Article

Copy Number Variants of GSTM1 and GSTT1 in Relation to Lung Cancer Risk in a Prospective Cohort Study

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
Annals of epidemiology (Impact Factor: 2.15). 05/2009; 19(8):546-52. DOI: 10.1016/j.annepidem.2009.03.003
Source: PubMed

ABSTRACT Previous studies did not discriminate wild-type from hemizygous genotypes of GSTM1 and GSTT1. In this study, we investigated wild-type, hemizygous deletion, and homozygous deletion genotypes of GSTM1 and GSTT1 and lung cancer risk.
We conducted a nested case-control study of 143 primary incident lung cancer cases matched to 447 cancer-free controls. Genotyping was carried out using a real-time polymerase chain reaction (PCR)-based assay. Conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI).
Compared to GSTM1 wild-type carriers, the relative odds of lung cancer increased from 1.49 (95% CI=0.66-3.40) to 1.80 (95% CI=0.81-4.02) for the hemizygous and homozygous deletion genotypes, respectively (p-trend=0.13). The strongest associations were seen among those who smoked less than one pack per day and had greater than or equal to one deletion variant of GSTM1 (OR=3.25; 95% CI=0.93-11.34; p-trend=0.07) whereas the reverse was observed for smokers who smoked greater than or equal to one pack per day (OR=0.80; 95% CI=0.24-2.67; p-interaction=0.08). No clear associations were observed for GSTT1 genotypes.
Risk of lung cancer increased as the number of deletion variants increased for GSTM1, although the associations were nonsignificant. Discriminating between the wild-type, hemizygous, and homozygous deletion GSTM1 genotypes permitted a more precise characterization of the associations between GSTM1 deletion variants and lung cancer.

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    ABSTRACT: Background: Asbestos is a well known cancer-causing mineral fibre, which has a synergistic effect on lung cancer risk in combination with tobacco smoking. Several in vitro and in vivo experiments have demonstrated that asbestos can evoke chromosomal damage and cause alterations as well as gene expression changes. Lung tumours, in general, have very complex karyotypes with several recurrently gained and lost chromosomal regions and this has made it difficult to identify specific molecular changes related primarily to asbestos exposure. The main aim of these studies has been to characterize asbestos-related lung cancer at a molecular level. Methods: Samples from asbestos-exposed and non-exposed lung cancer patients were studied using array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) to detect copy number alterations (CNA) as well as microsatellite analysis to detect allelic imbalance (AI). In addition, asbestos-exposed cell lines were studied using gene expression microarrays. Results: Eighteen chromosomal regions showing differential copy number in the lung tumours of asbestos-exposed patients compared to those of non-exposed patients were identified. The most significant differences were detected at 2p21-p16.3, 5q35.3, 9q33.3-q34.11, 9q34.13-q34.3, 11p15.5, 14q11.2 and 19p13.1-p13.3 (p<0.005). The alterations at 2p and 9q were validated and characterized in detail using AI and FISH analysis in a larger study population. Furthermore, in vitro studies were performed to examine the early gene expression changes induced by asbestos in three different lung cell lines. The results revealed specific asbestos-associated gene expression profiles and biological processes as well as chromosomal regions enriched with genes believed to contribute to the common asbestos-related responses in the cell lines. Interestingly, the most significant region enriched with asbestos-response genes was identified at 2p22, close to the previously identified region showing asbestos-related CNA in lung tumours. Additionally, in this thesis, the dysregulated biological processes (Gene Ontology terms) detected in the cell line experiment were compared to dysregulated processes identified in patient samples in a later study (Ruosaari et al., 2008a). Commonly affected processes such as those related to protein ubiquitination, ion transport and surprisingly sensory perception of smell were identified. Conclusions: The identification of specific CNA and dysregulated biological processes shed some light on the underlying genes acting as mediators in asbestos-related lung carcinogenesis. It is postulated that the combination of several asbestos-specific molecular alterations could be used to develop a diagnostic method for the identification of asbestos-related lung cancer. Bakgrund: Asbest är en välkänd cancerframkallande mineralfiber, som i kombination med tobaksrökning ökar risken för lungcancer flerfalt. Flera in vitro och in vivo studier har visat att asbest kan framkalla kromosomskador och förändringar i genexpression. Lungtumörer har i allmänhet mycket komplicerade karyotyper med flera återkommande duplicerade och deleterade kromosomregioner, vilket har gjort det svårt att identifiera specifika molekylära avvikelser som kan associeras med asbestexponering. Det främsta syftet med dessa studier har varit att karaktärisera asbestrelaterad lungcancer på molekylär nivå. Metoder: Prover från asbestexponerade och icke exponerade patienter med lungcancer undersöktes med hjälp av jämförande genomisk hybridisering på mikroarray (aCGH) och fluorescerande in situ hybridisering (FISH) för att identifiera kromosomavvikelser, samt med mikrosatellitanalys för att identifiera allel-obalans (AI). Dessutom utfördes in vitro studier på asbestexponerade cellinjer med hjälp av mikroarrays som mäter enskilda geners expression. Resultat: Aderton kromosomregioner med asbestrelaterade avvikelser identifierades. De mest markanta skillnaderna upptäcktes i 2p21-p16.3, 5q35.3, 9q33.3-q34.11, 9q34.13-q34.3, 11p15.5, 14q11.2 och 19p13.1-p13.3 (p<0,005). Avvikelserna på kromosomarmarna 2p och 9q karakteriserades i detalj och verifierades med hjälp av AI- och FISH-analys på prover från ett ökat antal patienter. In vitro studier genomfördes för att undersöka tidiga förändringar i genexpression som orsakats av asbestexponering i tre olika lungcellinjer. Resultaten avslöjade särskilda asbestrelaterade genexpressionsprofiler och biologiska processer, samt kromosomregioner berikade med gener som antas bidra till de gemensamma asbestrelaterade responserna i cellinjerna. Den mest signifikanta regionen, överrepresenterad med asbestresponsgener, var 2p22 som ligger nära det tidigare identifierade området på 2p med asbestrelaterade kromosomavvikelser i lungtumörer. I denna avhandling jämfördes också de förändrade biologiska processerna (genontologiska termerna) som upptäcktes i cellinjeexperimentet med förändrade processer som identifierats i asbestexponerade och icke exponerade patienters prover, i en senare studie (Ruosaari et al., 2008a). Gemensamt förändrade processer var bl.a. kopplade till protein ubiquitinering, jontransport och överraskande nog, luktförnimmelse. Slutsatser: Kartläggningen av specifika kromosomavvikelser och förändrade biologiska processer kastar ljus över de bakomliggande generna som fungerar som medlare i asbestrelaterad lungkarcinogenes. Det kan antas att en kombination av flera asbestspecifika molekylära förändringar kunde användas för att utveckla en diagnostisk metod, som följaktligen kunde särskilja mellan asbestrelaterad och icke asbestrelaterad lungcancer. TAUSTA: Asbesti on tunnettu syöpää aiheuttava mineraalikuitu, jolla on tupakoinnin yhteydessä synergistinen vaikutus keuhkosyövän riskiin. Useat in vitro- ja in vivo-tutkimukset ovat osoittaneet, että asbesti voi aiheuttaa kromosomivaurioita ja muutoksia geenien ilmentymisessä. Keuhkosyövän karyotyyppi on yleensä hyvin monimutkainen ja toistuvat kromosomialueiden monistumat sekä häviämät ovat yleisiä. Tästä syystä on ollut vaikeaa tunnistaa spesifisiä molekyylitason muutoksia, jotka liittyvät pääasiassa asbestialtistumiseen. Päätavoite näissä tutkimuksissa on ollut asbestiin liittyvän keuhkosyövän tunnistaminen molekyylitasolla. MENETELMÄT: Asbestialtistuneiden ja altistumattomien keuhkosyöpäpotilaiden näytteet tutkittiin käyttäen vertailevaa genomista hybridisaatiota mikrosiruilla (aCGH) ja fluoresenssi in situ hybridisaatiota (FISH), joilla havaitaan kromosomialueiden kopiolukumuutokset, sekä mikrosatelliittianalyysia, jolla havaitaan alleeliepätasapaino (AI). Lisäksi asbestialtistuneita solulinjoja tutkittiin käyttäen geeniekspressiomikrosiruja. TULOKSET: Kahdeksallatoista kromosomialueella osoitettiin kopiolukueroja asbestialtistuneiden ja altistumattomien potilaiden näytteiden välillä. Merkittävimmät erot havaittiin kromosomialueilla 2p21-p16.3, 5q35.3, 9q33.3-q34.11, 9q34.13-q34.3, 11p15.5, 14q11.2 ja 19p13.1-p13.3 (p <0,005). Muutokset 2p ja 9q alueilla karakterisoitiin tarkemmin ja varmennettiin käyttäen AI- ja FISH-analyysejä laajemmassa tutkimusaineistossa. Lisäksi mikrosiruilla tutkittiin muutokset geenien ilmentymisessä asbestialtistuksen jälkeen kolmessa eri keuhkosolulinjassa. Tutkimuksessa tunnistettiin asbestialtistukseen liittyviä geenien ilmentymisprofiileja sekä muuttuneita biologisia prosesseja. Lisäksi havaittiin solulinjoille yhteisten asbestiin liittyvien vastegeenien rikastuttamia kromosomaalisia alueita. Merkittävin asbestivastegeenejä sisältävä alue oli 2p22, joka sijaitsee lähellä aiemmin keuhkosyövissä tunnistettua asbestiin liittyviä kopiolukumuutoksia sisältävää aluetta 2p:ssa. Tässä väitöskirjassa vertailtiin myös asbestialtistuneiden solulinjojen muuttuneita biologisia prosesseja (geeniontologiatermejä) niihin muuttuneisiin prosesseihin, joita myöhemmin havaittiin asbestialtistuneiden potilaiden näytteissä (RUOSAARI et al., 2008a). Yhteiset muuttuneet prosessit liittyivät proteiinien ubikitinaatioon, ionikuljetukseen ja yllättävästi hajuaistimukseen. JOHTOPÄÄTÖKSET: Spesifisten kopiolukumuutosten ja muuttuneiden biologisten prosessien tunnistaminen asbestiin liittyvässä keuhkosyövässä valottaa taustalla olevia geenejä, jotka toimivat välittäjinä asbestin aiheuttamassa keuhkokarsinogeneesissä. Useita asbestiin liittyviä molekyylitason muutoksia voitaisiin käyttää asbestiin liittyvän ja liittymättömän keuhkosyövän erottavien diagnostisten menetelmien kehittämisessä.
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