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).
Highlights
IntroductionCancer cells harbor distinct molecular and phenotypic features within a given tumor, a phenomenon termed intratumor heterogeneity (ITH) [1]
Genome-scale DNA methylation profiles were generated for the same cohort of 11 localized lung adenocarcinomas and matched normal lung tissues (Supplementary Table 1)
Among the top 1% most variable probes across all regions of tumors, 40% were located in open sea, 31% were within a CpG island, 20% were in shores and 9% were in shelves (Figure 1c), which was similar to the genomic distribution of all probes
Summary
Cancer cells harbor distinct molecular and phenotypic features within a given tumor, a phenomenon termed intratumor heterogeneity (ITH) [1]. DNA methylation is a major component of epigenetic modification of the genome and predominantly occurs at cytosine residues within CpG dinucleotides (CpG sites) and clusters of CpG sites are termed “CpG islands” [13]. The pattern of DNA methylation in any given cell is a result of a dynamic process of methylation and demethylation. Once established, these patterns can be inherited without significant change from one cell generation to the [14]. Altered DNA methylation is often observed in cancers with genome-wide DNA hypomethylation and site-specific hypermethylation of CpG islands [11, 15, 16]
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