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)

Cisplatin-based chemotherapy has long been the cornerstone of non-small cell lung cancer (NSCLC) management. However, median survival rarely exceeds 1 year. The identification of molecular markers can help to predict response, leading to a broad implementation of the new concept of customized chemotherapy. ERCC1 is an excision nuclease within the nucleotide excision repair pathway that forms a heterodimer with XPF. As a unit, they execute the 5' incision into the DNA strand relative to the site of DNA damage. The 5' excision is the last of several steps that are specific to excision of a platinum DNA lesion. In mouse models, normal ERCC1 function is critical to normal aging and brain development. Numerous studies indicate that ERCC1 influences the repair of platinum DNA damage. We report here our accumulated experience of ERCC1 mRNA expression and outcome in cisplatin-treated NSCLC patients and the preliminary confirmatory data on a prospective ERCC1 mRNA customized docetaxel-cisplatin trial, in which low ERCC1 mRNA levels in the tumor correlate with significantly better response. ERCC1 is one of several proteins involved in the repairosome, where other DNA repair genes, such as BRCA1, are also central to cisplatin resistance.
Lung Cancer 2005 Dec
PMID:Applications of genomics in NSCLC. 1655 72

At the time of diagnosis, half of lung cancer patients have advanced incurable disease. Different chemotherapy combinations--with or without targeted therapies--yield similar results in spite of the continuous efforts of clinicians. However, molecular biological studies have already shed a great deal of light on the existence of multiple genetic aberrations that can be useful for customizing treatment. mRNA transcripts involved in DNA repair pathways, such as ERCC1 and BRCA1, confer selective resistance to cisplatin or taxanes. Polymorphisms in DNA repair genes and methylation of checkpoint genes in circulating serum DNA could become important predictive markers of survival to certain cisplatin-based regimens. EGFR tyrosine kinase mutations are the crux of targeted therapies.
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PMID:From the bench to the bed: individualizing treatment in non-small-cell lung cancer. 1663 19

Homozygous carriers of a haplotype consisting of ERCC1 Asn118Asn(A), ASE-1 G-21A(G), RAI IVS1 A4364G(A) are at increased risk of lung cancer especially among women. Here, we analyse for gene-environment interactions with the predefined haplotype in a case cohort study including 428 lung cancer cases and a comparison group of 800 persons, all from the prospective Diet, Cancer and Health cohort of 57,000 Danes. At high smoking intensity (>20g tobacco/day), there was only additional risk of smoking intensity among women who were homozygous carriers of the haplotype (IRR=2.03; 95% CI: 1.10-3.73 per 5 additional g tobacco/day).
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PMID:Gene-environment interactions between smoking and a haplotype of RAI, ASE-1 and ERCC1 polymorphisms among women in relation to risk of lung cancer in a population-based study. 1669 Feb 7

Lung cancer is a worldwide problem. At the time of diagnosis, 50% of patients have advanced incurable disease. Different chemotherapy combinations--with or without targeted therapies--yield similar results despite the continuous efforts of clinicians. However, molecular biological studies have already shed a great deal of light on the existence of multiple genetic aberrations that can be useful for customizing treatment. mRNA transcripts involved in DNA repair pathways, such as ERCC1 and BRCA1, confer selective resistance to cisplatin or taxanes, whereas thioredoxin confers a broad spectrum of chemoresistance. Polymorphisms in DNA repair genes and methylation of checkpoint genes in circulating serum DNA could become important predictive markers of survival in certain cisplatin-based regimens. Epidermal growth factor receptor tyrosine kinase mutations are the crux of targeted therapies, whereas epithelial-mesenchymal transitions and HER3 mRNA levels are promising ancillary markers for treatment with epidermal growth factor receptor tyrosine kinase inhibitors.
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PMID:Predicting the outcome of chemotherapy for lung cancer. 1676 44

Approximately half of lung cancer patients present with metastases, and a large proportion will develop recurrent disease, with median survival to cisplatin-based chemotherapy of 11 months. No predictive factor of response to cisplatin-based chemotherapy is yet available in clinical practice. The nucleotide excision repair system plays a major role in repairing a variety of distorting lesions, notably platinum-induced DNA adducts. ERCC1 is a leading gene in repairing cisplatin DNA damage. We carried out three different studies examining individually the role of ERCC1, RRM1, and then both, mRNA expression in paraffin-embedded pretreatment bronchial biopsies from gemcitabine/cisplatin-treated advanced non-small-cell lung cancer (NSCLC) patients. Median survival was significantly prolonged in patients with low levels of ERCC1 or RRM1. BRCA1 is involved in homologous recombination repair, and we observed that low levels of BRCA1 mRNA significantly increased survival in gemcitabine/cisplatin-treated patients. Our observations lead us to recommend that tumors be regularly assessed for ERCC1 and BRCA1 mRNA expression in order to customize gemcitabine/cisplatin treatment.
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PMID:Pharmacogenomics and gemcitabine. 1680 41

This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in both the near and distant future. At least six lines of research have recently emerged as potential contributors to changes in clinical practice. Abundant pre-clinical and clinical data indicate that BRCA1 mRNA expression is a differential modulator of chemotherapy sensitivity. Low levels predict cisplatin sensitivity and antimicrotubule drug resistance, and the opposite occurs with high levels. Secondly, single nucleotide polymorphisms in the ERCC1 gene influence survival and toxicity with cisplatin-based chemotherapy. The main core of recent research has centered on EGFR mutations and gene copy numbers. For the first time, EGFR mutations have been shown to predict dramatic responses in metastatic lung adenocarcinomas, with a threefold increase in time to progression and survival in patients receiving EGFR tyrosine kinase inhibitors. In contrast, K-ras mutations confer a negative effect in these patients. Evidence has also been accumulated on the crosstalk between estrogen and EGFR receptor pathways, paving the way for clinical trials of EGFR tyrosine kinase inhibitors plus aromatase inhibitors. microRNAs control the expression of cognate target genes, and downregulation of Dicer has been shown to be a strong predictor of relapse in surgically resected non-small-cell lung cancer patients. Finally, overexpression of the Wingless-type (Wnt) genes and methylation of Wnt antagonists like WIF and secreted frizzled related proteins have been documented in non-small-cell lung cancer and are believed to be an important mechanism of cancer stem cell maintenance.
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PMID:Usefulness of predictive tests for cancer treatment. 1693 74

Surgery remains the initial treatment for patients with early-stage non-small-cell lung cancer (NSCLC). Additional therapy is necessary because of high rates of distant and local disease recurrence after surgical resection. Early trials of adjuvant chemotherapy and postoperative radiation were often plagued by small patient sample size, inadequate surgical staging, and ineffective or antiquated treatment. A 1995 meta-analysis found a nonsignificant reduction in risk of death for postoperative cisplatin-based chemotherapy. Since then, a new generation of randomized phase III trials have been conducted, some of which have reported a benefit for chemotherapy in the adjuvant setting. The role of postoperative radiation therapy remains to be defined. It may not be beneficial in early-stage NSCLC but still may have utility in stage IIIA disease. Improvement in survival outcomes from adjuvant treatment are likely to result from the evaluation of novel agents, identification of tumor markers predictive of disease relapse, and definition of factors that determine sensitivity to therapeutic agents. Some of the molecularly targeted agents such as the angiogenesis and epidermal growth factor receptor inhibitors are being incorporated into clinical trials. Preliminary results with gene-expression profiles and lung cancer proteomics have been promising. These techniques may be used to create prediction models to identify patients at risk for disease relapse. Molecular markers such as ERCC1 may determine response to treatment. All of these innovations will hopefully increase cure rates for lung cancer patients by maximizing the efficacy of adjuvant therapy.
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PMID:Adjuvant treatment of non-small-cell lung cancer: how do we improve the cure rates further? 1739 81

Lung cancer is the number one cause of cancer-related mortality. In order to improve the outcome of patients, advances in the understanding of cancer biology and the development of therapeutic modalities that target key proliferation and survival mechanisms are needed. In vitro data have demonstrated that the genes RRM1 and ERCC1 are important components of these mechanisms. Recently, how these genes affect lung cancer therapy has been explored in the clinical setting with the goal of finding customized treatment algorithms to optimize efficacy, improve outcomes and minimize toxicity.
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PMID:Molecular predictors of chemotherapy response in non-small-cell lung cancer. 1742 74

Non-small-cell lung cancer (NSCLC) accounts for 80% of all cases of lung cancer, which is the leading cause of cancer mortality. Most patients with NSCLC are diagnosed in the advanced stages, with the majority of patients presenting with Stage III or IV disease. Despite the introduction of more effective chemotherapeutic agents, it appears that a survival plateau has been reached. Thus, new treatment strategies are clearly needed. One such approach is the study of genes influencing drug activity, which offer the possibility of tailoring therapy according to the specific genetic profile of individual patients. Approximately 90% of lung cancer mortality among men and 80% among women is attributable to smoking. Cigarette smoking has been found to induce DNA damage. Lower DNA-repair capacities have been associated with a higher risk of lung cancer. Once cancer has been diagnosed, defective DNA-repair capacities can confer a favorable cytotoxic effect. The nucleotide excision repair system plays a major role in repairing a variety of distorting lesions, notably platinum-induced DNA adducts. The present review focuses on the excision repair cross-complementing (ERCC)1 which is the lead enzyme in the nucleotide excision repair process. Several groups have investigated the influence of ERCC1 on resistance to chemotherapy. Overall, the data suggest that ERCC1 is a marker for resistance to cisplatin. At present, molecular markers, such as ERCC1, represent a potential parameter to help guide clinical treatment decisions. Prospective pharmacogenomic studies are therefore a research priority in NSCLC.
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PMID:Testing for excision repair cross-complementing 1 in patients with non-small-cell lung cancer for chemotherapy response. 1748 33

The effect of the polymorphism of the DNA repair gene ERCC2/XPD Asp312Asn on the risk of lung cancer was investigated in a northeastern Chinese population. A hospital-based case-control study consisted of 201 lung cancer cases and 171 cancer-free controls matched to age, sex, and ethnicity. A polymerase chain reaction-restriction fragment length polymorphism method was used for genotyping. Frequency of the variant C-allele of ERCC2 Asp312Asn was 0.006 among the controls in present study, which differs markedly from previous reports both in European ancestry populations and in other Chinese populations (all P < 0.001). The polymorphism was not associated with risk of lung cancer. Haplotype analysis including three previously studied polymorphisms (ERCC1 Asn118Asn, ERCC2 Arg156Arg, and ERCC2 Lys751Gln) revealed that a haplotype consisting of ERCC1Asn118Asn(G)-ERCC2 Arg156Arg(C)-ERCC2 Asp312Asn(G)-ERCC2 Lys751Gln(C) was marginally associated with an increased risk of lung cancer (OR = 3.61, 95% CI = 1.00-13.06, P = 0.04). Our data suggest that the polymorphism ERCC2 Lys751Gln or a haplotype encompassing the variant allele is associated with risk of lung cancer in this population. Studies including larger sample sizes are needed to elucidate the effects of these polymorphisms on lung cancer risk in this northeastern Chinese population.
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PMID:A haplotype encompassing the variant allele of DNA repair gene polymorphism ERCC2/XPD Lys751Gln but not the variant allele of Asp312Asn is associated with risk of lung cancer in a northeastern Chinese population. 1749 57


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