Clinical Impact of High-Throughput Gene Expression Studies in Lung Cancer

Bioinformatics Program, Boston University School of Engineering, Boston, Massachusetts, USA.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer (Impact Factor: 5.28). 02/2009; 4(1):109-18. DOI: 10.1097/JTO.0b013e31819151f8
Source: PubMed


Lung cancer is the leading cause of cancer death in the United States and the world. The high mortality rate results, in part, from the lack of effective tools for early detection and the inability to identify subsets of patients who would benefit from adjuvant chemotherapy or targeted therapies. The development of high-throughput genome-wide technologies for measuring gene expression, such as microarrays, have the potential to impact the mortality rate of lung cancer patients by improving diagnosis, prognosis, and treatment. This review will highlight recent studies using high-throughput gene expression technologies that have led to clinically relevant insights into lung cancer. The hope is that diagnostic and prognostic biomarkers that have been developed as part of this work will soon be ready for wide-spread clinical application and will have a dramatic impact on the evaluation of patients with suspect lung cancer, leading to effective personalized treatment regimens.

Full-text preview

Available from:
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details.
    Preview · Article ·
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The thymidylate synthase (TS) enzyme plays a key role in de novo DNA synthesis, essential for DNA replication and repair, thus it is important in cell proliferation and it is a target for several chemotherapy agents. The thymidylate synthase (TYMS) gene, mapped on chromosome 18, is highly polymorphic in Humans. Three polymorphisms in the TYMS untranslated regions (UTRs) have been identified. TYMS enhancer region (TSER) polymorphism is a 28bp tandem repeat that can influence TYMS transcription or translation. A novel functional G>C single nucleotide polymorphism (SNP) present in the second repeat of 3R alleles has also been identified and the translation efficiency of the 3RC allele is equivalent to 2R allele. TYMS 1494del6, a 6bp deletion at nucleotide 1494 in the 3’UTR has been associated with decreased mRNA stability and lower intratumoral TS expression. The main goal of this study was to analyse the influence of functional TYMS polymorphisms as a prognostic marker in a series of non-small cell lung cancer (NSCLC) patients receiving, as first line chemotherapy regimens, an association of a platinum with a non-platinum agent. DNA was extracted from peripheral blood leukocytes of 152 NSCLC patients from the North region of Portugal, admitted at the Portuguese Institute of Oncology. TYMS genotypes were detected by PCR-RFLP techniques. Analysis of TYMS TSER and 3RG>C SNP polymorphisms were stratified according to the functional status in low expression (2R/2R, 2R/3RC and 3RC/3RC) and high expression (2R/3RG, 3RG/3RC and 3RG/3RG) genetic profile. TYMS 1494del6 genotypes were analysed according to the recessive model (homozygous ins versus del carriers). Survival was compared between different genotypes at 12 months, 36 months and for overall survival, using multivariate Cox proportional hazards regression models. Multivariate Cox models were adjusted for NSCLC tumour stage and histological type. Hazard ratio (HR) and 95% Confidence Interval (95%CI) were calculated. Our results showed that in TSER polymorphisms the high expression group was associated with a better outcome at 12 months (HR=0.12; 95%CI, 0.02-0.91; P=0.040) and at 36 months (HR=0.47; 95%CI, 0.21-1.05; P=0.066). TYMS 1494del6 polymorphism was associated with a better outcome at 12 months (HR=0.20; 95%CI, 0.07-0.60; P=0.004, for the recessive model). Analysis of TYMS polymorphisms may be useful as a prognostic factor in NSCLC patients. Nevertheless, since the genetic variants associated with better outcome have controversial end points when related to TS expression levels, our results further suggested that the clinical usefulness of TYMS genotyping should considered with caution and accompanied by means of protein quantification.
    Full-text · Article · Jul 2008 · EJC Supplements
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: Interindividual differences in quantitative expression could underlie a propensity for lung cancer. To determine precise individual gene expression signatures on a lung compartment-specific basis, we investigated the expression of carcinogen metabolism genes encoding cytochromes P450 (CYP) 1B1, 2A13, GSTP1, and a tumor suppressor gene p16 in laser capture-microdissected samples of human alveolar compartment (AC) and bronchial epithelial compartment (BEC) lung tissue from 62 smokers and nonsmokers. EXPERIMENTAL DESIGN: Tobacco exposure was determined by plasma nicotine, cotinine, and smoking history. Precise mRNA expression was determined using our RNA-specific qRT-PCR strategy, and correlated with detailed demographic and clinical characteristics. RESULTS: Several correlations of mRNA expression included (a) CYP1B1 in AC (positively with plasma nicotine level, P = 0.008; plasma cotinine level, P = 0.001), (b) GSTP1 in AC (positively with plasma cotinine level, P = 0.003), and (c) GSTP1 in BEC (negatively with smoke dose, P = 0.043; occupational risk, P = 0.019). CYP2A13 was rarely expressed in AC and not expressed in BEC. p16 expression was not correlated with any measured factor. For each gene, subjects showed expression that was individually concordant between these compartments. No clear association of mRNA expression with lung cancer risk was observed in this pilot analysis. CONCLUSIONS: The association between lung mRNA expression and tobacco exposure implies that gene-tobacco interaction is a measurable quantitative trait, albeit with wide interindividual variation. Gene expression tends to be concordant for alveolar and bronchial compartments for these genes in an individual, controlling for proximate tobacco exposure. (Clin Cancer Res 2009;15(24):7562-70).
    Full-text · Article · Dec 2009 · Clinical Cancer Research
Show more