BACKGROUND: The epigenetic structure of chromosomes in cancer tissue is altered with respect to histone modification, histone isoform and DNA modification composition as well as the composition of non-histone chromatin proteins - for example; the androgen receptor (AR) in prostate cancer.
Short (>180bp) fragments of tumor-derived cell free DNA circulate in the blood of cancer patients as mono-nucleosomes.
AIM: To evaluate whether epigenetically altered circulating nucleosomes provide a blood biomarker opportunity for early detection of cancers.
METHODS: We have developed more than 25 ELISA tests for circulating nucleosomes containing different epigenetic signals. These assays employ a solid phase anti-nucleosome antibody in combination with a labelled antibody directed to bind to a particular epigenetic signal - for example a histone modification, histone isoform, modified cytosine residue or a nucleosome-AR adduct. We have conducted clinical studies in collaboration with a number of centres to investigate the use of these ELISA tests for the detection of epigenetically altered circulating nucleosomes in serum samples taken from patients with lung cancer, colorectal cancer, pancreatic cancer and prostate cancer and from control subjects with no cancer and with or without concomitant disease of the same organ.
RESULTS: A collaborative study of 121 patients referred for colonoscopy at the CHU Dinant Godinne - UCL Namur, Belgium, who either showed potential symptoms of CRC or were high-risk subjects found that a panel test of five epigenetic nucleosome biomarker assays detected 87% of colorectal cancer cases and 67% of dysplastic polyps at 90% specificity.
A 59 subject collaborative study with Lund University, Sweden, including 25 patients with operable stage 2 pancreatic cancer, 10 patients with other pancreatic diseases and 24 healthy individuals found that a panel of 5 assays including 4 epigenetic nucleosome ELISA assays and CA19-9 detected 92% of early-stage pancreatic cancer cases, with 100% specificity among the healthy subjects and 2 false positives among patients with benign pancreatic disease.
A study of 73 patients conducted with the Liege University Hospital, Belgium, including 29 NSCLC cases, 22 COPD cases and 22 subjects healthy lungs showed that a panel of 4 epigenetic nucleosome assays combined with the smoking history detected 93% of NSCLC cases, with 91% specificity and also differentiated NSCLC and COPD cases.
Collaborative studies in prostate cancer have also shown excellent results and data from these studies will be presented at the conference.
CONCLUSION: Epigenetic profiling of circulating nucleosomes using simple ELISA methods offers a biomarker opportunity for the early detection of a variety cancers.
Citation Format: Jake V. Micallef. Epigenetically altered circulating nucleosomes as blood biomarkers for early detection of cancer: clinical studies in NSCLC, CRC, PCA and PC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4476.