Genomic landscape established by allelic imbalance in the cancerization field of a normal appearing airway

Yasminka Jakubek, Wenhua Lang, Selina Vattathil, Melinda Garcia, Li Xu, Lili Huang, Suk Young Yoo, Li Shen, Wei Lu, Chi Wan Chow, Zachary Weber, Gareth Davies, Jing Huang, Carmen Behrens, Neda Kalhor, Cesar Moran, Junya Fujimoto, Reza Mehran, Randa El-Zein, Stephen G. SwisherJing Wang, Jerry Fowler, Avrum E. Spira, Erik A. Ehli, Ignacio I. Wistuba, Paul Scheet, Humam Kadara

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Visually normal cells adjacent to, and extending from, tumors of the lung may carry molecular alterations characteristics of the tumor itself, an effect referred to as airway field of cancerization. This airway field has been postulated as a model for early events in lung cancer pathogenesis. Yet the genomic landscape of somatically acquired molecular alterations in airway epithelia of lung cancer patients has remained unknown. To begin to fill this void, we sought to comprehensively characterize the genomic architecture of chromosomal alterations inducing allelic imbalance (AI) in the airway field of the most common type of lung tumors, non-small cell lung cancer (NSCLC). To do so, we conducted a genome-wide survey of multiple spatially distributed normal-appearing airways, multiregion tumor specimens, and uninvolved normal tissues or blood from 45 patients with early-stage NSCLC. We detected alterations in airway epithelia from 22 patients, with an increased frequency in NSCLCs of squamous histology. Our data also indicated a spatial gradient of AI in samples at closer proximity to the NSCLC. Chromosome 9 displayed the highest levels of AI and comprised recurrent independent events. Furthermore, the airway field AI included oncogenic gains and tumor suppressor losses in known NSCLC drivers. Our results demonstrate that genomewide AI is common in the airway field of cancerization, providing insights into early events in the pathogenesis of NSCLC that may comprise targets for early treatment and chemoprevention.

Original languageEnglish
Pages (from-to)3676-3683
Number of pages8
JournalCancer Research
Volume76
Issue number13
DOIs
StatePublished - Jul 1 2016

Bibliographical note

Publisher Copyright:
© 2016 American Association for Cancer Research.

Funding

This work was supported in part by Molecular Genetics of Cancer training grant T32 CA009299 (Y. Jakubek), Department of Defense (DoD) grant W81XWH-10-1-1007 (I.I. Wistuba and H. Kadara.), Lung Cancer SPORE grant P50CA70907 from the NCI (I.I. Wistuba), Cancer Prevention and Research Institute of Texas (CPRIT) award RP150079 (P. Scheet and H. Kadara), NIH grant R01HG005859 (P. Scheet), and by the Institutional Cancer Center Support Grant CA16672.

FundersFunder number
Institutional Cancer Center SupportCA16672
Molecular Genetics of Cancer training grantT32 CA009299
National Institutes of Health (NIH)
U.S. Department of DefenseP50CA70907, W81XWH-10-1-1007
U.S. Department of Defense
National Human Genome Research InstituteR01HG005859
National Human Genome Research Institute
National Childhood Cancer Registry – National Cancer Institute
Cancer Prevention and Research Institute of TexasRP150079
Cancer Prevention and Research Institute of Texas

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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