Oncotarget

Research Papers:

DNA methylation intratumor heterogeneity in localized lung adenocarcinomas

Kelly Quek, Jun Li, Marcos Estecio, Jiexin Zhang, Junya Fujimoto, Emily Roarty, Latasha Little, Chi-Wan Chow, Xingzhi Song, Carmen Behrens, Taiping Chen, William N. William, Stephen Swisher, John Heymach, Ignacio Wistuba, Jianhua Zhang, Andrew Futreal and Jianjun Zhang _

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Oncotarget. 2017; 8:21994-22002. https://doi.org/10.18632/oncotarget.15777

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Abstract

Kelly Quek1,2,*, Jun Li2,*, Marcos Estecio3, Jiexin Zhang4, Junya Fujimoto5, Emily Roarty2, Latasha Little2, Chi-Wan Chow5, Xingzhi Song2, Carmen Behrens5, Taiping Chen4, William N. William1, Stephen Swisher6, John Heymach1,7, Ignacio Wistuba5, Jianhua Zhang2, Andrew Futreal2, Jianjun Zhang1,2

1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA

2Department of Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA

3Department of Epigenetics and Molecular Carcinogenesis, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA

4Department of Bioinformatics and Computational Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA

5Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA

6Department of Thoracic Surgery, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA

7Department of Cancer Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA

*Co-first authors

Correspondence to:

Jianjun Zhang, email: [email protected]

Andrew Futreal, email: [email protected]

Jianhua Zhang, email: [email protected]

Keywords: intra-tumor heterogeneity, non-small cell lung cancer, DNA methylation

Received: November 30, 2016     Accepted: January 27, 2017     Published: February 28, 2017

ABSTRACT

Cancers are composed of cells with distinct molecular and phenotypic features within a given tumor, a phenomenon termed intratumor heterogeneity (ITH). Previously, we have demonstrated genomic ITH in localized lung adenocarcinomas; however, the nature of methylation ITH in lung cancers has not been well investigated. In this study, we generated methylation profiles of 48 spatially separated tumor regions from 11 localized lung adenocarcinomas and their matched normal lung tissues using Illumina Infinium Human Methylation 450K BeadChip array. We observed methylation ITH within the same tumors, but to a much less extent compared to inter-individual heterogeneity. On average, 25% of all differentially methylated probes compared to matched normal lung tissues were shared by all regions from the same tumors. This is in contrast to somatic mutations, of which approximately 77% were shared events amongst all regions of individual tumors, suggesting that while the majority of somatic mutations were early clonal events, the tumor-specific DNA methylation might be associated with later branched evolution of these 11 tumors. Furthermore, our data showed that a higher extent of DNA methylation ITH was associated with larger tumor size (average Euclidean distance of 35.64 (> 3cm, median size) versus 27.24 (<= 3cm), p = 0.014), advanced age (average Euclidean distance of 34.95 (above 65) verse 28.06 (below 65), p = 0.046) and increased risk of postsurgical recurrence (average Euclidean distance of 35.65 (relapsed patients) versus 29.03 (patients without relapsed), p = 0.039).


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