TY - JOUR
T1 - DNA methylation intratumor heterogeneity in localized lung adenocarcinomas
AU - Quek, Kelly
AU - Li, Jun
AU - Estecio, Marcos
AU - Zhang, Jiexin
AU - Fujimoto, Junya
AU - Roarty, Emily
AU - Little, Latasha
AU - Chow, Chi Wan
AU - Song, Xingzhi
AU - Behrens, Carmen
AU - Chen, Taiping
AU - William, William N.
AU - Swisher, Stephen
AU - Heymach, John
AU - Wistuba, Ignacio
AU - Zhang, Jianhua
AU - Futreal, Andrew
AU - Zhang, Jianjun
N1 - Funding Information:
This study was supported by MD Anderson Moon Shot Program, MD Anderson Physician Scientist Program, Conquer Cancer Foundation Young Investigator Award, NIH CCSG Award (CA016672), Khalifa Scholar Award, the Cancer Prevention and Research Institute of Texas (R120501), the Cancer Prevention and Research Institute of Texas Multi-Investigator Research Award (CPRIT MIRA) grant (RP160668), the University of Texas (UT) Systems Stars Award (PS100149), the Welch Foundation Robert A. Welch Distinguished University Chair Award (G-0040), Department of Defense PROSPECT grant (W81XWH-07-1-0306), the UT Lung Specialized Programs of Research Excellence grant (P50CA70907) and the MD Anderson Cancer Center Support grant (CA016672). The authors thank Dr. Charles Swanton from Francis Crick Institute for constructive discussions.
PY - 2017
Y1 - 2017
N2 - 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).
AB - 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).
KW - DNA methylation
KW - Intra-tumor heterogeneity
KW - Non-small cell lung cancer
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U2 - 10.18632/oncotarget.15777
DO - 10.18632/oncotarget.15777
M3 - Article
C2 - 28423542
AN - SCOPUS:85016400868
SN - 1949-2553
VL - 8
SP - 21994
EP - 22002
JO - Oncotarget
JF - Oncotarget
IS - 13
ER -