Global DNA methylation reflects spatial heterogeneity and molecular evolution of lung adenocarcinomas

Abstract

Lung adenocarcinoma (ADC) is the most prevalent subtype of lung cancer and characterized by considerable morphological and mutational heterogeneity. However, little is known about the epigenomic intratumor variability between spatially separated histological growth patterns of ADC. In order to reconstruct the clonal evolution of histomorphological patterns, we performed global DNA methylation profiling of 27 primary tumor regions, seven matched normal tissues and six lymph node metastases from seven ADC cases. Additionally, we investigated the methylation data from 369 samples of the TCGA ADC cohort. All regions showed varying degrees of methylation changes between segments of different, but also of the same growth patterns. Similarly, copy number variations were seen between spatially distinct segments of each patient. Hierarchical clustering of promoter methylation revealed extensive heterogeneity within and between the cases. Intratumor DNA methylation heterogeneity demonstrated a branched clonal evolution of ADC regions driven by genomic instability with subclonal copy number changes. Notably, methylation profiles within tumors were not more similar to each other than to those from other individuals. In two cases, different tumor regions of the same individuals were represented in distant clusters of the TCGA cohort, illustrating the extensive epigenomic intratumor heterogeneity of ADCs. We found no evidence for the lymph node metastases to be derived from a common growth pattern. Instead, they had evolved early and separately from a particular pattern in each primary tumor. Our results suggest that extensive variation of epigenomic features contributes to the molecular and phenotypic heterogeneity of primary ADCs and lymph node metastases.

Identification and validation of novel DNA methylation markers for early diagnosis of lung adenocarcinoma

“…In addition, three independent validation datasets including GSE114989, GSE83842, and GSE85845 were obtained from the GEO [20]. GSE114989 [21] included 27 primary tumors and 7 matched normal tissues from 7 LUAD patients, GSE83842 [22] contained 12 cases with paired tumor and normal tissue, and GSE85845 [23] included 8 LUAD and adjacent nontumor tissues.…”

Spatial and Temporal Heterogeneity of Panel-Based Tumor Mutational Burden in Pulmonary Adenocarcinoma: Separating Biology From Technical Artifacts

“…ITH is a well-described phenomenon in lung adenocarcinoma (ADC) on a radiologic, histopathologic, genetic, epigenetic, and tumormicroenvironmental level. [22][23][24][25][26][27][28][29][30][31] According to the most widely accepted theory, ITH is mainly the result of subclonal evolution during natural tumor progression and therapeutic interventions. 32,33 The great molecular variability associated with high levels of ITH is seen as one of the leading causes for lack of response or development of resistance under therapy.…”

Genetic and epigenetic modifications of HPDL and SOX17 associated with breast cancer prognosis: a study based on The Cancer Genome Atlas

“…Several studies have found that areas with high DNA methylation (such as CpG islands) are accompanied by copy number variation, and these genomic variations affect the level of DNA methylation [23]. For example, in lung adenocarcinoma, DNA methylation heterogeneity 4 demonstrates branch clonal evolution of lung adenocarcinoma regions driven by genomic instability, and subclone copy number variation [24]. Here, we investigated the association between genomic variation (such as CNV) in regulatory regions of BRCA and corresponding changes in DNA methylation.…”