Integrative DNA methylome analysis of pan-cancer biomarkers in cancer discordant monozygotic twin-pairs

Clin Epigenetics. 2016 Jan 20;8:7. doi: 10.1186/s13148-016-0172-y. eCollection 2016.

Abstract

Background: A key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues. Several studies have identified malignancy-associated DNA methylation changes in blood, yet no general cancer biomarker has been identified to date. Here, we explore the potential of blood DNA methylation as a biomarker of pan-cancer (cancer of multiple different origins) in 41 female cancer discordant monozygotic (MZ) twin-pairs sampled before or after diagnosis using the Illumina HumanMethylation450 BeadChip.

Results: We analysed epigenome-wide DNA methylation profiles in 41 cancer discordant MZ twin-pairs with affected individuals diagnosed with tumours at different single primary sites: the breast, cervix, colon, endometrium, thyroid gland, skin (melanoma), ovary, and pancreas. No significant global differences in whole blood DNA methylation profiles were observed. Epigenome-wide analyses identified one novel pan-cancer differentially methylated position at false discovery rate (FDR) threshold of 10 % (cg02444695, P = 1.8 × 10(-7)) in an intergenic region 70 kb upstream of the SASH1 tumour suppressor gene, and three suggestive signals in COL11A2, AXL, and LINC00340. Replication of the four top-ranked signals in an independent sample of nine cancer-discordant MZ twin-pairs showed a similar direction of association at COL11A2, AXL, and LINC00340, and significantly greater methylation discordance at AXL compared to 480 healthy concordant MZ twin-pairs. The effects at cg02444695 (near SASH1), COL11A2, and LINC00340 were the most promising in biomarker potential because the DNA methylation differences were found to pre-exist in samples obtained prior to diagnosis and were limited to a 5-year period before diagnosis. Gene expression follow-up at the top-ranked signals in 283 healthy individuals showed correlation between blood methylation and gene expression in lymphoblastoid cell lines at PRL, and in the skin tissue at AXL. A significant enrichment of differential DNA methylation was observed in enhancer regions (P = 0.03).

Conclusions: We identified DNA methylation signatures in blood associated with pan-cancer, at or near SASH1, COL11A2, AXL, and LINC00340. Three of these signals were present up to 5 years prior to cancer diagnosis, highlighting the potential clinical utility of whole blood DNA methylation analysis in cancer surveillance.

Keywords: Biomarker; Cancer; DNA methylation; Discordant monozygotic twins; Epigenetics; Twin study.

Publication types

  • Research Support, Non-U.S. Gov't
  • Twin Study

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Breast Neoplasms / genetics
  • Colonic Neoplasms / genetics
  • DNA Methylation / genetics*
  • Diseases in Twins / genetics*
  • Endometrial Neoplasms / genetics
  • Epigenomics
  • Female
  • Genetic Markers / genetics
  • Humans
  • Male
  • Melanoma / genetics
  • Middle Aged
  • Neoplasms / genetics*
  • Ovarian Neoplasms / genetics
  • Pancreatic Neoplasms / genetics
  • Risk Factors
  • Skin Neoplasms / genetics
  • Smoking / adverse effects
  • Thyroid Neoplasms / genetics
  • Twins, Monozygotic / genetics*
  • Uterine Cervical Neoplasms / genetics

Substances

  • Genetic Markers