title: Pulmonary Metastases Exhibit Epigenetic Clonality: Implications for Precision Cancer Therapy.
abstract: BACKGROUND
  Development of effective cancer therapies may be limited by intratumoral heterogeneity, which facilitates outgrowth and organ-specific dissemination of treatment resistant clones. At present, limited information is available regarding epigenetic landscapes of pulmonary metastases. This study was undertaken to characterize epigenetic signatures of pulmonary metastases and to identify potential therapeutic targets.
  
  
  METHODS
  RNA and DNA were extracted from 65 pulmonary metastases resected from 12 patients (5 with sarcoma, 7 with adrenocortical carcinoma). Quantitative reverse transcription polymerase chain reaction techniques were used to evaluate expression levels of cancer-testis (CT) genes (NY-ESO-1, MAGE-A3, MAGE-A9, MAGE-A12, GAGE1, CT-45, SSX-1, and SSX-2), tumor suppressor (TS) genes (p16 and RASSF1A), and genes encoding epigenetic modifiers (DNMT1, DNMT3A, DNMT3B, EZH2, EED, and SUZ12), aberrantly expressed in human malignant diseases. Pyrosequencing techniques were used to quantitate DNA methylation levels in LINE1, NBL2, and D4Z4 repetitive sequences and promoter methylation status of differentially regulated genes. Results of these analyses were compared with a standardized panel of normal lung tissues.
  
  
  RESULTS
  Pulmonary metastases exhibited histologically related and patient-specific global DNA demethylation. Significant interpatient heterogeneity of gene expression was observed even among patients with similar tumor histologic features. Epigenetic signatures appeared consistent among metastases from the same patient, irrespective of the time of resection (synchronous/metachronous) or the anatomic location. EZH2, EED, and SUZ12 (core components of Polycomb repressive complex-2 [PRC-2]) were upregulated in the majority of metastases.
  
  
  CONCLUSIONS
  Pulmonary metastases exhibit patient-specific epigenetic clonality, which may be exploited for precision therapies targeting aberrant CT or TS gene expression. PRC-2 may be a shared target for epigenetic therapy of pulmonary metastases.
authors: Thoracic Epigenetics Laboratory, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Emily S
authors: ES
authors: Reardon
authors: Thoracic Epigenetics Laboratory, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Julie A
authors: JA
authors: Hong
authors: Thoracic Epigenetics Laboratory, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: David M
authors: DM
authors: Straughan
authors: Thoracic Epigenetics Laboratory, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Saïd C
authors: SC
authors: Azoury
authors: Thoracic Epigenetics Laboratory, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Mary
authors: M
authors: Zhang
authors: Thoracic Epigenetics Laboratory, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Electronic address: david.schrump@nih.gov.
authors: David S
authors: DS
authors: Schrump
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D057285:Precision Medicine; D055815:Young Adult