Molecular differences and similarities between histological subtypes of non-small cell lung cancer
Date
2011-07-21
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Uuringuks kasutati 147 mitteväikerakulise kopsuvähi tõttu opereeritud patsiendi koematerjali ning fenotüübi ja elulemuse andmeid. Geeniekspressiooni katse viidi läbi Illumina Human-6 ülegenoomi kiibiga mis sisaldab rohkem kui 48000 transkripti. Leitud markerite arvu vähendamiseks säilitati geenid mis näitasid vähemalt kahekordset ekspressiooni erinevust vähivabast normkoest. Erinevate vähitüüpide ja staadiumite molekulaarsete profiilide erinevuste visualiseerimiseks kasutati peakomponentanalüüsi. Metageeni leidmiseks piirati andmestiku suurust, klasterdades sarnase ekspressiooniga geene hierarhiliselt täieliku aheldatuse meetodil, kasutades sarnasusmõõduna Pearsoni korrelatsiooni. I b staadiumi patsientide geeniekspressiooni andmed jagati 500 gruppi ning iga klastri profiili keskmine moodustas metageeni.
Uuringu tulemusena leiti mitteväikerakulises kopsuvähis normaalsest kopsukoest vähemalt kahekordse ekspressiooni erinevusega 672 alla- ja 1103 üles reguleeritud geeni. Lisaks leiti 18 uut potentsiaalset biomarkerit edasisteks kopsuvähi uuringuteks. Geeniekspressiooni profiili peakomponentanalüüs aitas eristada erinevaid vähitüüpe teineteisest ja mõnel juhul ka algkollet metastaasist. Samas ei eristu mitteväikerakulise kopsuvähi geeniekspressiooni profiilil ega ka selle peakomponentanalüüsil TNM il põhinevad vähkide kliinilised staadiumid. Kasutades p väärtust 10-6 ei õnnestunud veenvalt leida adenokartsinoomi ja bronhioloalveolaarset vähki eristavaid markereid.
Ib staadiumi patsientide prognoosi hindamiseks leiti kaks statistilise olulisuse ja aktsepteeritava veapiiriga metageeni mis jaotas haigusjuhud ekspressiooni profiilide järgi kahte prognostilisse gruppi elulemusega vastavalt <757 ja >1225 päeva. Kahe grupi eristamiseks valisime kokkuleppeliselt 1000 päeva piiri.
In this thesis, 48,000 known transcripts of the human genome were analyzed in comparison with 147 patients NSCLC and corresponding cancer-free lung tissue. An Illumina BeadChip platform and a HumanWG-6_V2 Expression Bead Chip containing 48,000 transcript probes were used for microarray gene expression experiments. For genes exhibiting at least a 2-fold change in expression, and a p-value of at least 10-6, 1,775 markers were identified that distinguished NSCLC tissue from normal tissue. In addition, 18 potentially novel biomarkers were identified for NSCLC. Two metagenes, associated with a prognostic value for stage Ib patients, were able to distinguish the entire cohort into two different survival groups; those surviving > 1000 days, and those surviving < 1000 days. The contribution of this thesis to cancer biology includes the potential identification of novel biomarkers for NSCLC, and an improved understanding of the NSCLC microenvironment. The results of this thesis also have clinical value in that the design of array-based diagnostic, prognostic, and predictive tests were demonstrated for NSCLC. Integration of the gene expression data obtained with data regarding environmental risk factors, epidemiologic data, and clinical course (including prognostic and predictive data) will further help to elucidate mechanistic details of NSCLC, and these will need to be confirmed with additional studies.
In this thesis, 48,000 known transcripts of the human genome were analyzed in comparison with 147 patients NSCLC and corresponding cancer-free lung tissue. An Illumina BeadChip platform and a HumanWG-6_V2 Expression Bead Chip containing 48,000 transcript probes were used for microarray gene expression experiments. For genes exhibiting at least a 2-fold change in expression, and a p-value of at least 10-6, 1,775 markers were identified that distinguished NSCLC tissue from normal tissue. In addition, 18 potentially novel biomarkers were identified for NSCLC. Two metagenes, associated with a prognostic value for stage Ib patients, were able to distinguish the entire cohort into two different survival groups; those surviving > 1000 days, and those surviving < 1000 days. The contribution of this thesis to cancer biology includes the potential identification of novel biomarkers for NSCLC, and an improved understanding of the NSCLC microenvironment. The results of this thesis also have clinical value in that the design of array-based diagnostic, prognostic, and predictive tests were demonstrated for NSCLC. Integration of the gene expression data obtained with data regarding environmental risk factors, epidemiologic data, and clinical course (including prognostic and predictive data) will further help to elucidate mechanistic details of NSCLC, and these will need to be confirmed with additional studies.
Description
Väitekirja elektrooniline versioon ei sisalda publikatsioone.
Keywords
kopsuvähk, geenid, geeniekspressioon, biomarkerid, lung cancer, genes, gene expression, biomarkers