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@ARTICLE{Dietz:142862,
      author       = {S. Dietz$^*$ and A. Lifshitz and D. Kazdal$^*$ and A.
                      Harms$^*$ and V. Endris and H. Winter and A. Stenzinger$^*$
                      and A. Warth and M. Sill$^*$ and A. Tanay and H.
                      Sültmann$^*$},
      title        = {{G}lobal {DNA} methylation reflects spatial heterogeneity
                      and molecular evolution of lung adenocarcinomas.},
      journal      = {International journal of cancer},
      volume       = {144},
      number       = {5},
      issn         = {0020-7136},
      address      = {Bognor Regis},
      publisher    = {Wiley-Liss},
      reportid     = {DKFZ-2019-00492},
      pages        = {1061 - 1072},
      year         = {2019},
      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.},
      cin          = {B063 / B062 / L101},
      ddc          = {610},
      cid          = {I:(DE-He78)B063-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)L101-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30350867},
      doi          = {10.1002/ijc.31939},
      url          = {https://inrepo02.dkfz.de/record/142862},
}