Showing papers by "Qingyi Wei published in 2011"

Shortened Telomere Length Is Associated with Increased Risk of Cancer: A Meta-Analysis

Abstract: Background: Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting. Methods: A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. Heterogeneity among studies and their publication bias were further assessed by the x 2 -based Q statistic test and Egger’s test, respectively. Results: The results showed that shorter telomeres were significantly associated with cancer risk (OR=1.35, 95% CI=1.14‐ 1.60), compared with longer telomeres. In the stratified analysis by tumor type, the association remained significant in subgroups of bladder cancer (OR=1.84, 95% CI=1.38‐2.44), lung cancer (OR=2.39, 95% CI=1.18‐4.88), smoking-related cancers (OR=2.25, 95% CI=1.83‐2.78), cancers in the digestive system (OR=1.69, 95% CI=1.53‐1.87) and the urogenital system (OR=1.73, 95% CI=1.12‐2.67). Furthermore, the results also indicated that the association between the relative telomere length and overall cancer risk was statistically significant in studies of Caucasian subjects, Asian subjects, retrospective designs, hospital-based controls and smaller sample sizes. Funnel plot and Egger’s test suggested that there was no publication bias in the current meta-analysis (P=0.532). Conclusions: The results of this meta-analysis suggest that the presence of shortened telomeres may be a marker for susceptibility to human cancer, but single larger, well-design prospective studies are warranted to confirm these findings.

A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium

Abstract: Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

Genome-wide association study identifies three new melanoma susceptibility loci

Abstract: We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

Clinical Correlates of NRAS and BRAF Mutations in Primary Human Melanoma

Abstract: Purpose: NRAS and BRAF mutations are common in cutaneous melanomas, although rarely detected mutually in the same tumor. Distinct clinical correlates of these mutations have not been described, despite in vitro data suggesting enhanced oncogenic effects. This study was designed to test the hypothesis that primary human cutaneous melanomas harboring mutations in NRAS or BRAF display a more aggressive clinical phenotype than tumors wild type at both loci. Experimental Design: Microdissection of 223 primary melanomas was carried out, followed by determination of the NRAS and BRAF mutational status. Genotypic findings were correlated with features known to influence tumor behavior including age, gender, Breslow depth, Clark level, mitotic rate, the presence of ulceration, and American Joint Committee on Cancer (AJCC) staging. Results: Breslow depth and Clark level varied significantly among the genotypes, with NRAS mutants showing the deepest levels and wild-type tumors the least depth. Ulceration also differed significantly among the genotypes, with BRAF mutants demonstrating the highest rate. In addition, tumors with mutated NRAS were more likely to be located on the extremities. Patients whose tumors carried either mutation presented with more advanced AJCC stages compared with patients with wild-type tumors, and specifically, were more likely to have stage III disease at diagnosis. Overall survival did not differ among the 3 groups. Conclusions: Distinct clinical phenotypes exist for melanomas bearing NRAS and BRAF mutations, whether considered together or separately, and are associated with features known to predict aggressive tumor behavior. The impact of these mutations is most evident at earlier stages of disease progression. Clin Cancer Res; 17(2); 229–35. ©2010 AACR . Clin Cancer Res; 17(2); 229–35. ©2010 AACR .

Genome-wide association study identifies novel loci predisposing to cutaneous melanoma

Abstract: We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.

Relationship Between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 Variation and Smoking Behaviors and Lung Cancer Risk

Abstract: Genetic variations in the CYP2A6 nicotine metabolic gene and the CHRNA5-CHRNA3-CHRNB4 (CHRNA5-A3-B4) nicotinic gene cluster have been independently associated with lung cancer. With genotype data from ever-smokers of European ancestry (417 lung cancer patients and 443 control subjects), we investigated the relative and combined associations of polymorphisms in these two genes with smoking behavior and lung cancer risk. Kruskal–Wallis tests were used to compare smoking variables among the different genotype groups, and odds ratios (ORs) for cancer risk were estimated using logistic regression analysis. All statistical tests were two-sided. Cigarette consumption (P A) risk group. The combined risk group also exhibited the greatest lung cancer risk (OR = 2.03; 95% confidence interval [CI] = 1.21 to 3.40), which was even higher among those who smoked 20 or fewer cigarettes per day (OR = 3.03; 95% CI = 1.38 to 6.66). Variation in CYP2A6 and CHRNA5-A3-B4 was independently and additively associated with increased cigarette consumption, nicotine dependence, and lung cancer risk. CYP2A6 and CHRNA5-A3-B4 appear to be more strongly associated with smoking behaviors and lung cancer risk, respectively.

ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis.

Abstract: Purpose: Nucleotide excision repair (NER) modulates platinum-based chemotherapeutic efficacy by removing drug-produced DNA damage. To summarize published data on the association between polymorphisms of NER genes ( ERCC1 and ERCC2 ) and responses to oxaliplatin-based chemotherapies, we carried out a meta-analysis of gastric and colorectal cancer for commonly studied polymorphisms ERCC1 rs11615C>T and ERCC2 rs13181T>G. Patients and Methods: In 17 previously published studies, 1,787 cancer patients were treated with the oxaliplatin-based regimen. Primary outcomes included therapeutic response (TR; i.e., complete response + partial response vs. stable disease + progressive disease), progression-free survival (PFS), and overall survival (OS). We calculated OR or HR with 95% CIs to estimate the risk or hazard. Results: We found consistent and clinically substantial risk or hazard for TR, PFS, and OS in the oxaliplatin-treated gastric and colorectal cancer patients with an ethnic discrepancy. For ERCC1 rs11615C>T, the T allele was associated with reduced response and poor PFS and OS in Asians (TR: OR = 0.53 and 95% CI = 0.35–0.81; PFS: HR = 1.69 and 95% CI = 1.05–2.70; and OS: HR = 2.03 and 95% CI = 1.60–2.59). For ERCC2 rs13181T>G, the G allele was associated with reduced response and poor PFS and OS in Caucasians (TR: OR = 0.56 and 95% CI = 0.35–0.88; PFS: HR = 1.41 and 95% CI = 1.02–1.95; and OS: HR = 1.42 and 95% CI = 1.11–1.81). Conclusions: NER ERCC1 rs11615C>T and ERCC2 rs13181T>G polymorphisms are useful prognostic factors in oxaliplatin-based treatment of gastric and colorectal cancer. Larger studies and further clinical trials are warranted to confirm these findings. Clin Cancer Res; 17(6); 1632–40. ©2011 AACR.

Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

Abstract: We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 x 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 x 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

Genome-wide association study identifies novel alleles associated with risk of cutaneous basal cell carcinoma and squamous cell carcinoma

Abstract: We conducted a genome-wide association study on cutaneous basal cell carcinoma (BCC) among 2045 cases and 6013 controls of European ancestry, with follow-up replication in 1426 cases and 4845 controls. A non-synonymous SNP in the MC1R gene (rs1805007 encoding Arg151Cys substitution), a previously well-documented pigmentation gene, showed the strongest association with BCC risk in the discovery set (rs1805007[T]: OR (95% CI) for combined discovery set and replication set [1.55 (1.45–1.66); P= 4.3 × 10−17]. We identified that an SNP rs12210050 at 6p25 near the EXOC2 gene was associated with an increased risk of BCC [rs12210050[T]: combined OR (95% CI), 1.24 (1.17–1.31); P= 9.9 × 10−10]. In the locus on 13q32 near the UBAC2 gene encoding ubiquitin-associated domain-containing protein 2, we also identified a variant conferring susceptibility to BCC [rs7335046 [G]; combined OR (95% CI), 1.26 (1.18–1.34); P= 2.9 × 10−8]. We further evaluated the associations of these two novel SNPs (rs12210050 and rs7335046) with squamous cell carcinoma (SCC) risk as well as melanoma risk. We found that both variants, rs12210050[T] [OR (95% CI), 1.35 (1.16–1.57); P= 7.6 × 10−5] and rs7335046 [G] [OR (95% CI), 1.21 (1.02–1.44); P= 0.03], were associated with an increased risk of SCC. These two variants were not associated with melanoma risk. We conclude that 6p25 and 13q32 are novel loci conferring susceptibility to non-melanoma skin cancer.

Differences in history of sexual behavior between patients with oropharyngeal squamous cell carcinoma and patients with squamous cell carcinoma at other head and neck sites.

Abstract: Background An emerging epidemic of human papillomavirus (HPV)-associated oropharyngeal cancer has been proposed. We compared the sexual behaviors of patients with squamous cell carcinoma of the oropharynx (SCCOP) and patients with squamous cell carcinoma of non-oropharyngeal head and neck sites (SCCNOP) to expand our understanding of sexual behavior as a risk factor for HPV-associated head and neck cancer.

Association of Sequence Variants on Chromosomes 20, 11, and 5 (20q13.33, 11q23.3, and 5p15.33) With Glioma Susceptibility in a Chinese Population

Abstract: Two genome-wide association studies of glioma in European populations identified 14 genetic variants strongly associated with risk of glioma, but it is unknown whether these variants are associated with glioma risk in Asian populations. The authors genotyped these 14 variants in 976 glioma patients and 1,057 control subjects to evaluate their associations with risk of glioma, particularly high-grade glioma (glioblastoma; n = 312), in a Chinese population (2004-2009). Overall, the authors identified 3 susceptibility loci for glioma risk at 20q13.33 (RTEL1 rs6010620 (P = 2.79 x 10 -6 )), 11q23.3 (PHLDB1 rs498872 (P = 3.8 x 10 -6 )), and 5p15.33 (TERT rs2736100 (P = 3.69 × 10- 4 )) in this study population; these loci were also associated with glioblastoma risk (20q13.33: RTEL 1 rs6010620 (P = 3.57 x 10 -7 ); 11 q23.3: PHLDB1 rs498872 (P = 7.24 × 10 -3 ); 5p15.33: TERT rs2736100 and TERT rs2736098 (P = 1.21 × 10 -4 and P = 2.84 x 10- 4 , respectively)). This study provides further evidence for 3 glioma susceptibility regions at 20q13.33, 11q23.3, and 5p15.33 in Chinese populations.

A functional variant at the miR-184 binding site in TNFAIP2 and risk of squamous cell carcinoma of the head and neck

Abstract: Although the role of TNFAIP2 is still unclear, it is an important gene involved in apoptosis, and there are single-nucleotide polymorphisms (SNPs) at its microRNA (miRNA)-binding sites that could modulate miRNA target gene function. In this study, we evaluated associations of four selected SNPs (rs8126 T > C, rs710100 G > A, rs1052912 G > A and rs1052823 G > T) in the miRNA-binding sites of the 3' untranslated region (UTR) with squamous cell carcinoma of the head and neck (SCCHN) risk in 1077 patients with SCCHN and 1073 cancer-free controls in a non-Hispanic White population. We found that, compared with the rs8126 TT genotype, the variant C allele were associated with increased SCCHN risk in an allele dose-response manner (adjusted odds ratio = 1.48 and 95% confidence interval = 1.06-2.05 for CC, respectively; P(trend) = 0.009). No significant associations were seen for the other three SNPs (rs710100 G > A, rs1052912 G > A and rs1052823 G > T). Additionally, we identified that the rs8126 T > C SNP is within the miR-184 seed binding region in the 3' UTR of TNFAIP2. Further functional analyses showed that the rs8126 variant C allele led to significantly lower luciferase activity, compared with the T allele. In the genotype-phenotype correlation analysis of peripheral blood mononuclear cells from 64 SCCHN patients, the rs8126 CC genotype was associated with reduced expression of TNFAIP2 messenger RNA. Taken together, these findings indicate that the miR-184 binding site SNP (rs8126 T > C) in the 3' UTR of TNFAIP2 is functional by modulating TNFAIP2 expression and contributes to SCCHN susceptibility. Larger replication studies are needed to confirm our findings.

The role of polymorphisms in circadian pathway genes in breast tumorigenesis.

Abstract: Disruption of the circadian rhythm or biological clock, which is regulated by a number of clock genes, including circadian locomotor output cycles kaput (CLOCK), period genes (PERs), and cryptochrome genes (CRYs), is a risk factor for breast cancer. We hypothesized that genetic variation in these clock genes may influence breast cancer risk. To test this hypothesis, we designed a hospital-based study that included 1,538 breast cancer patients and 1,605 healthy controls. We genotyped subjects for five single nucleotide polymorphisms (SNPs) and a length variant of the circadian clock genes and evaluated their associations with breast cancer risk. These polymorphisms were determined by TaqMan allelic discrimination assays and the polymerase chain reaction-restriction fragment length polymorphism method. Univariate logistic regression analysis showed that polymorphisms of the CLOCK and CRY1 genes were associated with breast cancer risk. We found that carriers of the CLOCK CT and combined CT+TT genotypes had a significantly higher risk of breast cancer than carriers of the CC genotype (aOR = 1.35, 95% CI = 1.12-1.63 and aOR = 1.30, 95% CI = 1.09-1.56, respectively). Carriers of the CRY1 GT genotype had a decreased risk of breast cancer (aOR = 0.84, 95% CI = 0.71-0.99). We also observed a lower risk of breast cancer in carriers of the CRY2 CC genotype who were ER-positive than in those who were ER-negative (OR = 0.15, 95% CI = 0.04-0.67). When stratified by the CLOCK genotype, patients with the CLOCK CT/ CRY2 CC genotypes had significantly lower cancer risk than those with the GG genotype (aOR = 0.36, 95% CI = 0.14-0.95). Individuals carrying both the CLOCK CC and PER2 AA genotypes had an increased cancer risk (aOR = 2.28, 95% CI = 1.22-4.26). Our study suggests that genetic variants of the circadian rhythm regulatory pathway genes contribute to the differential risk of developing breast cancer in Chinese populations.

DNA Repair Capacity in Peripheral Lymphocytes Predicts Survival of Patients With Non–Small-Cell Lung Cancer Treated With First-Line Platinum-Based Chemotherapy

Abstract: Purpose Platinum-based regimens are the standard chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC). DNA repair capacity (DRC) in tumor cells plays an important role in resistance to platinum-based drugs. We have previously reported that efficient DRC, as assessed by an in vitro lymphocyte-based assay, was a determinant of poor survival in patients with NSCLC in a relatively small data set. In this larger independent study of 591 patients with NSCLC, we further evaluated whether DRC in peripheral lymphocytes predicts survival of patients with NSCLC who receive platinum-based chemotherapy. Patients and Methods All patients were recruited at The University of Texas MD Anderson Cancer Center and donated blood samples before the start of any chemotherapy. We measured DRC in cultured T lymphocytes by using the host-cell reactivation assay, and we assessed associations between DRC in peripheral lymphocytes and survival of patients with NSCLC who were treated with first-line platinum-base...

Polymorphisms of homologous recombination genes and clinical outcomes of non-small cell lung cancer patients treated with definitive radiotherapy.

Abstract: The repair of DNA double-strand breaks (DSBs) is the major mechanism to maintain genomic stability in response to irradiation. We hypothesized that genetic polymorphisms in DSB repair genes may affect clinical outcomes among non-small cell lung cancer (NSCLC) patients treated with definitive radio(chemo)therapy. We genotyped six potentially functional single nucleotide polymorphisms (SNPs) (i.e., RAD51 -135G>C/rs1801320 and -172G>T/rs1801321, XRCC2 4234G>C/rs3218384 and R188H/rs3218536 G>A, XRCC3 T241M/rs861539 and NBN E185Q/rs1805794) and estimated their associations with overall survival (OS) and radiation pneumonitis (RP) in 228 NSCLC patients. We found a predictive role of RAD51 -135G>C SNP in RP development (adjusted hazard ratio [HR] = 0.52, 95% confidence interval [CI], 0.31-0.86, P = 0.010 for CG/CC vs. GG). We also found that RAD51 -135G>C and XRCC2 R188H SNPs were independent prognostic factors for overall survival (adjusted HR = 1.70, 95% CI, 1.14-2.62, P = 0.009 for CG/CC vs. GG; and adjusted HR = 1.70; 95% CI, 1.02-2.85, P = 0.043 for AG vs. GG, respectively) and that the SNP-survival association was most pronounced in the presence of RP. Our study suggests that HR genetic polymorphisms, particularly RAD51 -135G>C, may influence overall survival and radiation pneumonitis in NSCLC patients treated with definitive radio(chemo)therapy. Large studies are needed to confirm our findings.

Functional Polymorphisms of Base Excision Repair Genes XRCC1 and APEX1 Predict Risk of Radiation Pneumonitis in Patients With Non–Small Cell Lung Cancer Treated With Definitive Radiation Therapy

Abstract: Purpose To explore whether functional single nucleotide polymorphisms (SNPs) of base-excision repair genes are predictors of radiation treatment-related pneumonitis (RP), we investigated associations between functional SNPs of ADPRT , APEX1 , and XRCC1 and RP development. Methods and Materials We genotyped SNPs of ADPRT (rs1136410 [V762A]), XRCC1 (rs1799782 [R194W], rs25489 [R280H], and rs25487 [Q399R]), and APEX1 (rs1130409 [D148E]) in 165 patients with non–small cell lung cancer (NSCLC) who received definitive chemoradiation therapy. Results were assessed by both Logistic and Cox regression models for RP risk. Kaplan-Meier curves were generated for the cumulative RP probability by the genotypes. Results We found that SNPs of XRCC1 Q399R and APEX1 D148E each had a significant effect on the development of Grade ≥2 RP ( XRCC1 : AA vs. GG, adjusted hazard ratio [HR] = 0.48, 95% confidence interval [CI], 0.24–0.97; APEX1 : GG vs. TT, adjusted HR = 3.61, 95% CI, 1.64–7.93) in an allele-dose response manner (Trend tests: p = 0.040 and 0.001, respectively). The number of the combined protective XRCC1 A and APEX1 T alleles (from 0 to 4) also showed a significant trend of predicting RP risk ( p = 0.001). Conclusions SNPs of the base-excision repair genes may be biomarkers for susceptibility to RP. Larger prospective studies are needed to validate our findings.

Genome-wide association study identifies nidogen 1 (NID1) as a susceptibility locus to cutaneous nevi and melanoma risk

Abstract: We conducted a genome-wide association study on the number of melanocytic nevi reported by 9136 individuals of European ancestry, with follow-up replication in 3581 individuals. We identified the nidogen 1 (NID1) gene on 1q42 associated with nevus count (two linked single nucleotide polymorphisms with r2 > 0.9: rs3768080 A allele associated with reduced count, P = 6.5 × 10−8; and rs10754833 T allele associated with reduced count, P = 1.5 × 10−7). We further determined that the rs10754833 [T] was associated with a decreased melanoma risk in 2368 melanoma cases and 7432 controls [for CT genotype: odds ratio (OR) = 0.86, 95% confidence interval (CI) = 0.75–0.99, P = 0.04; for TT genotype: OR = 0.84, 95% CI = 0.71–0.98, P = 0.03]. Expression level of the NID1 locus was 2-fold higher for the rs10754833 T allele carriers than that with the CC genotype (P = 0.017) in the 87 HapMap CEU cell lines. The NID1 gene is a biologically plausible locus for nevogenesis and melanoma development, with decreased expression levels of NID1 in benign nevi (P = 3.5 × 10−6) and in primary melanoma (P = 4.6 × 10−4) compared with the normal skin.

Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck.

Abstract: Background Phospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN). A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share similar risk factors with SCCHN. Therefore, we investigated the association between potentially functional SNPs in PLCE1 and susceptibility to SCCHN.

Effects of MDM2 promoter polymorphisms and p53 codon 72 polymorphism on risk and age at onset of squamous cell carcinoma of the head and neck.

Abstract: Both p53 tumor suppressor and murine double minute 2 (MDM2) oncoprotein are crucial in carcinogenesis. We hypothesized that MDM2 promoter single nucleotide polymorphism (SNP)309, A2164G, and p53 codon 72 SNP are associated with risk and age at onset of squamous cell carcinoma of head and neck (SCCHN). We genotyped these SNPs in a study of 1,083 Caucasian SCCHN cases and 1,090 cancer-free controls. Although none of these SNPs individually had a significant effect on risk of SCCHN, nor did their combined putative risk genotypes (i.e. MDM2 SNP309 GT + GG, 2164 AA, and p53 codon 72 CC), we found that individuals with 2–3 risk genotypes had significantly increased risk of non-oropharyngeal cancer (OR = 1.42; 95% CI=1.07–1.88). This increased risk was more pronounced among young subjects, men, smokers, and drinkers. In addition, female patients carrying the MDM2 SNP309 GT and GG genotypes showed a 3-year (56.7 years) and 9-year (51.2 years) earlier age at onset of non-oropharyngeal cancer (Ptrend = 0.007), respectively, compared with those carrying the TT genotype (60.1 years). The youngest age (42.5 years) at onset of non-oropharyngeal cancer was observed in female patients with the combined MDM2 SNP309 GG and p53 codon 72 CC genotypes. The findings suggest that MDM2 SNP309, A2164G, and p53 codon 72 SNPs may collectively contribute to non-oropharyngeal cancer risk and that MDM2 SNP309 individually or in combination with p53 codon 72 may accelerate the development of non-oropharyngeal cancer in women. Further studies with large sample sizes are warranted to validate these results.

An examination of male and female odds ratios by BMI, cigarette smoking, and alcohol consumption for cancers of the oral cavity, pharynx, and larynx in pooled data from 15 case–control studies

Abstract: Background Greater tobacco smoking and alcohol consumption and lower body mass index (BMI) increase odds ratios (OR) for oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers; however, there are no comprehensive sex-specific comparisons of ORs for these factors.

Genetic variants at the miR-124 binding site on the cytoskeleton-organizing IQGAP1 gene confer differential predisposition to breast cancer.

Abstract: IQGAP1 knockout mice develop gastric cancer, but the IQGAP1 protein is associated with some advanced-stage human cancers. IQGAP1 expression is regulated by a microRNA, miR-124, through a binding site at the 3'-untranslated region, where a single nucleotide polymorphism (SNP) exists in the core binding region. We asked whether IQGAP1 expression is associated with breast cancer development and whether genetic variants at the miR-124 binding site are important. We genotyped the IQGAP1 SNP rs1042538 A/T in 1,541 breast cancer cases and 1,598 controls and analyzed the frequency of the variant and interactions with major risk factors in these populations. We also measured the expression of IQGAP1 at both mRNA and protein levels in different IQGAP1 genotypes. The IQGAP1 TT genotype, compared with the AA genotype, was associated with a significantly lower risk of developing breast cancer [P=0.049, odds ratio (OR), 0.78; 95% confidence interval (CI), 0.61-0.99]. In case-only analyses, the TT, compared with the AA, genotype was associated with progesterone receptor-positive subjects (OR, 1.35; 95% CI, 1.00-1.83). The expression levels of IQGAP1 protein were significantly higher in the TT genotype compated to the AA genotype. The presence of SNPs at the miR-124 binding site may be a marker for predicting breast cancer risk and prognosis.

Telomere Length and TERT Functional Polymorphisms are not Associated with Risk of Squamous Cell Carcinoma of the Head and Neck

Abstract: Background: Recent studies reported associations of the relative telomere length (RTL) and TERT variants with risk of several cancers, which have not been comprehensively investigated in squamous cell carcinoma of the head and neck (SCCHN). Methods: We detected RTL in peripheral blood lymphocytes and genotyped six selected functional single-nucleotide polymorphisms (SNP) of the TERT gene in 888 SCCHN cases and 885 cancer-free controls of non-Hispanic whites. Results: Overall, we did not observe significant associations between RTL and SCCHN risk (adjusted OR = 0.97; 95% CI = 0.80–1.17 for below versus above the median; P trend = 0.618) nor between the six TERT SNPs and SCCHN risk. We also found no associations between RTL and TERT SNPs. Conclusions: Our results suggest that RTL and TERT functional polymorphisms may not play a major role in the etiology of SCCHN. Large prospective studies are needed to validate our findings. Impact: Although our results suggest no association among RTL, TERT functional polymorphisms, and SCCHN risk, this study may contribute to future meta-analysis. Cancer Epidemiol Biomarkers Prev; ©2011 AACR .

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

Abstract: BACKGROUND: p14ARF, 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 p14ARF 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 p14ARF 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 p14ARF 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 p14ARF thymine-thymine (TT) and guanine-guanine (GG) genotypes, the variant genotypes of p14ARF TG/GG and guanine-adenine (GA)/AA were associated with a significantly moderately increased risk of developing an SPM (p14ARF rs3731217: adjusted hazard ratio [aHR], 1.48; 95% confidence interval [CI], 1.00-2.19; p14ARF 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 p14ARF polymorphism, and there is an even greater risk of developing an SPM for patients with combined variant genotypes of the 2 SNPs. Therefore, p14ARF polymorphisms may be susceptible markers of the risk of developing an SPM in patients with SCCHN. Cancer 2011. © 2010 American Cancer Society.

Prospective analysis of DNA damage and repair markers of lung cancer risk from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial

Abstract: Mutagen challenge and DNA repair assays have been used in case–control studies for nearly three decades to assess human cancer risk. The findings still engender controversy because blood was drawn after cancer diagnosis so the results may be biased, a type called ‘reverse causation’. We therefore used Epstein–Barr virus-transformed lymphoblastoid cell lines established from prospectively collected peripheral blood samples to evaluate lung cancer risk in relation to three DNA repair assays: alkaline Comet assay, host cell reactivation (HCR) assay with the mutagen benzo[a]pyrene diol epoxide and the bleomycin mutagen sensitivity assay. Cases (n = 117) were diagnosed with lung cancer between 0.3 and 6 years after blood collection and controls (n = 117) were frequency matched on calendar year and age at blood collection, gender and smoking history; all races were included. Case and control status was unknown to laboratory investigators. In unconditional logistic regression analyses, statistically significantly increased lung cancer odds ratios (ORadjusted) were observed for bleomycin mutagen sensitivity as quartiles of chromatid breaks/cell [relative to the lowest quartile, OR = 1.2, 95% confidence interval (CI): 0.5–2.5; OR = 1.4, 95% CI: 0.7–3.1; OR = 2.1, 95% CI: 1.0–4.4, respectively, Ptrend = 0.04]. The magnitude of the association between the bleomycin assay and lung cancer risk was modest compared with those reported in previous lung cancer studies but was strengthened when we included only incident cases diagnosed more than a year after blood collection (Ptrend = 0.02), supporting the notion the assay may be a measure of cancer susceptibility. The Comet and HCR assays were unrelated to lung cancer risk.

TNFRSF1B +676 T>G polymorphism predicts survival of non-Small cell lung cancer patients treated with chemoradiotherapy

Abstract: The dysregulation of gene expression in the TNF-TNFR superfamily has been involved in various human cancers including non-small cell lung cancer (NSCLC). Furthermore, functional polymorphisms in TNF-α and TNFRSF1B genes that alter gene expression are likely to be associated with risk and clinical outcomes of cancers. However, few reported studies have investigated the association between potentially functional SNPs in both TNF-α and TNFRSF1B and prognosis of NSCLC patients treated with chemoradiotherapy. We genotyped five potentially functional polymorphisms of TNF-α and TNFRSF1B genes [TNF-α -308 G>A (rs1800629) and -1031 T>C (rs1799964); TNFRSF1B +676 T>G (rs1061622), -1709A>T(rs652625) and +1663A>G (rs1061624)] in 225 NSCLC patients treated with chemoradiotherapy or radiotherapy alone. Kaplan-Meier survival analysis, log-rank tests and Cox proportional hazard models were used to evaluate associations between these variants and NSCLC overall survival (OS). We found that the TNFRSF1B +676 GG genotype was associated with a significantly better OS of NSCLC (GG vs. TT: adjusted HR = 0.38, 95% CI = 0.15-0.94; GG vs. GT/TT: adjusted HR = 0.35, 95% CI = 0.14-0.88). Further stepwise multivariate Cox regression analysis showed that the TNFRSF1B +676 GG was an independent prognosis predictor in this NSCLC cohort (GG vs. GT/TT: HR = 0.35, 95% CI = 0.14-0.85), in the presence of node status (N2-3 vs. N0-1: HR = 1.60, 95% CI = 1.09-2.35) and tumor stage (T3-4 vs. T0-2: HR = 1.48, 95% CI = 1.08-2.03). Although the exact biological function for this SNP remains to be explored, our findings suggest a possible role of TNFRSF1B +676 T>G (rs1061622) in the prognosis of NSCLC. Further large and functional studies are needed to confirm our findings.

Polymorphisms in the SULF1 gene are associated with early age of onset and survival of ovarian cancer.

Abstract: SULF1 (sulfatase 1) selectively removes the 6-O-sulphate group from heparan sulfate, changing the binding sites for extracellular growth factors. SULF1 expression has been reported to be decreased in various cancers, including ovarian cancer. We hypothesized that single nucleotide polymorphisms (SNPs) of SULF1 would impact clinicopathologic characteristics. We genotyped five common (minor allele frequency>0.05) regulatory SNPs with predicted functionalities (rs2623047 G>A, rs13264163 A>G, rs6990375 G>A, rs3802278 G>A, and rs3087714 C>T) in 168 patients with primary epithelial ovarian cancer, using the polymerase chain reaction-restriction fragment length polymorphism method. We found that rs2623047 G>A was significantly associated with an early age of onset of ovarian cancer in the G allele dose-response manner (P = 0.027; P trend = 0.007) and that rs2623047 GG/GA genotypes were associated with longer progression-free survival; rs6990375 G>A was also associated with the early age of onset in the A allele dose-response manner (P = 0.013; P trend = 0.009). The significant differences in age of disease onset persisted among carriers of haplotypes of rs2623047 and rs6990375 (P = 0.014; P trend = 0.004). In luciferase reporter gene assays, rs2623047 G allele showed a slightly higher promoter activity than the A allele in the SKOV3 tumorigenic cell line. These findings suggest that genetic variations in SULF1 may play a role in ovarian cancer onset and prognosis. Further studies with large sample sizes and of the mechanistic relevance of SULF1 SNPs are warranted.