Polymorphisms of EpCAM gene and prognosis for non‐small‐cell lung cancer in Han Chinese

The epithelial cell adhesion molecule (EpCAM) is overexpressed in a wide variety of human cancers and is associated with patient prognosis, including those with lung cancer. However, the association of single nucleotide polymorphisms (SNPs) in the EpCAM gene with the prognosis for non‐small‐cell lung cancer (NSCLC) patients has never been investigated. We evaluated the association between two SNPs, rs1126497 and rs1421, in the EpCAM gene and clinical outcomes in a Chinese cohort of 506 NSCLC patients. The SNPs were genotyped using the Sequenom iPLEX genotyping system. Multivariate Cox proportional hazards model and Kaplan–Meier curves were used to assess the association of EpCAM gene genotypes with the prognosis of NSCLC. We found that the non‐synonymous SNP rs1126497 was significantly associated with survival. Compared with the CC genotype, the CT+TT genotype was a risk factor for both death (hazard ratio, 1.40; 95% confidence interval [CI], 1.02–1.94; P = 0.040) and recurrence (hazard ratio, 1.34; 95% CI, 1.02–1.77; P = 0.039). However, the SNP rs1421 did not show any significant effect on patient prognosis. Instead, the AG+GG genotype in rs1421 was significantly associated with early T stages (T1/T2) when compared with the AA genotype (odds ratio for late stage = 0.65; 95% CI, 0.44–0.96, P = 0.029). Further stratified analysis showed notable modulating effects of clinical characteristics on the associations between variant genotypes of rs1126497 and NSCLC outcomes. In conclusion, our study indicated that the non‐synonymous SNP rs1126497 may be a potential prognostic marker for NSCLC patients.     

Genetic variation of PSCA gene is associated with the risk of both diffuse‐ and intestinal‐type gastric cancer in a Chinese population

Prostate stem cell antigen (PSCA), a member of the LY‐6/Thy‐1 family of glycosylphosphatidylinositol‐anchored cell surface proteins, is considered to be involved in the cell‐proliferation inhibition and/or cell‐death induction activity. Two single nucleotide polymorphisms (SNPs) (rs2976392 and rs2294008) in the PSCA gene were recently identified as the susceptibility loci of gastric cancer, especially in diffuse type. Therefore, this study was to investigate whether these 2 SNPs were associated with the risk of gastric cancer in Chinese population. We genotyped rs2976392 and rs2294008 in PSCA in a case–control study including 1,053 incident gastric cancer patients and 1,100 cancer‐free controls in a high‐risk Chinese population. We found that variant genotypes of rs2976392 (GA/AA) were associated with a significantly 37% increased risk of gastric cancer (adjusted OR =1.37, 95% CI = 1.15–1.62), compared with variant homozygote GG, and the associations were all consistently significant in both intestinal and diffuse subtypes, and among different subgroups stratified by age, sex, drinking or smoking status. Interestingly, a significant multiplicative interaction between rs2976392 (GA/AA) and alcohol drinking was detected on the development of intestinal‐type gastric cancer (p = 0.009). However, rs2294008 variant genotypes (CT/TT) were associated with a nonsignificant increased risk of gastric cancer (adjusted OR = 1.14, 95% CI = 0.96–1.36). A small meta‐analysis including 5 case–control studies showed undoubtedly associations between PSCA rs2294008 and rs2976392 and gastric cancer risk (OR = 1.83, 95% CI: 1.29–2.60 and OR = 1.84, 95% CI: 1.33–2.56, respectively). These findings provide further evidence supporting that the genetic variants of PSCA gene may contribute to the gastric carcinogenesis.     

Association Between CASP8 and CASP10 Polymorphisms and Toxicity Outcomes With Platinum‐Based Chemotherapy in Chinese Patients With Non‐Small Cell Lung Cancer

Caspase‐8 and caspase‐10 play crucial roles in both cancer development and chemotherapy efficacy. In this study, we aimed to comprehensively assess single nucleotide polymorphisms (SNPs) of the caspase‐8 (CASP8) and caspase‐10 (CASP10) genes in relation to toxicity outcomes with first‐line platinum‐based chemotherapy in patients with advanced non‐small cell lung cancer (NSCLC). We genotyped 13 tag SNPs of CASP8 and CASP10 in 663 patients with advanced NSCLC treated with platinum‐based chemotherapy regimens. Associations between SNPs and chemotherapy toxicity outcomes were identified in a discovery set of 279 patients and then validated in an independent set of 384 patients. In both the discovery and validation sets, variant homozygotes of CASP8 rs12990906 and heterozygotes of CASP8 rs3769827 and CASP10 rs11674246 and rs3731714 had a significantly lower risk for severe toxicity overall. However, only the association with the rs12990906 variant was replicated in the validation set for hematological toxicity risk. In a stratified analysis, we found that some other SNPs, including rs3769821, rs3769825, rs7608692, and rs12613347, were significantly associated with severe toxicity risk in some subgroups, such as in nonsmoking patients, patients with adenocarcinoma, and patients treated with cisplatin combinations. Consistent results were also found in haplotype analyses. Our results provide novel evidence that polymorphisms in CASP8 and CASP10 may modulate toxicity outcomes in patients with advanced NSCLC treated with platinum‐based chemotherapy. If validated, the findings will facilitate the genotype‐based selection of platinum‐based chemotherapy regimens.     

CYP1A1, GSTM1 and GSTT1 genetic polymorphisms and gastric cancer risk among Japanese: A nested case–control study within a large‐scale population‐based prospective study

Cytochrome P450 (CYP) 1A1 and glutathione S‐transferases (GST) M1 and T1 are major enzymes in the carcinogen metabolizing pathway. We examined the association between single nucleotide polymorphisms (SNPs) of CYP1A1 (rs4646421, rs4646422 and rs1048943), GSTM1 and GSTT1 and gastric cancer risk in Japan. This is a nested case–control study (457 cases and 457 matched controls) of our population‐based cohort involving 36,745 subjects who answered a baseline questionnaire and supplied blood samples. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression models. We found that CYP1A1 (rs4646422) variant allele was associated with a statistically significant increased risk of gastric cancer compared with the homozygous wild‐type genotype (OR = 1.65; 95% CI = 1.17–2.32). GSTM1 null, GSTT1 null and GSTM1/T1 both or either null genotypes were associated with increased risk, but not statistically significantly. Combination of the CYP1A1 (rs4646422) variant allele and GSTM1/T1 both or either null genotypes was associated with a statistically significant increased risk compared with the combination of the CYP1A1 homozygous wild‐type genotype and the GSTM1/T1 both active genotypes. In addition, compared with CYP1A1 (rs4646422) homozygous wild‐type genotypes in those who were never‐smokers, CYP1A1 variant alleles in those who smoked ≥30 pack‐years were associated with an increased risk; neither gene–gene nor gene–environment interactions were significant. The CYP1A1 (rs4646422) polymorphism might be involved in gastric carcinogenesis among the Japanese population.     

Potentially functional genetic variants in PLIN2, SULT2A1 and UGT1A9 genes of the ketone pathway and survival of nonsmall cell lung cancer

The ketone metabolism pathway is a principle procedure in physiological homeostasis and induces cancer cells to switch between glycolysis and oxidative phosphorylation for energy production. We conducted a two-phase analysis for associations between genetic variants in the ketone metabolism pathway genes and survival of nonsmall cell lung cancer (NSCLC) by analyzing genotyping data from two published genome-wide association studies (GWASs). In the discovery, we used a genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the multivariable Cox proportional hazards regression analysis. We used Bayesian false discovery probability (≤0.80) for multiple testing correction to evaluate associations between 25,819 (2,176 genotyped and 23,643 imputed) single-nucleotide polymorphisms (SNPs) in 162 genes and survival of 1,185 NSCLC patients. Subsequently, we validated the identified significant SNPs with an additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility GWAS study. Finally, we found that three independent and potentially functional SNPs in three different genes (i.e., PLIN2 rs7867814 G>A, SULT2A1 rs2547235 C>T and UGT1A9 rs2011404 C>T) were independently associated with risk of death from NSCLC, with a combined hazards ratio of 1.22 [95% confidence interval = 1.09–1.36 and p = 0.0003], 0.82 (0.74–0.91 and p = 0.0002) and 1.21 (1.10–1.33 and p = 0.0001), respectively. Additional expression quantitative trait loci analysis found that the survival-associated PLIN2 rs7867814 GA + AA genotypes, but not the genotypes of other two SNPs, were significantly associated with increased mRNA expression levels (p = 0.005). These results indicated that PLIN2 variants may be potential predictors of NSCLC survival through regulating the PLIN2 expression.     

E-selectin rs5361 and FCGR2A rs1801274 variants were associated with increased risk of gastric cancer in a Chinese population

Host immune responses are critical steps for carcinogenesis. Single nucleotide polymorphisms (SNPs) in immunoregulatory genes may influence gastric cancer risk. We performed a genotyping analysis for immunoregulatory genes in 311 gastric cancer cases and 425 controls from a Chinese population. We found that there were significant differences of E‐selectin variant rs5361 (A>C) and FCGR2A variant rs1801274 (T>C) between cases and controls (P = 0.022 and P = 0.0001, respectively). Logistic regression analysis indicated that genotype of E‐selectin rs5361AC increased the risk of gastric cancer significantly (P = 0.026, adjusted Odds ratio (OR) = 2.84, 95% confidence interval (CI) = 1.13–7.12). C allele of E‐selectin rs5361 showed a significant increased frequency in cases (P = 0.023). However, the E‐selectin variant did not affect the protein expression. E‐selectin protein was observed not only in tumor interstitial vascular endothelial cells, but also in gastric cancer cells at primary and metastatic sites. The protein was associated with clinicopathological characteristics of gastric cancer, such as age (P = 0.008), tumor size (P = 0.027), differentiation (P = 0.000), and tumor‐node‐metastasis (TNM) stage (P = 0.006). CT and CC + CT genotypes of FCGR2A variant rs1801274 increased gastric cancer risk (P = 0.000, adjusted OR = 1.92, 95%CI = 1.36–2.72; P = 0.003, adjusted OR = 1.68, 95%CI = 1.20–2.35, respectively). Interleukin‐4 receptor (IL‐4R) variant rs2107356 presented negative correlations to E‐selectin variant rs5361 and FCGR2A variant rs1801274 (P = 0.035 and P = 0.023) in conferring susceptibility to gastric cancer. We concluded E‐selectin variant rs5361 and FCGR2A variant rs1801274 were significantly associated with gastric cancer risk. Expression of E‐selectin protein would promote progression of gastric cancer. © 2011 Wiley Periodicals, Inc.     

The association between −1304T>G polymorphism in the promoter of MKK4 gene and the risk of sporadic colorectal cancer in southern Chinese population

MKK4 (mitogen‐activated protein kinase kinase 4, NM_003010.2), which belongs to the mitogen‐activated protein kinase pathways, possesses functions in tumorigenesis. We hypothesized the genetic variants in MKK4 gene may alter its functions and thus cancer risk. In current hospital‐based case‐control study of 706 patients with sporadic colorectal cancer (CRC) and 723 sex‐age–frequency‐matched control subjects in a southern Chinese population, we genotyped two polymorphisms of MKK4 promoter (i.e., ?1304T>G, rs3826392 and ?1044A>T, rs3809728) and assessed their associations with the risk of sporadic CRC. Compared with ?1304TT genotypes, ?1304TG had a significantly decreased risk of CRC (adjusted odds ratios [OR] = 0.56; 95% CI = 0.44–0.72; p = 3.53 × 10^?6), the ?1304GG carriers had a further decreased risk of CRC (OR = 0.40; 95% CI = 0.23–0.70; p = 1.32 × 10^?3), and there was a significant trend for an allele dose effect on risk of CRC (p_trend = 2.64 × 10^?7). The decreased risk associated with ?1304G variant genotypes (i.e., TG+GG) was more pronounced in the subjects older than 60 years (adjusted OR = 0.41; 95% CI = 0.29–0.57; p = 2.25 × 10^?7), in ever drinkers (adjusted OR = 0.41; 95% CI = 0.28–0.59; p = 2.42 × 10^?6). The age and alcohol drinking status interacted with ?1304G variant genotypes on reducing cancer risk (p values for interaction were 0.015 and 0.043, respectively). Western blotting analysis showed that the levels of Mkk4 protein in sporadic CRC neoplastic tissues were significantly higher in the carriers of ?1304G variant genotypes than that in those with ?1304TT genotypes. However, no significant association was observed between ?1044A>T polymorphism and risk of CRC. To the best of our knowledge, this is the first study of genetic variants in MKK4 and cancer susceptibility. Larger studies are needed to validate our findings. © 2009 UICC     

A nonsynonymous polymorphism in IL23R gene is associated with risk of gastric cancer in a Chinese population

Interleukin‐23 receptor (IL‐23R) is a key element in T helper (Th)17 cell‐mediated inflammatory process, which plays an important role in pathogenesis of gastric cancer. Genetic variants of IL‐23R have been identified as the predisposing factors for immunopathologic process. In this study, we hypothesized that the functional genetic variants of IL‐23R gene may modify the risk of gastric cancer. To test this hypothesis, we conducted a case–control study including 1043 gastric cancer patients and 1089 controls in a Chinese population to assess the association between two potentially functional single nucleotide polymorphisms (SNPs) rs6682925 T>C and rs1884444 T>G of IL‐23R and risk of gastric cancer. We found that the variant allele (G) of rs1884444 T>G, with amino acid His substituted by Gln at codon 3, was significantly associated with a decreased risk of gastric cancer [adjusted allelic odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.68–0.88]. In the stratified analysis, we found that this protective effect of rs1884444 G allele was mainly evident in intestinal‐type gastric cancer (adjusted allelic OR = 0.75, 95% CI = 0.65–0.87) other than in diffuse‐type gastric cancer (adjusted allelic OR = 0.96, 95% CI = 0.76–1.22). However, we did not find any significant association of rs6682925 T>C with gastric cancer risk. These findings indicate, for the first time, that the nonsynonymous variant rs1884444 T>G of IL‐23R may contribute to gastric cancer susceptibility, especially in intestinal‐type gastric cancer, in Chinese population. © 2010 Wiley‐Liss, Inc.     

An ERCC4 regulatory variant predicts grade‐3 or ‐4 toxicities in patients with advanced non‐small cell lung cancer treated by platinum‐based therapy

Platinum‐based chemotherapy (PBC) in combination with the 3^rd generation drugs is the first‐line treatment for patients with advanced non‐small cell lung cancer (NSCLC); however, the efficacy is severely hampered by grade 3–4 toxicities. Nucleotide excision repair (NER) pathway is the main mechanism of removing platinum‐induced DNA adducts that contribute to the toxicity and outcome of PBC. We analyzed data from 710 Chinese NSCLC patients treated with PBC and assessed the associations of 25 potentially functional single nucleotide polymorphisms (SNPs) in nine NER core genes with overall, gastrointestinal and hematologic toxicities. Through a two‐phase study, we found that ERCC4 rs1799798 was significantly associated with overall and gastrointestinal toxicities [all patients: GA/AA vs. GG, odds ratio (OR)_adj=1.61 and 2.35, 95% confidence interval (CI)=1.11–2.33 and 1.25–4.41, and P_adj=0.012 and 0.008, respectively]. Our prediction model for the overall toxicity incorporating rs1799798 demonstrated a significant increase in the area under the curve (AUC) value, compared to that for clinical factors only (all patients: AUC = 0.61 vs. 0.59, 95% CI = 0.57–0.65 vs. 0.55–0.63, P = 0.010). Furthermore, the ERCC4 rs1799798 A allele was associated with lower ERCC4 mRNA expression levels according to the expression quantitative trait loci (eQTL) analysis. Our study provided some new clue in future development of biomarkers for assessing toxicity and outcomes of platinum drugs in lung cancer treatment.     

Multigene pathway‐based analyses identify nasopharyngeal carcinoma risk associations for cumulative adverse effects of TERT‐CLPTM1L and DNA double‐strand breaks repair

The genetic etiology of nasopharyngeal carcinoma (NPC) and mechanisms for inherited susceptibility remain unclear. To examine genetic risk factors for NPC, we hypothesized that heritable risk is attributable to cumulative effects of multiple common low‐risk variants. With the premise that individual SNPs only confer subtle effects for cancer risk, a multigenic pathway‐based approach was used to systematically examine associations between NPC genetic susceptibility with SNPs in genes in DNA repair pathways and from previously identified cancer genome‐wide association study analyses. This case–control study covers 161 genes/loci and focuses on pathway‐based analyses in 2,349 Hong Kong individuals, allowing stratification according to NPC familial status for meaningful association analysis. Three SNPs (rs401681, rs6774494 and rs3757318) corresponding to TERT/CLPTM1L (OR 95% CI = 0.77, 0.68–0.88), MDS1‐EVI1 (OR 95% CI=0.79 0.69–0.89) and CCDC170 (OR 95% CI = 0.76, 0.66–0.86) conferred modest protective effects individually for NPC risk by the logistic regression analysis after multiple testing adjustment (p_Bonferroni < 0.05). Stratification of NPC according to familial status identified rs2380165 in BLM (OR 95% CI = 1.49, 1.20–1.86, p_Bonferroni < 0.05) association with family history‐positive NPC (FH+ NPC) patients. Multiple SNPs pathway‐based analysis revealed that the combined gene dosage effects for increasing numbers of unfavorable genotypes in TERT‐CLPTM1L and double‐strand break repair (DSBR) conferred elevated risk in FH+ and sporadic NPC patients (ORs per allele, 95% CIs = 1.37, 1.22–1.55, p_Bonferroni = 5.00 × 10^?6; 1.17, 1.09–1.26, p_Bonferroni = 4.58 × 10^?4, respectively, in TERT/NHEJ pathways). Our data suggested cumulative increased NPC risk associations with TERT‐CLPTM1L and DSBR pathways contribute to genetic susceptibility to NPC and have potential translational relevance for patient stratification and therapeutics.     

Potentially functional genetic variants in the TNF/TNFR signaling pathway genes predict survival of patients with non‐small cell lung cancer in the PLCO cancer screening trial

The tumor necrosis factor (TNF)/TNF receptor (TNFR) pathway is known to influence survival of patients with cancer. We hypothesize that single nucleotide polymorphisms (SNPs) in the TNF/TNFR pathway genes related to apoptosis are associated with survival of patients with non‐small cell lung cancer (NSCLC). We used 1185 patients with NSCLC in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study as the discovery and validation datasets, respectively. We selected 6788 SNPs in 71 genes in the TNF/TNFR signaling pathway and extracted their genotyping data from the PLCO genowide‐association study (GWAS) dataset. We performed Cox proportional hazards regression analysis to evaluate associations between the identified SNPs and survival and validated the significant SNPs, which were further analyzed for their functional relevance. We found that genotypes of two validated SNPs, IKBKAP rs4978754 CT + TT and TNFRSF1B rs677844 TC + CC, as well as their combined genotypes predicted a better overall survival (P = 0.004, 0.002 and <0.001, respectively). These two validated SNPs were predicted by the RegulomeDB score to be potentially functional. In addition, IKBKAP mRNA expression levels were significantly higher, while TNFRSF1B mRNA expression levels were significantly lower in lung cancer tissues than in adjacent normal tissues (P < 0.001). The Cancer Genome Atlas (TCGA)‐based expression quantitative trait loci analysis showed that IKBKAP rs4978754 and TNFRSF1B rs677844 genotypes were significantly associated with their corresponding mRNA expression levels in lung cancer tissues in a recessive model (P = 0.035 and 0.045, respectively). Therefore, we identified two potentially functional SNPs (IKBKAP rs4978754 C > T and TNFRSF1B rs677844 T > C) to be associated with survival of patients with NSCLC.     

Two genetic variants in prostate stem cell antigen and gastric cancer susceptibility in a chinese population

Genetic factors play important roles in pathogenesis of human cancer. A recent genome‐wide association study (GWAS) linked two single nucleotide polymorphisms (SNPs) in prostate stem cell antigen (PSCA), rs2294008C>T and rs2976392G>A, to risk of diffuse‐type of gastric cancer in Japanese and Korean populations. We hypothesized that these two SNPs are also associated with risk of gastric cancer in Chinese population. We examined genotypes and haplotypes of PSCA, rs2294008C/T and rs2976392G/A in 716 patients with cardia gastric carcinoma (CGC), 1020 patients with noncardia gastric carcinoma (NCGC), and 1020 controls. We found that individuals with at least one copy of the rs2294008T allele (CT or TT genotype) had an elevated risk for developing NCGC compared with those without this allele (OR = 1.35, 95% CI = 1.13–1.61). Individuals with at least one copy of the rs2976392A allele (GA or AA genotype) had nonsignificantly increased risk for NCGC compared with those without this allele (OR = 1.20, 95% CI = 1.01–1.43). Stratification analysis showed that the increased risk associated with the SNPs was restricted in female subjects. Moreover, the rs2294008T and rs2976392A allele carriers were predisposed to developing poorly differentiated and high stage NCGC at diagnosis. However, no such association was detected for CGC. In addition, we observed considerably lower allelic and genotype frequencies of these genetic variants in Chinese population compared with Japanese and Korean populations. These findings are in general consistent with previous GWAS and suggest that PSCA may play a role in the development of NCGC in Chinese population. © 2009 Wiley‐Liss, Inc.     

Lung cancer susceptibility and prognosis associated with polymorphisms in the nonhomologous end‐joining pathway genes

BACKGROUND:

Nonsmall cell lung cancer (NSCLC) frequently exhibits genomic instability, such as high fractional allelic loss (FAL). Genomic instability may result from unrepaired or misrepaired double‐strand breaks (DSBs). The authors of this report postulated that polymorphisms in genes of the nonhomologous end‐joining (NHEJ) pathway, which is the major DSB repair pathway in mammalian cells, may modulate lung cancer susceptibility and prognosis.

METHODS:

Patients with NSCLC (n = 152) and a group of appropriate age‐matched and sex‐matched controls (n = 162) were subjected to genotype analysis of the NHEJ pathway genes x‐ray repair complementing defective repair in Chinese hamster cells 6 (Ku70) (reference single nucleotide polymorphism number [rs] 2267437), x‐ray repair complementing defective repair in Chinese hamster cells 5 (Ku80) (rs3835), x‐ray repair complementing defective repair in Chinese hamster cells 4 (XRCC4) (rs1805377), and DNA ligase IV (LIG4) (rs1805388). The gene‐gene interaction (joint effect), genotype‐environmental (ie, smoking) correlation, and genotype‐phenotype (ie, FAL) correlation were examined. The Kaplan‐Meier method and log‐rank tests were used to assess the prognostic effect.

RESULTS:

There was a significant association between the XRCC4 and LIG4 genotypes with NSCLC risk in an analysis of individual polymorphism associations, and the risk of NSCLC increased further in a combined analysis of multiple polymorphisms (adjusted odds ratio [OR], 8.74). The patients who had a homozygous variant guanine/guanine genotype of the XRCC4 gene had a poorer prognosis compared with other patients (P = .015). There was a significant difference between the patient smokers and controls for XRCC4 (adjusted OR, 2.67) and LIG4 (adjusted OR, 2.04). In addition, polymorphisms in XRCC4 and LIG4 were linked significantly with patients who had high FAL (adjusted OR, 2.03‐3.84).

CONCLUSIONS:

To the authors' knowledge, this is the first nested case‐control study to demonstrate a significant association between the polymorphisms of genes in the NHEJ pathway and lung cancer susceptibility and prognosis. The results may be useful for risk assessment and disease monitoring of patients with NSCLC. Cancer 2009. © 2009 American Cancer Society.     

Potentially functional polymorphisms in DNA repair genes and non-small-cell lung cancer survival: a pathway-based analysis

To assess systematically whether potentially functional polymorphisms in DNA repair genes influence the clinical behavior of non‐small‐cell lung cancer (NSCLC), we examined the impact of a comprehensive panel of 218 signal nucleotide polymorphisms (SNP) in 50 candidate DNA repair genes on overall survival of NSCLC in a case‐cohort of 568 lung cancer patients. SNPs associated with lung cancer prognosis primarily mapped to 14 genes in different repair pathways, and 6 SNPs were remained in the final model after multivariate stepwise Cox regression analysis: ATM rs189037; MRE11A rs11020802; ERCC2 rs1799793; MBD4 rs140693; XRCC1 rs25487, and PMS1 rs5742933. In the combined analysis of these 6 SNPs, an increasing number of unfavorable loci was associated with a poorer prognosis (P for trend: <0.0001) and patients having 2–4 unfavorable loci had a 1.99‐fold elevated risk of death 95% confidence interval (CI) = 1.58–2.50, compared with those carrying 0–1 unfavorable loci, and this elevated risk was more evident among stages I–II patients (hazard ratio = 3.04, 95% CI = 1.86–4.98, P for heterogeneity: 0.07). Furthermore, a significant effect of SNPs in nucleotide excision repair pathway on lung cancer survival was observed among 185 stages III–IV patients treated with platinum‐based chemotherapy without surgical operation: XPC rs2228000 (Ala499Val; P = 0.002) and ERCC1 rs11615 (Asn118Asn; P = 0.012). Our data indicate that potentially functional polymorphisms in DNA repair genes may serve as candidate prognostic markers of clinical outcome of NSCLC. © 2011 Wiley Periodicals, Inc.     

Genetic variants in the platelet‐derived growth factor subunit B gene associated with pancreatic cancer risk

The platelet‐derived growth factor (PDGF) signaling pathway plays important roles in development and progression of human cancers. In our study, we aimed to identify genetic variants of the PDGF pathway genes associated with pancreatic cancer (PC) risk in European populations using three published genome‐wide association study datasets, which consisted of 9,381 cases and 7,719 controls. The expression quantitative trait loci (eQTL) analysis was also performed using data from the 1000 Genomes, TCGA and GTEx projects. As a result, we identified two potential susceptibility loci (rs5757573 and rs6001516) of PDGFB associated with PC risk [odds ratio (OR) = 1.10, 95% confidence interval (CI) = 1.05–1.16, and p = 4.70 × 10^?5 for the rs5757573 C allele and 1.21, 1.11–1.32, and 2.01 × 10^?5 for the rs6001516 T allele]. Haplotype analysis revealed that the C‐T haplotype carriers had a significantly increased risk of PC than those carrying the T‐C haplotype (OR = 1.23, 95% CI = 1.12–1.34, p =5.00 × 10^?6). The multivariate regression model incorporating the number of unfavorable genotypes (NUGs) with age and sex showed that carriers with 1–2 NUGs, particularly among 60–70 age group or males, had an increased risk of PC, compared to those without NUG. Furthermore, the eQTL analysis revealed that both loci were correlated with a decreased mRNA expression level of PDGFB in lymphoblastoid cell lines and pancreatic tumor tissues (p = 0.015 and 0.071, respectively). Our results suggest that genetic variants in PDGFB may play a role in susceptibility to PC. Further population and functional validations of our findings are warranted.     

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

Genetic variations in genes involved in repairing platinum‐induced DNA lesions may contribute to the toxicity of platinum‐based chemotherapy. The role of single‐nucleotide polymorphisms (SNPs) within DNA repair pathways in the occurrence of severe toxicity is not yet understood. Current studies prefer to do original works rather than analyze previously published data. Our study aimed to replicate associations between previously investigated SNPs and toxicities and to identify new genetic makers. We systematically examined the relevance of 97 SNPs in 54 candidate genes responsible for repairing DNA interstrand and intrastrand cross‐links to severe toxicity in a discovery cohort of 437 NSCLC patients receiving platinum‐based chemotherapy. Statistically significant SNPs were then assessed for replication in an independent validation cohort of 781 NSCLC patients. We found that 7 SNPs were significant at p < 0.01 (RRM1 rs12806698, XPC rs2228000, XPF rs1799801, hMLH1 rs1800734, PMS2 rs1062372, REV3L rs462779 and FANCC rs4647554) in the discovery cohort. Among them, two SNPs (RRM1 rs12806698 and hMLH1 rs1800734) remained significant after Bonferroni correction. XPC rs2228000 showed a significant relationship with severe gastrointestinal toxicity in the validation cohort. When the two cohorts were combined, XPC rs2228000 presented better tolerance of severe hematologic toxicity, gastrointestinal toxicity and leukopenia (OR = 0.677, 95% CI: 0.510–0.899, p = 0.007; OR = 0.565, 95% CI: 0.368–0.869, p = 0.009; OR = 0.628, 95% CI: 0.439–0.899, p = 0.011, respectively). Our findings can offer comprehensive pharmacogenetic information for platinum‐induced toxicities.     

Genetic variation and circulating levels of IGF‐I and IGFBP‐3 in relation to risk of proliferative benign breast disease

Insulin‐like growth factor‐I (IGF‐I) and its major binding protein IGFBP‐3 have been implicated in breast carcinogenesis. We examined the associations between genetic variants and circulating levels of IGF‐I and IGFBP‐3 with proliferative benign breast disease (BBD), a marker of increased breast cancer risk, in the Nurses' Health Study II (NHSII). Participants were 359 pathology‐confirmed proliferative BBD cases and 359 matched controls. Circulating IGF‐I and IGFBP‐3 levels were measured in blood samples collected between 1996 and 1999. Thirty single nucleotide polymorphisms (SNPs) in IGF‐I, IGFBP‐1, and IGFBP‐3 genes were selected using a haplotype tagging approach and genotyped in cases and controls. Circulating IGF‐I levels were not associated with proliferative BBD risk. Higher circulating IGFBP‐3 levels were significantly associated with increased risk of proliferative BBD (highest vs. lowest quartile odds ratio (OR) [95% confidence interval (CI)], 1.70 (1.06–2.72); p‐trend = 0.03). The minor alleles of 2 IGFBP‐3 SNPs were associated with lower proliferative BBD risk (homozygous variant vs. homozygous wild‐type OR (95% CI): rs3110697: 0.6 (0.4–0.9), p‐trend = 0.02; rs2132570: 0.2 (0.1–0.6), p‐trend = 0.02). Three other IGFBP‐3 SNPs (rs2854744, rs2960436 and rs2854746) were significantly associated with circulating IGFBP‐3 levels (p < 0.01). Although these SNPs were not significantly associated with proliferative BBD risk, there was suggestive evidence that the alleles associated with higher circulating IGFBP‐3 levels were also associated with higher risk of proliferative BBD. These results suggest that genetic variants and circulating levels of IGFBP‐3 may play a role in the early stage of breast carcinogenesis.     

Single‐nucleotide polymorphisms in the p53 pathway genes modify cancer risk in BRCA1 and BRCA2 carriers of Jewish‐Ashkenazi descent

Germline mutations in the BRCA1 and BRCA2 genes are associated with a significantly increased lifetime risk for developing breast and/or ovarian cancer. However, incomplete penetrance and substantial variability in age of disease onset among carriers of the same mutation suggests the involvement of additional modifier genes and/or environmental factors. Somatic inactivating mutations in the p53 gene and genes of the p53 pathway often accompany BRCA1/2‐associated tumors. Therefore, we assessed whether these genes are modifiers of penetrance. We genotyped Jewish‐Ashkenazi women for functional single‐nucleotide polymorphisms (SNPs) in the AKT1 (C>T rs3730358) and the PERP (C>T rs2484067) genes that affect p53‐mediated apoptosis, as well as two tag‐SNPs in the CHEK2 (C>T rs743184) and the ZBRK1/ZNF350 (G>A rs2278414) genes that encode for proteins involved in growth arrest following DNA damage. The study population included 138 healthy women, 148 breast/ovarian cancer BRCA1/2 mutation carriers, 121 asymptomatic BRCA1/2 mutation carriers, and 210 sporadic noncarrier breast cancer patients. Utilizing λ² and Kaplan–Meier analysis revealed a hazard ratio (HR) of 3.23 (95% CI: 1.44–54, P = 0.0184) for the TT genotype of AKT (rs3730358), HR = 2.105 (95% CI: 1.049–7.434, P = 0.039) for CHEK2 CC genotype (rs743184), and HR = 2.4743 (95% CI: 1.205–11.53, P = 0.022) for the AG genotype of ZBRK1/ZNF350 (rs2278414). No significant association between PERP variants and cancer was identified HR = 0.662 (95% CI: 0.289–1.324, P = 0.261). Our results suggest that genes that act upstream of p53, or participate in the DNA damage response, may modify the risk of cancer in women with mutant BRCA1/2 alleles. © 2010 Wiley‐Liss, Inc.