Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ERCC1 (excision repair cross complementation group 1) is a subunit of the nucleotide excision repair complex, which can perform DNA strand incision correction of DNA damage. Association studies on the ERCC1 polymorphisms (C8092A and T19007C) in cancer had shown conflicting results. We performed a meta-analysis from all eligible case-control studies to assess the purported associations. Overall, the 19007C allele (3 853 patients and 4 349 controls) showed no significant effect on cancer risk compared to 19007T allele (P=0.39, odds ratio (OR)=0.95; 95% confidence interval (CI) 0.85-1.06, P(heterogeneity)=0.001) in all subjects. Meta-analysis under other genetic contrasts did not reveal any significant association of T19007C to cancer in all subjects, Caucasians and Asians. The 19007C allele (2 279 patients and 2 808 controls) showed no significant effect on lung cancer risk compared to 19007T allele (P=0.72, OR=0.94, 95% CI 0.69-1.29, P(heterogeneity)=0.0001) in all subjects. No significant effect of 8092A allele (3 865 patients and 3 750 controls) on cancer risk in all subjects (P=0.85, OR=1.01, 95% CI 0.94-1.08, P(heterogeneity)=0.92) and in Caucasians and Asians compare to 8092C. No evidences of association of C8092A (501 patients and 620 controls) to squamous cell carcinoma were found. The accumulated evidence indicated ERCC1 T19007C and C8092A might not be risk factors for cancer. Significant between-study heterogeneity existed in T19007C, which arose from a study showing significant protecting effect of 19007C allele compare to 19007T allele in smokers. More studies based on larger, stratified case-control population should be required to further evaluate the role of ERCC1 C8092A and T19007C polymorphisms in different cancer, especially in smokers.
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PMID:No association of ERCC1 C8092A and T19007C polymorphisms to cancer risk: a meta-analysis. 1752 21

Increasing knowledge regarding multiple genetic disturbances found in human lung cancers, particularly non-small cell lung cancer (NSCLC), have enabled predictive markers to be used in specialised centres in tailoring chemotherapy regimens and improving survival and response in subgroups of patients. Impressive responses are observed in patients with epidermal growth factor receptor (EGFR) tyrosine kinase mutations following treatment with gefitinib and erlotinib; and methylation of the mitotic checkpoint gene 14-3-3sigma in circulating tumour serum DNA predicts response to cisplatin/gemcitabine therapy. Expression of markers of DNA repair, ERCC1, RRM1 and BRCA1 are also determinants of response to cisplatin/gemcitabine, with low levels of mRNA predicting improved survival. Patients harbouring the Met/Met mutation in XRCC3 240 have significantly better survival compared with other mutations. These findings are presented in this article, as well as their relevance in customising chemotherapy - illustrated by a hypothetical model guiding treatment decisions in the management of NSCLC.
Lung Cancer 2007 Aug
PMID:How could pharmacogenomics help improve patient survival? 1768 45

Cancer chemotherapy and radiotherapy kill cancer cells by inducing DNA damage, unless the lesions are repaired by intrinsic repair pathways. DNA double-strand breaks (DSB) are the most deleterious type of damage caused by cancer therapy. Homologous recombination (HR) is one of the major repair pathways for DSB and is thus a potential target of cancer therapy. Cells with a defect in HR have been shown to be sensitive to a variety of DNA-damaging agents, particularly interstrand crosslink (ICL)-inducing agents such as mitomycin C and cisplatin. These findings have recently been applied to clinical studies of cancer therapy. ERCC1, a structure-specific endonuclease involved in nucleotide excision repair (NER) and HR, confers resistance to cisplatin. Patients with ERCC1-negative non-small-cell lung cancer were shown to benefit from adjuvant cisplatin-based chemotherapy. Imatinib, an inhibitor of the c-Abl kinase, has been investigated as a sensitizer in DNA-damaging therapy, because c-Abl activates Rad51, which plays a key role in HR. Furthermore, proteins involved in HR have been shown to repair DNA damage induced by a variety of other chemotherapeutic agents, including camptothecin and gemcitabine. These findings highlight the importance of HR machinery in cancer therapy.
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PMID:Clinical relevance of the homologous recombination machinery in cancer therapy. 1795 11

Recent years have brought tremendous progress in the development of genomic and proteomic platforms to study cancer biology. Tests based on these platforms are helpful in early diagnosis, prognosis, and prediction of treatment benefit. Molecular studies performed on minimally invasive material (plasma, sputum) from individuals participating in longitudinal or case-control studies have approximately 70%-90% sensitivity and specificity to detect lung cancer. In operable non-small-cell lung cancer, genomic and proteomic studies yield better prognostic information than pathologic staging. There are several examples of successful identification of predictive assays for benefit from chemotherapy (ERCC1, RRM1, p27Kip1, and p53 expression) or targeted therapies (epidermal growth factor receptor [EGFR] gene copy number, EGFR activating mutations, EGFR protein expression, serum proteomic profile). These markers should be prospectively tested in clinical studies before they can be routinely used in the clinic.
Clin Lung Cancer 2008 Mar
PMID:Advances in genomic and proteomic studies of non-small-cell lung cancer: clinical and translational research perspective. 1850 Oct 93

The validation of predictive biomarkers to tailor chemotherapy is a key issue in the development of effective treatment modalities against cancer. Examples of how genetics might affect drug response are offered by gemcitabine. A substantial number of potential biomarkers for sensitivity or resistance to gemcitabine have been proposed, including ribonucleotide reductase and cytidine deaminase polymorphisms, human equilibrative transporter-1 and ribonucleotide reductase gene-expression and AKT phosphorylation status. These markers displayed a significant relationship with disease response to the drug; however, their robustness needs to be evaluated within prospective studies. Moreover, recent trials of customized chemotherapy based on genetic markers have been carried out in non-small-cell lung cancer and promising pharmacogenetic determinants are gaining momentum, including BRCA1 and ERCC1. Hopefully, biomarkers to select patients most likely to respond to gemcitabine will be validated in the near future.
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PMID:Pharmacogenomics of gemcitabine in non-small-cell lung cancer and other solid tumors. 1910 17

Chemotherapies are widely used in the treatment of lung cancer. However, little is known about their effect in the expression of different tissue markers. Seventeen lung cancer tissue blocks obtained by bronchoscopic biopsies together with their corresponding surgical biopsies after neoadjuvant chemotherapy were studied. They included 9 adenocarcinomas (ADC) and 8 squamous cell carcinomas (SCC). Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues to study the expression of Ki-67, p53, Bcl-2, Bax, Fas-ligand and ERCC1 (excision repair cross-complementation group 1). Out of 17 NSCLC 6 expressed proapoptotic markers and 4 expressed antiapoptotic markers, while in 7 cases the apoptotic markers did not show detectable changes after neoadjuvant chemotherapy. Six of 17 bronchoscopic NSCLC cases expressed increased level of Ki-67 after neoadjuvant treatment. Eight bronchoscopic NSCLC tissues (6 SCC, 2 ADC) expressed ERCC1. All but one ADC became ERCC1 negative after neoadjuvant therapy. There was no newly expressed ERCC1 positive case in the surgical biopsy group. Platinum-based neoadjuvant chemotherapy had no effect on the apoptotic activity of 17 patients' tumor specimen, however, 6 of 17 bronchoscopic NSCLC cases expressed increased level of Ki-67 after neoadjuvant treatment, in 3 cases the level of Ki-67 became decreased, while 8 cases had no detectable change of proliferation activity. The results of the present study suggest that platinum-based chemotherapy probably induces a selection of tumor cells with more aggressive phenotype, and also affects the expression of tissue marker (ERCC1) that could have predictive value.
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PMID:Platinum-based chemotherapy in lung cancer affects the expression of certain biomarkers including ERCC1. 1925 35

An impressive number of publications refer to prognostic and predictive factors in lung cancer. TNM classification and performance status significantly influence the choice of treatment and strongly predict patients' survival. Depending on the population studied (small cell or non-small cell cancer, operable or not) other independent factors improve the prediction of prognosis; they are clinical, biological, radiological or molecular and pertain to the tumor or the patient. Molecular targeted therapies development has renewed the interest towards predictive factors. New strategies are developed to explore individual response to treatment such as EGFR tyrosine-kinase inhibitors, without success for anti-angiogenic treatments. Conventional cytotoxic agents may also be customized with predictive factors (i.e. ERCC1 or RRM1). Large multicenter studies are needed to validate new independent prognostic factors and increase our current knowledge aiming at separating patients who will really benefit from therapies of those who will only experience the side effects.
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PMID:[Prognostic and predictive factors in lung cancer]. 1935 14

Herein are highlights from National Lung Cancer Partnership's Annual Meeting, held May 30, 2008 in Chicago. Aiming to improve the match between lung cancer patients and their drug treatments, speakers described potential predictive and prognostic biomarkers. Approaches included: (1) in non-small cell lung cancer, testing for predictive links between tumor expression levels of DNA synthesis (RRM1) and repair (ERCC1) enzymes and response to gemcitabine and cisplatin respectively, and looking for a prognostic link with ERCC1 expression; (2) validating a predictive "meta-gene profile" from gene expression microarray studies to distinguish drug-responsive from unresponsive lung cancer tumors; and (3) developing proteomics profiling to distinguish lung cancer patients, including squamous and nonsquamous cell carcinoma patients, who respond to epidermal growth factor receptor tyrosine kinase inhibitors from those who do not. The notion that cancer stem cells are fundamental in the development and progression of solid tumors including lung cancers was also discussed. Potential strategies for using this information to identify useful targets for next-generation therapies were suggested.
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PMID:2008 Meeting of the National Lung Cancer Partnership: a summary of meeting highlights. 1939 13

PURPOSE To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens. METHODS We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non-small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m(2)) and carboplatin (area under the concentration-time curve, 6). Genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1, and ERCC2 were analyzed by pyrosequencing or by PCR restriction fragment length polymorphism. Results were assessed by Cox model for survival and by logistic regression for response and toxicity. Results Clinical results were similar in the two Japanese trials, and were significantly different from the US trial, for survival, neutropenia, febrile neutropenia, and anemia. There was a significant difference between Japanese and US patients in genotypic distribution for CYP3A4*1B (P = .01), CYP3A5*3C (P = .03), ERCC1 118 (P < .0001), ERCC2 K751Q (P < .001), and CYP2C8 R139K (P = .01). Genotypic associations were observed between CYP3A4*1B for progression-free survival (hazard ratio [HR], 0.36; 95% CI, 0.14 to 0.94; P = .04) and ERCC2 K751Q for response (HR, 0.33; 95% CI, 0.13 to 0.83; P = .02). For grade 4 neutropenia, the HR for ABCB1 3425C-->T was 1.84 (95% CI, 0.77 to 4.48; P = .19). CONCLUSION Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients. In an exploratory analysis, genotype-related associations with patient outcomes were observed for CYP3A4*1B and ERCC2 K751Q. This common-arm approach facilitates the prospective study of population-related pharmacogenomics in which ethnic differences in antineoplastic drug disposition are anticipated.
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PMID:Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics. 1947 Sep 25

In lung cancer, expressive survival has not yet been achieved in non surgical stages. Non-small cell lung cancer (NSCLC) patients are treated with platinum and other drugs. To choose these agents we can actual ly define predictive biomarkers to preview therapeutic response. A literature revision was done in order to define the role of ERCC1 e RRM1 genes in the response to chemotherapy based in platinum and gemcitabine respectively. The expression of these genes is faced as a predictive marker to the chemotherapy response in patients with adenocarcinomas and squamous cell carcinomas, providing a personalized therapy. Published data supports this behaviour and is useful to individualize therapy accordingly to individual levels of ERCC1 which are modified by genetic mutations. Polymorphisms in codons 118 C/T and C8092A, seem to influence the carcinogenesis, cytostatic resistance, survival and even the prognosis. Clinical and laboratorial trials showed that high expression of RRM1 gene in NSCLC has impact in the tumoral phenotype. Patients having done surgical resection and presenting high expression of RRM1 have better survival than those with lower expression. However, patients with advanced NSCLC and treated with chemotherapy with gemcitabine and cisplatin appear to have a poor outcome if the tumor express elevated levels of RRM1 gene.
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PMID:[ERCC1 and RRM1 genes in lung cancer]. 1955 12


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