with p73 variant genotypes (GC/AT and AT/AT; adjusted OR, 7.96; 95% CI, 3.83‐16.5). Moreover, the risk of HPV‐16‐associated SCCOP for individuals who had p73 variant genotypes was particularly high in never smokers and never drinkers.

CONCLUSIONS.

The p73 G4C14‐to‐A4T14 polymorphism may modulate the risk of HPV‐16‐associated SCCOP, and the p73 variant genotypes may be markers of genetic susceptibility to HPV‐16‐associated SCCOP, particularly in never smokers and never drinkers. Cancer 2008. © 2008 American Cancer Society.     

p14ARF expression in invasive breast cancers and ductal carcinoma in situ – relationships to p53 and Hdm2

Introduction  

p14^ARF stabilises nuclear p53, with a variable expression of p14^ARF mRNA in breast cancers. In vitro, nuclear p14^ARF binds Hdm2 to block Hdm2-dependent nucleocytoplasmic shuttling of p53, which is required before cytoplasmic degradation of p53. p14^ARF is negatively regulated by p53 and through p53-independent pathways. No studies have yet examined levels of p14^ARF protein expression in breast cancer and their relationship to Hdm2/p53 immunoreactivity or subcellular localisation. Previously, immunohistochemical expression of cytoplasmic p14^ARF, p53 and Hdm2 has been described. HER-2 (c-erbB2/neu) predicts prognosis and interacts with the p14^ARF/Hdm2 pathway to inactivate p14^ARF and to influence Hdm2 activity and localisation. This study examined p14^ARF and p53/Hdm2 expression and subcellular localisation by using immunohistochemistry in a series of invasive ductal breast cancers (IDCs) with concomitant ductal carcinoma in situ (DCIS), to evaluate whether findings in vitro were related to clinicopathological parameters such as HER-2 and their effect on patient outcome.     

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.     

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.     

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.     

Modifying effect of MDM4 variants on risk of HPV16-associated squamous cell carcinoma of oropharynx

BACKGROUND:

The p53 pathway plays a critical role in maintaining genomic stability and preventing tumor formation. Given the roles of both MDM4 and HPV16 E6 oncoproteins in inhibition of p53 activity, we tested the hypothesis that MDM4 polymorphisms are associated with the risk of HPV16‐associated squamous cell carcinoma of head and neck (SCCHN).

METHODS:

Genotyping was conducted on 3 tagging single nucleotide polymorphisms (rs11801299 G>A, rs10900598 G>T, and rs1380576 C>G) in MDM4, and serology was used to determine HPV 16 exposure in 380 cases and 335 cancer‐free controls that were frequency‐matched by age, sex, smoking, and drinking status.

RESULTS:

None of 3 MDM4 polymorphisms alone was significantly associated with risk of overall SCCHN. With further analysis stratified by HPV16 serology and tumor site, we found that each polymorphism individually modified the risk of HPV16‐associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly pronounced in never smokers and never drinkers.

CONCLUSION:

The risk of HPV16‐associated SCCOP could be modified by MDM4 polymorphisms. Large and prospective studies are needed to validate our findings. Cancer 2011;. © 2011 American Cancer Society.     

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.     

Genetic variants in the genes encoding rho GTPases and related regulators predict cutaneous melanoma‐specific survival

Rho GTPases control cell division, motility, adhesion, vesicular trafficking and phagocytosis, which may affect progression and/or prognosis of cancers. Here, we investigated associations between genetic variants of Rho GTPases‐related genes and cutaneous melanoma‐specific survival (CMSS) by re‐analyzing a published melanoma genome‐wide association study (GWAS) and validating the results in another melanoma GWAS. In the single‐locus analysis of 36,018 SNPs in 129 Rho‐related genes, 427 SNPs were significantly associated with CMSS (p < 0.050 and false‐positive report probability <0.2) in the discovery dataset, and five SNPs were replicated in the validation dataset. Among these, four SNPs (i.e ., RHOU rs10916352 G > C, ARHGAP22 rs3851552 T > C, ARHGAP44 rs72635537 C > T and ARHGEF10 rs7826362 A > T) were independently predictive of CMSS (a meta‐analysis derived p = 9.04 × 10^?4, 9.58 × 10^?4, 1.21 × 10^?4 and 8.47 × 10^?4, respectively). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had markedly reduced CMSS in both discovery dataset and validation dataset (p _trend=1.47 × 10^?7 and 3.12 × 10^?5). The model including the NUGs and clinical variables demonstrated a significant improvement in predicting the five‐year CMSS. Moreover, rs10916352C and rs3851552C alleles were significantly associated with an increased mRNA expression levels of RHOU (p = 1.8 × 10^?6) and ARHGAP22 (p = 5.0 × 10^?6), respectively. These results may provide promising prognostic biomarkers for CM personalized management and treatment.     

Ratio of Expression of p16INK4a to p14ARF Correlates with the Progression of Non-small Cell Lung Cancer

The CDKN2 gene is located on the short arm of chromosome 9p and encodes two unrelated proteins, p16^INK4a and p14^ARF, through the use of independent first exons and shared exons 2 and 3. p16^INK4a is a cyclin‐dependent kinase inhibitor, whereas p14^ARF regulates the cell cycle through a p53 and MDM2–dependent pathway. We have examined the expression of p16^INK4a and p14^ARF using competitive RT‐PCR in 60 non‐small cell lung cancers (NSCLCs) and matching normal lung tissues. The intensities of bands for p16^INK4a and p14^ARF were nearly equal or the intensity of the p16^INK4a band slightly exceeded that of p14^ARF in the normal lung tissues (n=60). In 38 tumors the intensity of the p16^INK4a band was similar to or slightly weaker than that of p14^ARF. In 6 tumors the intensity of the p16^INK4a band was weaker than that of p14^ARF. In 15 tumors the intensity of the p14^ARF band was very strong and the p16^INK4a band was barely visible. In only one tumor was the intensity of the p16^INK4a band very strong, while the band of p14^ARF was barely visible. The ratio of the intensity of p16^INK4a to p14^ARF had an interesting correlation with the tumor's clinicopathological characteristics. The p stage II‐IV tumors had significantly lower p16^INK4a to p14^ARF ratios than the p stage I tumors (P=0.036). The T2–4 tumors had significantly lower p16^INK4a to p14^ARF ratios than the T1 tumors (P=0.005). The N1–3 tumors had significantly lower p16^INK4a to p14^ARF ratios than the NO tumors (P=0.014). Our results suggest that the ratio of expression of p16^INK4a to p14^ARFtends to decrease during the progression of NSCLC.     

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.     

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.     

Polymorphisms in ERCC2, MSH2, and OGG1 DNA repair genes and gallbladder cancer risk in a population of Northern India

BACKGROUND:

Genetic variants of DNA repair enzymes may lead to genetic instability and contribute to gallbladder (GB) carcinogenesis.

METHODS:

A case‐control study (230 GB carcinogenesis patients and 230 controls) was undertaken to evaluate whether genetic variations in 3 DNA repair genes ERCC2 (Asp312Asn [rs1799793] and Lys751Gln [rs13181]), MSH2 (?118T>C [rs2303425] and IVS1 + 9G>C [rs2303426]), and OGG1 (Ser326Cys [rs1052133] and 748‐15C>G [rs2072668]) are associated with GB carcinogenesis risk in a North Indian population.

RESULTS:

The authors found that the ERCC2 Asp312Asn AA, MSH2 IVS1 + 9G>C CC, OGG1 Ser326Cys GG and CG + GG, and OGG1 748‐15C>G GG and CG + GG genotypes were significantly associated with an increased risk of GB carcinogenesis (odds ratio [OR], 2.1, 1.8, 2.5, 1.8, 2.0, and 1.6, respectively). In contrast, ERCC2 Lys751Gln, and MSH2 ?118T>C markers showed no significant associations with GB carcinogenesis risk, although because of the small sample size their effects cannot be ruled out. Female GB carcinogenesis patients with the OGG1 748‐15C>G GG, OGG1 Ser326Cys GG, and ERCC2 Asp312Asn genotypes had a greater risk for developing the disease (OR, 3.6, 7.7, and 2.7, respectively). There was a significant interaction between MSH2 IVS1 + 9G>C and OGG1 748‐15C>G polymorphisms (P = .001). Furthermore, individuals with >6 variant alleles of the studied polymorphisms were at 4‐fold increased risk for developing GB carcinogenesis. Classification and Regression Tree analysis revealed potential higher‐order gene‐gene interactions and categorized a few higher‐risk subgroups for GB carcinogenesis.

CONCLUSIONS:

These results suggest that genetic variants in the DNA repair pathways may be involved in GB carcinogenesis etiology. Cancer 2010. © 2010 American Cancer Society.