Epidermal Growth Factor Receptor Single Nucleotide Polymorphisms Research Articles

Side effects of tyrosine kinase inhibitors therapy in patients with non-small cell lung cancer and associations with EGFR polymorphisms: A systematic review and meta-analysis.

Rash and diarrhea are common side effects of tyrosine kinase inhibitor (TKI) therapy administered to patients with non-small cell lung cancer (NSCLC). The polymorphisms of the epidermal growth factor receptor (EGFR) gene may be a potential predictor of these side effects. The aim of the present meta-analysis was to examine the association of EGFR polymorphisms and TKI-associated toxicities. Electronic databases (PubMed, Scopus and ISI Web of Science) were searched for relevant studies. According to the inclusion and exclusion criteria, a search of the databases identified 4,918 results, among which 6 clinical trials were obtained with 1,318 patients with NSCLC. A total of 9 EGFR single nucleotide polymorphisms (SNPs) associated with TKI toxicity were identified including, rs11568315, rs712829, rs712830, rs2227983, rs2075102, rs2293347, rs11977388, rs4947492 and rs884225. The data associated with skin toxicity from rs11568315, rs712829 and rs712830 were analyzed in the present meta-analysis. Data from rs11568315 were also analyzed in relation to diarrhea. Among all the examined SNPs, statistically significant results were obtained under the dominant genetic model for CA repeats in rs11568315 (SS vs. SL+LL) with skin toxicity. The long CA repeat (SL+LL) carriers were more likely to experience skin toxicity associated with TKIs (P=0.005). By contrast, there was no significant result for diarrhea (P=0.661) under dominant genetic model for CA repeats.

Analyses of P16INK4a gene promoter methylation relative to molecular, demographic and clinical parameters characteristics in non-small cell lung cancer patients: A pilot study.

The aim of this study was to examine the methylation status of p16INK4a promoter region in non small cell lung cancer (NSCLC) patients and their associations with single nucleotide polymorphisms (SNPs) of the epidermal growth factor receptor (EGFR) gene, as well as with demographic or clinical characteristics. Formalin-fixed and paraffin-embedded (FFPE) DNA samples extracted from 22 NSCLC patients were analyzed with methylation-specific polymerase chain reaction (PCR) method to obtain promoter methylation profile. The same cohort was genotyped for - 216G > T, -191C > A, and 181,946C > T EGFR SNPs. There was a significant association between methylated p16INK4a in patients prior therapy (p = 0.017) since a significantly higher frequency of methylated p16INK4a was detected in these patients (40.9%) in comparison to frequency in patients after therapy (31.8%). Also, a higher frequency of methylated p16INK4a was detected among patients with leucopenia (p = 0.056). No associations were observed between the methylation status of the p16INK4a promoter region and EGFR SNPs or other clinical and demographic data in this cohort. High frequency of methylation of the p16INK4a gene promoter was observed in NSCLC patients prior therapy and with leucopenia that can indicate their significance related to advanced clinical stage.

Polymorphisms in EGFR Gene Predict Clinical Outcome in Unresectable Non-Small Cell Lung Cancer Treated with Radiotherapy and Platinum-Based Chemoradiotherapy.

For non-small cell lung cancer (NSCLC), radiotherapy (RT) and platinum-based chemotherapy (CHT) are among the main treatment options. On the other hand, radioresistance and cytotoxic drug resistance are common causes of failure. The epidermal growth factor receptor (EGFR) plays an important role in radioresponse and therapy resistance. We hypothesized that single nucleotide polymorphisms (SNPs) in the EGFR gene might affect individual sensitivity to these treatments, and thus, therapy outcome and prognosis. The association between functional EGFR SNPs and overall (OS), locoregional recurrence-free (LFRS), and metastasis-free (MFS) survival was examined in 436 patients with unresectable NSCLC receiving RT and platinum-based CHTRT. In a multivariate analysis, the rs712830 CC homozygotes showed reduced OS in the whole group (p = 0.039) and in the curative treatment subset (p = 0.047). The rs712829 TT genotype was strongly associated with decreased LRFS (p = 0.006), and the T-C haplotype was a risk factor for locoregional recurrence in our patients (p = 0.003). The rs2227983 GG alone and in combination with rs712829 T was an indicator of unfavorable LRFS (p = 0.028 and 0.002, respectively). Moreover, significant independent effects of these SNPs on OS, LRFS, and MFS were observed. Our results demonstrate that inherited EGFR gene variants may predict clinical outcomes in NSCLC treated with DNA damage-inducing therapy.

Effect of epidermal growth factor receptor gene polymorphisms on prognosis in glioma patients.

Previous studies suggested that single nucleotide polymorphisms (SNPs) in epidermal growth factor receptor (EGFR) are associated with risk of glioma. However, the associations between these SNPs and glioma patient prognosis have not yet been fully investigated. Therefore, the present study was aimed to evaluate the effects of EGFR polymorphisms on the glioma patient prognosis. We retrospectively evaluated 269 glioma patients and investigated associations between EGFR SNPs and patient prognosis using Cox proportional hazard models and Kaplan-Meier curves. Univariate analysis revealed that age, gross-total resection and chemotherapy were associated with the prognosis of glioma patients (p < 0.05). In addition, four EGFR SNPs (rs11506105, rs3752651, rs1468727 and rs845552) correlated with overall survival (OS) (Log-rank p = 0.011, 0.020, 0.008, and 0.009, respectively) and progression-free survival PFS (Log-rank p = 0.026, 0.024, 0.019 and 0.009, respectively). Multivariate analysis indicated that the rs11506105 G/G genotype, the rs3752651 and rs1468727 C/C genotype and the rs845552 A/A genotype correlated inversely with OS and PFS. In addition, OS among patients with the rs730437 C/C genotype (p = 0.030) was significantly lower OS than among patients with A/A genotype. These data suggest that five EGFR SNPs (rs11506105, rs3752651, rs1468727, rs845552 and rs730437) correlated with glioma patient prognosis, and should be furthered validated in studies of ethnically diverse patients.

Identification of epidermal growth factor receptor (EGFR) genetic variants that modify risk for head and neck squamous cell carcinoma

EGFR polymorphisms have not been thoroughly evaluated for association with head and neck squamous cell carcinoma (HNSCC) risk. We genotyped 578 HNSCC patients and 588 cancer-free controls for 60 EGFR single nucleotide polymorphisms (SNPs) and tested associations with HNSCC risk.EGFR intronic SNPs rs12535536, rs2075110, rs1253871, rs845561 and rs6970262 and synonymous SNP rs2072454 were associated with HNSCC risk among all subjects (p < 0.05). SNPs rs12538371, rs845561, and rs6970262 were significantly associated with HNSCC risk (p < 0.05) among never tobacco users. We identified EGFR variants that likely modify risk for HNSCC including three variants that contribute to tobacco-independent risk.

Epidermal growth factor receptor (EGFR) mutations as biomarker for head and neck squamous cell carcinomas (HNSCC)

Context: Mutations in tyrosine kinase domain (TK) of epidermal growth factor receptor (EGFR) lead to signalling interruptions in several cancers.Objective: To understand EGFR mutations in head and neck squamous cell carcinomas (HNSCC), and their role as biomarkers.Methods: Screened 129 HNSCC patients and 150 controls for mutations in the TK domain using polymerase chain reaction (PCR), single strand confirmatory polymorphism (SSCP) and sequencing.Results: 81.39% of HNSCC had four mutations: G2155C, G2176A, C2188G and G2471A among these two mutations were also reported in other cancers where as two novel mutations are being reported for the first time in HNSCC. Mutational frequency was significantly associated with an advanced stage of HNSCC, habits of tobacco/alcohol and ages above 49 years.Conclusion: EGFR single nucleotide polymorphisms could be useful biomarkers of HNSCC.

Abstract 1340: Identification of epidermal growth factor receptor (EGFR) polymorphisms that modify risk for squamous cell carcinoma of the head and neck (HNSCC).

Abstract Background: EGFR is overexpressed in HNSCC and contributes to disease progression. HNSCC arising in individuals with and without tobacco use histories represent distinct disease etiologies. A thorough evaluation of EGFR polymorphisms for association with HNSCC risk has not been reported. Methods: We determined the genotypes at 60 EGFR single nucleotide polymorphisms (SNPs) in 578 white HNSCC patients and 588 white cancer-free controls using the iPLEX gold mass spectrometry-based genotyping assay. EGFR SNPs were selected based on hypothesized function and/or tagging of EGFR with r2 ≥0.8 and minor allele frequencies of ≥5%. Associations with HNSCC risk were tested using the Fisher's exact test for genotype and for trend for number of alleles of each SNP. We also performed these analyses stratified by tobacco use. SNPs significantly associated with HNSCC (p&amp;lt;0.05 for either test) were further tested using multivariable logistic regression (MLR) analysis. SNPs significant in MLR models were evaluated in an independent cohort of 408 white HNSCC patients and 408 white cancer-free subjects. Expression of non-coding RNA transcript EGFR-AS1 was detected by PCR amplification following reverse-transcription of RNA isolated from Fadu, CAL33 and LICR-LON-HN5 HNSCC cell lines. Results: Of the 60 EGFR SNPs tested, 5 intronic SNPs (rs12535536, rs2075110, rs12538371, rs845561 and rs6970262) and 1 synonymous coding SNP (rs2072454) were found to be associated (p&amp;lt;0.05) with HNSCC risk in the entire case-control cohort after adjustment for sex, age, and use of alcohol and tobacco. Among never tobacco users, rs12538371, rs845561, and rs6970262, residing within introns 15, 20 and 21, respectively, were significantly associated with HNSCC risk (p&amp;lt;0.05) after adjustment for age and sex. Two of these SNPs (rs845561 and rs6970262) reside near histone H3 lysine27 acetylation-enriched regions in ENCODE cell lines and sequences encoding the 2.8 kb spliced non-coding transcript EGFR AS1, which we detected in HNSCC cell lines. rs17586365 was significantly associated with HNSCC risk in MLR models restricted to tobacco users. However, SNPs rs6593206, rs2075110, rs12538371, rs845561 and rs6970262 were not associated with HNSCC risk in an independent cohort where all HNSCC cases had histories of tobacco use. Conclusions: Common EGFR genetic variants may modify risk for HNSCC independent of known risk factors. The difference in tobacco use histories between two different cohorts may account for the discrepancy in the association between certain SNPs and HNSCC risk association. Three EGFR variants may specifically contribute to tobacco-independent HNSCC. The functional consequences of these SNPs or risk-conferring polymorphisms in linkage disequilibrium have yet to be defined. Citation Format: Christopher Fung, Kerry Trent, Sonali Joyce, Pei Zhou, Tomoko Nukui, Daniel E. Weeks, Brenda Diergaarde, Yuanqing Ye, Xifeng Wu, Jian-Min Yuan, Jennifer Grandis, Joel L. Weissfeld, Marjorie Romkes, Ann Marie Egloff. Identification of epidermal growth factor receptor (EGFR) polymorphisms that modify risk for squamous cell carcinoma of the head and neck (HNSCC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1340. doi:10.1158/1538-7445.AM2013-1340

Role of EGFR SNPs in survival of advanced lung adenocarcinoma patients treated with Gefitinib

AimAs a novel molecularly targeting agent for non-small-cell lung cancer (NSCLC), Gefitinib can block its tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Genetic variations in EGFR may affect its protein function or expression and lead to diverse outcomes in NSCLC patients after Gefitinib therapy. Therefore, this prospective study examined whether EGFR single nucleotide polymorphisms (SNPs) are associated with different survival time in advanced lung adenocarcinoma patients treated with Gefitinib. MethodsOne hundred and twenty-eight patients with stage IIIB or IV lung adenocarcinoma receiving Gefitinib target therapy between 2008 and 2010 were recruited in this study. Six EGFR haplotype-tagging SNPs were genotyped by the Sequenom MassArray system. Survival by different genotypes was compared using Kaplan–Meier methods. Cox proportional hazards models were applied to estimate the effect of prognostic factors on overall survival (OS) and progression-free survival (PFS). ResultsAfter the median 16.6months of follow-up, the unfavorable EGFR rs2293347AA or GA genotype was significantly correlated with shorter OS (AA vs. GG: 2.0 vs. 21.0months; hazard ratio (HR)=2.44, 95% confidence interval (CI)=1.06–5.56; P=0.036; GA vs. GG: 15.0 vs. 21.0months; HR=1.75, 95%CI=1.08–2.86, P=0.025) compared with the favorable rs2293347GG genotype. The prognostic significance of EGFR rs4947492 polymorphism on OS also existed (GG carriers vs. AA carriers: median OS=24.6 vs. 14.9months, HR=0.29, 95%CI=0.10–0.83, P=0.021). No significant associations were found among other EGFR SNPs and survival. ConclusionEGFR rs2293347 and rs4947492 SNPs might be potential predictive markers of OS in advanced lung adenocarcinoma patients treated with Gefitinib.

EGFR polymorphisms, hormone replacement therapy and lung adenocarcinoma risk: analysis from a genome-wide association study in never-smoking women

Hormone replacement therapy (HRT) and epidermal growth factor receptor (EGFR) single nucleotide polymorphisms (SNPs) have been reported as risk factors for lung cancer in never smokers. We investigate the interaction of EGFR SNPs and HRT for lung adenocarcinoma risk in never-smoking women. This study included 532 never-smoking female lung adenocarcinoma patients and 532 controls, with EGFR SNPs retrieved from a genome-wide association study. The associations of EGFR SNPs with the lung adenocarcinoma risk were estimated by multivariate-adjusted logistic regression. The Haploview program was used to select tagged EGFR SNPs interacted with HRT and construct haplotype blocks. The Benjamini and Hochberg method was used to reduce the multiple testing effects. Among 84 EGFR SNPs retrieved, 11 tagging EGFR SNPs showed an interaction with HRT and lung adenocarcinoma risk, which were mostly located near the tyrosine kinase domain. Eight of the tagged SNPs were in two haplotype blocks. The interactions between HRT and numbers of protective EGFR SNP genotypes are significant in both blocks (P for interaction = 0.0004 and 0.0032, respectively). A trend of decrease in lung adenocarcinoma risk was found in subjects with HRT harboring an increasing number of protective EGFR SNP genotypes in both blocks (P = 0.0032 and 0.0046, respectively). In conclusion, HRT use may modify the association of EGFR SNPs with lung adenocarcinoma risk. The EGFR SNPs have a cumulative effect on decreasing lung adenocarcinoma risk in never-smoking women with HRT use.

Association of rheumatoid arthritis risk with EGFR genetic polymorphisms in Taiwan’s Han Chinese population

The involvement of the epidermal growth factor receptor (EGFR) in the pathogenesis of cancer is well documented. In contrast, its role in rheumatoid arthritis (RA) development is not that well defined although previous studies suggested the possible link between autoimmune diseases and malignancy. Therefore, we aimed to examine whether there is a link between the EGFR genetic polymorphisms and the RA. Our study gauged the effects of EGFR (rs11543848 and rs17337023) single-nucleotide polymorphisms (SNPs) on RA among Taiwan's Han Chinese population. Polymorphism of EGFR gene was analyzed in 188 RA patients and 128 control subjects. Genotyping for EGFR SNPs was performed by restriction fragment length polymorphism (RFLP) assay. Our data confirmed statistically significant increased risk of RA development in subjects with A carrier at rs17337023 SNP (P < 0.0001), and subjects with A allele at rs17337023 SNP (odds ratio [OR] = 1.52; 95% confidence interval [CI] = 1.10-2.09). Furthermore, comparison of haplotype frequencies between patients and controls suggested GA and AT haplotypes were more "at-risk" for RA development (P < 0.0001 and P < 0.01, respectively). However, comparisons of the clinical features of RA patients according to different genotypes and haplotypes revealed no significant difference. In conclusion, our data yield the new information on EGFR polymorphisms (rs11543848 and rs17337023) with the susceptibility of RA development and polymorphism revealed by this study merit further investigation.

Association of an EGFR intron 1 SNP with never-smoking female lung adenocarcinoma patients

Epidermal growth factor receptor (EGFR) plays an important role in the development and progression of a variety of malignant tumors. To test single nucleotide polymorphisms (SNPs) and haplotypes of the EGFR in modulating the lung cancer susceptibility, we conducted a matched case–control study of 730 lung cancer patients and 730 healthy controls for examining the association in Taiwanese population. Fourteen tag SNPs distributed in EGFR were selected for genotyping and one SNP 8227G>A (rs763317) located in the intron 1 of EGFR was significantly associated with lung cancer ( P = 0.009). Interestingly, the increase of lung cancer risk is significantly associated with never-smoking female adenocarcinoma patients harboring 8227A allele. In never-smoking female population, ORs for 8227G>A were significantly increased in adenocarcinoma subtype (adjusted odds ratio (OR) for GA genotype = 1.23, 95% confidence interval (CI) = 0.87–1.75; and adjusted OR for AA genotype = 3.52, 95% CI = 1.32–9.37, respectively). The ORs in dominant or recessive genetic model were also significantly increased in female lung adenocarcinoma subtype (adjusted OR = 1.35, 95% CI = 1.05–1.90; and adjusted OR = 3.26, 95% CI = 1.24–8.62, respectively). Haplotype analyses of 14 EGFR SNPs revealed that haplotype comprising the rare allele of 8227G>A and the common allele of the other 13 SNPs was associated with a significantly increased risk of female adenocarcinoma (OR = 2.81, 95% CI = 1.02–7.77). Together, our results suggest that polymorphisms or haplotypes of the EGFR play an important role in the development of lung cancer in Taiwan, particularly in never-smoking female lung adenocarcinoma.