Association of XPC Polymorphisms and Lung Cancer Risk: A Meta-Analysis

Background

Xeroderma pigmentosum complementation group C gene (XPC) is a key member of nucleotide excision repair pathway and plays an important role in human DNA repair system. It is reported that several common polymorphisms of XPC are associated with susceptibility to lung cancer. However, the conclusion is still elusive.

Method

This meta-analysis was performed to determine the relationship between XPC polymorphisms (Lys939Gln, Ala499Val, and PAT) and lung cancer risk. Published literatures were identified by searching online databases and reference lists of relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association strength. Publication bias were detected by Egger’s and Begg’s test.

Result

After strict screening, we identified 14 eligible studies in this meta-analysis, including 5647 lung cancer cases and 6908 controls. By pooling all eligible studies, we found that the homozygote Gln939Gln genotype was associated with a significantly increased risk of lung cancer in Asian population (GlnGln vs LysLys, OR = 1.229, 95% CI: 1.000–1.510; GlnGln vs LysLys/LysGln, OR = 1.257, 95% CI: 1.038–1.522). As for the PAT polymorphism, in Caucasian population, we found carriers of the −/− genotype were associated significantly reduced risk of lung cancer in homozygote comparison model (−/− vs +/+, OR = 0.735, 95% CI: 0.567–0.952).

Conclusion

In this meta-analysis we found that Gln939Gln genotype was associated with significantly increased risk of lung cancer in Asian population; the PAT −/− genotype significantly reduced susceptibility to lung cancer in Caucasian population; while the XPC Ala499Val polymorphism was not associated with lung cancer risk.     

Vitamin D Metabolic Pathway Genes and Pancreatic Cancer Risk

Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008–0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk.     

No Association Between Base Excision Repair Gene Polymorphisms and Risk of Lung Cancer

In a nested case-cohort study, we have investigated the occurrence of lung cancer in relation to polymorphisms in base excision repair genes XRCC1 and OGG1. Among 54,220 members of a Danish prospective cohort study, aged 50-65 years at entry, 265 lung cancer cases were identified and a subcohort comprising 272 individuals was used for comparison. No associations were found between the polymorphisms OGG1 Ser326Cys, XRCC1 Arg280His, and XRCCI Arg399Gln and risk of lung cancer. This is the first study of polymorphisms in base excision repair genes in relation to lung cancer among Danes.     

Interaction between Polymorphisms in Pre-MiRNA Genes and Cooking Oil Fume Exposure on the Risk of Lung Cancer in Chinese Non-Smoking Female Population

Background

Both genetic polymorphisms and environmental risk factors play important roles in the development of human chronic diseases including lung cancer. This is the first case-control study of interaction between polymorphisms in pre-miRNA genes and cooking oil fume exposure on the risk of lung cancer.

Methods

A hospital-based case-control study of 258 cases and 310 controls was conducted. Six polymorphisms in miRNAs were determined by Taqman allelic discrimination method. The gene-environment interactions were assessed on both additive and multiplicative scale. The statistical analyses were performed mostly with SPSS.

Results

The combination of the risk genotypes of five miRNA SNPs (miR-146a rs2910164, miR-196a2 rs11614913, miR-608 rs4919510, miR-27a rs895819 and miR-423 rs6505162) with risk factor (cooking oil fume exposure) contributed to a significantly higher risk of lung cancer, and the corresponding ORs (95% confidence intervals) were 1.91(1.04-3.52), 1.94 (1.16-3.25), 2.06 (1.22-3.49), 1.76 (1.03-2.98) and 2.13 (1.29-3.51). The individuals with both risk genotypes of miRNA SNPs and exposure to risk factor (cooking oil fumes) were in a higher risk of lung cancer than persons with only one of the two risk factors (ORs were 1.91, 1.05 and 1.41 for miR-146a rs2910164, ORs were 1.94, 1.23 and 1.34 for miR-196a2 rs11614913, ORs were 2.06, 1.41 and 1.68 for miR-608 rs4919510, ORs were 1.76, 0.82 and 1.07 for miR-27a rs895819, and ORs were 2.13, 1.15 and 1.02 for miR-423 rs6505162, respectively). All the measures of biological interaction indicate that there were not indeed biological interactions between the six SNPs of miRNAs and exposure to cooking oil fumes on an additive scale. Logistic models suggested that the gene-environment interactions were not statistically significant on a multiplicative scale.

Conclusions

The interactions between miRNA SNPs and cooking oil fume exposure suggested by ORs of different combination were not statistically significant.     

UGT1A6 Polymorphisms Modulated Lung Cancer Risk in a Chinese Population

Uridine diphosphoglucuronosyltransferases (UGTs) 1A6 is the only UGT1A isoform expressed in lung tissue. It is responsible for the detoxification of carcinogens such as benezo[a]pyrene from cigarette smoke. The purpose of this study was to evaluate the association of UGT1A6 polymorphisms and haplotypes with lung cancer risk and to evaluate the functional significance of UGT1A6 polymorphisms. Genomic DNA was isolated from leukocytes. Eight UGT1A6 polymorphisms were sequenced in a test set of 72 Chinese lung cancer patients and 62 healthy controls. Potential risk modifying alleles were validated in a separate set of 95 Chinese lung cancer patients and 100 healthy controls. UGT1A6 19T>G, 541A>G and 552A>C showed significant association with increased lung cancer risk, while UGT1A6 105C>T and IVS1+130G>T were significantly associated with reduced lung cancer risk. Multivariate logistic regression analysis demonstrated a significant association of lung cancer with UGT1A6 541A>G (OR: 3.582, 95% CI: 1.27–10.04, p = 0.015), 552A>C (OR: 5.364, 95% CI: 1.92–14.96, p = 0.001) and IVS1+130G>T (OR: 0.191, 95% CI: 0.09–0.36, p<0.001). Functional test demonstrated that UGT1A6 105C>T increased mRNA stability, providing a plausible explanation of its association with reduced lung cancer risk. Thus UGT1A6 polymorphisms may be used to identify people with increased risk of developing lung cancer.     

Expression of Tumor Necrosis Factor-Alpha-Mediated Genes Predicts Recurrence-Free Survival in Lung Cancer

In this study, we conducted a meta-analysis on high-throughput gene expression data to identify TNF-α-mediated genes implicated in lung cancer. We first investigated the gene expression profiles of two independent TNF-α/TNFR KO murine models. The EGF receptor signaling pathway was the top pathway associated with genes mediated by TNF-α. After matching the TNF-α-mediated mouse genes to their human orthologs, we compared the expression patterns of the TNF-α-mediated genes in normal and tumor lung tissues obtained from humans. Based on the TNF-α-mediated genes that were dysregulated in lung tumors, we developed a prognostic gene signature that effectively predicted recurrence-free survival in lung cancer in two validation cohorts. Resampling tests suggested that the prognostic power of the gene signature was not by chance, and multivariate analysis suggested that this gene signature was independent of the traditional clinical factors and enhanced the identification of lung cancer patients at greater risk for recurrence.     

Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: A Nested Case-Control Study

Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.     

Common Single Nucleotide Polymorphisms in Genes Related to Immune Function and Risk of Papillary Thyroid Cancer

Accumulating evidence suggests that alterations in immune function may be important in the etiology of papillary thyroid cancer (PTC). To identify genetic markers in immune-related pathways, we evaluated 3,985 tag single nucleotide polymorphisms (SNPs) in 230 candidate gene regions (adhesion-extravasation-migration, arachidonic acid metabolism/eicosanoid signaling, complement and coagulation cascade, cytokine signaling, innate pathogen detection and antimicrobials, leukocyte signaling, TNF/NF-kB pathway or other) in a case-control study of 344 PTC cases and 452 controls. We used logistic regression models to estimate odds ratios (OR) and calculate one degree of freedom P values of linear trend (P_SNP-trend) for the association between genotype (common homozygous, heterozygous, variant homozygous) and risk of PTC. To correct for multiple comparisons, we applied the false discovery rate method (FDR). Gene region- and pathway-level associations (P_Region and P_Pathway) were assessed by combining individual P_SNP-trend values using the adaptive rank truncated product method. Two SNPs (rs6115, rs6112) in the SERPINA5 gene were significantly associated with risk of PTC (P_SNP-FDR/P_SNP-trend = 0.02/6×10⁻⁶ and P_SNP-FDR/P_SNP-trend = 0.04/2×10⁻⁵, respectively). These associations were independent of a history of autoimmune thyroiditis (OR = 6.4; 95% confidence interval: 3.0–13.4). At the gene region level, SERPINA5 was suggestively associated with risk of PTC (P_Region-FDR/P_Region =0.07/0.0003). Overall, the complement and coagulation cascade pathway was the most significant pathway (P_Pathway = 0.02) associated with PTC risk largely due to the strong effect of SERPINA5. Our results require replication but suggest that the SERPINA5 gene, which codes for the protein C inhibitor involved in many biological processes including inflammation, may be a new susceptibility locus for PTC.     

MicroRNA Related Polymorphisms and Breast Cancer Risk

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.     

Contributory Role of Five Common Polymorphisms of RAGE and APE1 Genes in Lung Cancer among Han Chinese

Background

Lung cancer is the leading cause of cancer mortality in China. Given the ubiquitous nature of gene-to-gene interaction in lung carcinogenesis, we sought to evaluate five common polymorphisms from advanced glycosylation end product-specific receptor (RAGE) and apurinic/apyrimidinic endonuclease 1 (APE1) genes in association with lung cancer among Han Chinese.

Methods and Results

819 patients with lung cancer and 803 cancer-free controls were recruited from Qiqihar city. Genotypes of five examined polymorphisms (RAGE gene: rs1800625, rs1800624, rs2070600; APE1 gene: rs1760944, rs1130409) were determined by ligase detection reaction method. Data were analyzed by R software and multifactor dimensionality reduction (MDR). Hardy-Weinberg equilibrium was satisfied for all five polymorphisms. Overall differences in the genotype and allele distributions were significant for rs1800625 (P_genotype<0.0005; P_allele<0.0005), rs2070600 (P_genotype = 0.005; P_allele = 0.004) and rs1130409 (P_genotype = 0.009; P_allele = 0.004) polymorphisms. Haplotype C-A-A (alleles in order of rs1800625, rs1800624 and rs2070600) of RAGE gene was overrepresented in patients, and conferred a 2.1-fold increased risk of lung cancer (95% confidence interval: 1.52–2.91), independent of confounding factors. Further application of MDR method to five examined polymorphisms identified the overall best interaction model including rs2070600 and rs1130409 polymorphisms. This model had a maximal testing accuracy of 64.63% and a maximal cross-validation consistency of 9 out of 10 at the significant level of 0.006.

Conclusions

Our findings demonstrated a potential interactive contribution of RAGE and APE1 genes to the pathogenesis of lung cancer among Han Chinese. Further studies are warranted to confirm or refute these findings.     

Polymorphisms in ERCC1 and XPF Genes and Risk of Gastric Cancer in an Eastern Chinese Population

Background

Inherited functional single nucleotide polymorphisms (SNPs) in DNA repair genes may alter DNA repair capacity and thus contribute to cancer risk.

Methods

Three ERCC1 functional SNPs (rs2298881C>A, rs3212986C>A and rs11615G>A) and two XPF/ERCC4 functional SNPs (rs2276466C>G and rs6498486A>C) were genotyped for 1125 gastric adenocarcinoma cases and 1196 cancer-free controls by Taqman assays. Odds ratios (OR) and 95% confidence intervals (CI) were used to estimate risk associations, and false-positive report probabilities (FPRP) were calculated for assessing significant findings.

Results

ERCC1 rs2298881C and rs11615A variant genotypes were associated with increased gastric cancer risk (adjusted OR = 1.33, 95% CI = 1.05–1.67 for rs2298881 AC/CC and adjusted OR = 1.23, 95% CI = 1.05–1.46 for rs11615 AG/AA, compared with their common genotype AA and GG, respectively). Patients with 2–3 ERCC1 risk genotypes had significant increased risk (adjusted OR = 1.56, 95% CI = 1.27–1.93), compared with those with 0–1 ERCC1 risk genotypes, and this risk was more significantly in subgroups of never drinkers, non-gastric cardia adenocarcinoma (NGCA) and clinical stage I+II. All these risks were not observed for XPF SNPs.

Conclusions

These findings suggest that functional ERCC1 SNPs may contribute to risk of gastric cancer. Larger and well-designed studies with different ethnic populations are needed to validate our findings.     

Association between XRCC1 and XRCC3 Polymorphisms with Lung Cancer Risk: A Meta-Analysis from Case-Control Studies

Many studies have reported the association of X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln, Arg194Trp, Arg280His, −77T>C, and X-ray repair cross-complementing group 3 (XRCC3) T241M polymorphisms with lung cancer risk, but the results remained controversial. Hence, we performed a meta-analysis to investigate the association between lung cancer risk and XRCC1 Arg399Gln (14,156 cases and 16,667 controls from 41 studies), Arg194Trp (7,426 cases and 9,603 controls from 23 studies), Arg280His (6,211 cases and 6,763 controls from 16 studies), −77T>C (2,487 cases and 2,576 controls from 5 studies), and XRCC3 T241M (8,560 cases and 11,557 controls from 19 studies) in different inheritance models. We found that −77T>C polymorphism was associated with increased lung cancer risk (dominant model: odds ration [OR] = 1.45, 95% confidence interval [CI] = 1.27–1.66, recessive model: OR = 1.73, 95% CI = 1.14–2.62, additive model: OR = 1.91, 95% CI = 1.24–1.94) when all the eligible studies were pooled into the meta-analysis. In the stratified and sensitive analyses, significantly decreased lung cancer risk was observed in overall analysis (dominant model: OR = 0.83, 95% CI = 0.78–0.89; recessive model: OR = 0.90, 95% CI = 0.81–1.00; additive model: OR = 0.82, 95% CI = 0.74–0.92), Caucasians (dominant model: OR = 0.82, 95% CI = 0.76–0.87; recessive model: OR = 0.89, 95% CI = 0.80–0.99; additive model: OR = 0.81, 95% CI = 0.73–0.91), and hospital-based controls (dominant model: OR = 0.81, 95% CI = 0.76–0.88; recessive model: OR = 0.89, 95% CI = 0.79–1.00; additive model: OR = 0.80, 95% CI = 0.71–0.90) for XRCC3 T241M. In conclusion, this meta-analysis indicates that XRCC1 −77T>C shows an increased lung cancer risk and XRCC3 T241M polymorphism is associated with decreased lung cancer risk, especially in Caucasians.     

基于扩展起始节点和加权融合策略预测肺癌风险致病基因

肺癌风险致病基因预测有助于了解疾病发病机制、提高临床治疗效果.目前,以重启游走为框架的风险致病基因预测算法,普遍存在起始节点少、节点转移概率相同、信息源单一的问题.为此,本文提出一种基于扩展起始节点和加权融合策略的风险致病基因预测算法(命名为AFMFSC),并在肺癌中验证算法有效性.首先,基于增广模糊测量思想,计算疾病表型近似基因间的增广功能相似得分,从中选出重要基因与致病基因作为扩展起始节点;其次,采用节点拓扑相似度转移矩阵及基因表达差异相关性转移矩阵,分别在蛋白质网络中重启随机游走,并将两种结果加权融合排序;最后,通过富集分析排名靠前基因,得到有显著意义的风险致病基因.AFMFSC算法预测的73个肺癌风险致病基因,均与肺癌发生、发展有密切联系,生物学意义显著.与其他排序算法相比,AFMFSC算法的Top 1%、Top 5%和AUC值比较大,平均排名和受拓扑特性偏差影响程度小;融合策略排名性能优于单一转移矩阵或普通邻接矩阵游走排名.AFMFSC算法不仅能准确有效地预测肺癌风险致病基因,而且可推广预测其他疾病风险致病基因,为探索癌症致病机理提供新视角及依据.     

TEM1mRNA 在非小细胞肺癌中的表达及临床意义*

目的:揭示TEM1其与非小细胞肺癌侵袭和转移的可能关系,为靶向治疗提供理想的药物作用靶点。方法:实时荧光定量PCR方法检测56例非小细胞肺癌肿瘤组织及癌旁组织中TEM1 mRNA表达水平,分析其在不同组中的表达差异。结果:TEM1在56例非小细胞肺癌组织中都有表达。TEM1表达水平在肿瘤组织中比癌旁组织表达高,并且其表达水平与淋巴结转移及肿瘤分期密切相关(P<0.05),但与患者的病理类型,年龄及性别无关(P>0.05)。结论:TEM1表达水平与非小细胞肺癌分期密切相关,表明其可能是一个参与非小细胞肺癌侵袭及转移有价值的分子标记物。TEM1可能成为潜在的基因治疗靶点。     

Quantitative Assessment of the Influence of TP63 Gene Polymorphisms and Lung Cancer Risk: Evidence Based on 93,751 Subjects

Background

Several genome-wide association studies on lung cancer (LC) have reported similar findings of a new susceptibility locus, 3q28. After that, a number of studies reported that the rs10937405, and rs4488809 polymorphism in chromosome 3q28 has been implicated in LC risk. However, the studies have yielded contradictory results.

Methods

PubMed, ISI web of science, EMBASE and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between rs10937405, rs4488809 polymorphism at 3q28 and susceptibility to LC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Heterogeneity and publication bias were also tested.

Results

A total of 9 studies including 35,961 LC cases and 57,790 controls were involved in this meta-analysis. An overall random-effects per-allele OR of1.19 (95% CI: 1.14–1.25; P<10⁻⁵) and 1.19 (95% CI: 1.13–1.25; P<10⁻⁵) was found for the rs10937405 and rs4488809 polymorphism respectively. Similar results were also observed using dominant or recessive genetic model. After stratified by ethnicity, significant associations were found among East Asians (per-allele OR = 1.22, 95% CI: 1.17–1.27; P<10⁻⁵); whereas no significant associations were found among Caucasians for rs10937405. In the sub-group analysis by sample size, significantly increased risks were found for these polymorphisms in all genetic models. When analyzed according to histological type, the effects of rs10937405, and rs4488809 at 3q28 on the risk of lung cancer were significant mostly for lung adenocarcinoma.

Conclusions

Our findings demonstrated that rs10937405-G allele and rs4488809-G allele might be risk-conferring factors for the development of lung cancer, especially for East Asian populations.     

Tumor Necrosis Factor-A Polymorphisms and Colorectal Cancer Risk: A Meta-Analysis

Background and Objectives

Tumor necrosis factor-alpha (TNF-a) was related to inflammation and involved in the development of colorectal cancer. Polymorphisms located in TNF-a promoter region, such as 308G/A and 238G/A, could affect the risk of various types of cancer by regulating TNF-a production. In this study, a meta-analysis was performed to investigate the association between common polymorphisms of TNF-a promoter region and colorectal cancer susceptibility.

Methods

Searching of several databases was performed for all publications on the association between TNF-a polymorphisms and colorectal cancer. Summary odds ratios (ORs) with their 95% confidence intervals (95% CIs) were calculated using random-effects models. Stratified analyses based on ethnicity and control population source were also conducted.

Results

Overall, TNF-a 308A polymorphism showed a significant association with increased risk of colorectal cancer in worldwide populations under homozygote comparison [AA vs. GG, OR (95% CI) = 1.46 (1.07–1.97)] other than heterozygote comparison [AG vs. GG, OR (95% CI) = 1.05 (0.93–1.19)]. TNF-a 238A was not associated with colorectal cancer risk under homozygote or heterozygote comparisons. In stratified analysis, significant association was observed only in Western populations [AA vs. GG, OR (95% CI) = 1.39 (1.01–1.91)] other than in Eastern populations under homozygote comparison. No significant difference was observed between population-based subgroup and hospital-based subgroup.

Conclusions

TNF-a 308A was moderately associated with an increased risk of colorectal cancer in Western populations, and TNF-a 238A polymorphism was not significantly associated with colorectal cancer risk.     

Customized Treatment in Non-Small-Cell Lung Cancer Based on EGFR Mutations and BRCA1 mRNA Expression

Background

Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels.

Methodology/Principal Findings

We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1–1.7]; P = 0.05).

Conclusions/Significance

Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00883480","term_id":"NCT00883480"}}NCT00883480