Precision medicine based on epigenomics: the paradigm of carcinoma of unknown primary

Key Points

  • The identification of the tissue of origin leads to improved management and prognosis of patients with cancer of unknown primary (CUP)

  • Advances in the development of molecular platforms have enabled the achievement of higher sensitivity and specificity in the diagnosis of CUP

  • DNA methylation is a valid biomarker for clinical diagnosis, which enables discrimination between different tissues of origin

  • An epigenetic-guided prediction of tissue of origin provides a more robust CUP diagnosis than that achieved with other molecular-based platforms

  • The prediction of tissue of origin can provide preliminary evidence indicating the presence of particular genetic alterations for which specific treatments exist (drug-actionable targets)

Abstract

Epigenetic alterations are a common hallmark of human cancer. Single epigenetic markers are starting to be incorporated into clinical practice; however, the translational use of these biomarkers has not been validated at the 'omics' level. The identification of the tissue of origin in patients with cancer of unknown primary (CUP) is an example of how epigenomics can be incorporated in clinical settings, addressing an unmet need in the diagnostic and clinical management of these patients. Despite the great diagnostic advances made in the past decade, the use of traditional diagnostic procedures only enables the tissue of origin to be determined in 30% of patients with CUP. Thus, development of molecularly guided diagnostic strategies has emerged to complement traditional procedures, thereby improving the clinical management of patients with CUP. In this Review, we present the latest data on strategies using epigenetics and other molecular biomarkers to guide therapeutic decisions involving patients with CUP, and we highlight areas warranting further research to engage the medical community in this unmet need.

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Figure 1: Biopsy sites and frequencies of tumour types predicted by EPICUP.
Figure 2: Examples of histopathological validation of patients with CUP with an EPICUP-predicted tissue of origin.
Figure 3: Determination of the primary site in patients with CUP can enable the right selection of tailored-treatment.
Figure 4: Example of a patients with CUP who received EPICUP-predicted matching site-specific treatment.

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Acknowledgements

The authors have received funding from the AGAUR 2014SGR633 grant (to M.E.), the Cellex Foudation (to M.E.), the European Development Regional Fund 'A way to achieve Europe' (grants ERDF.CIBER 2016. CB16/12/00312, PIE13/00022 (ONCOPROFILE) and SAF2014-55000-R; to M.E.), the European Union's Horizon 2020 research and innovation programme under grant agreements No 640696 and No 727264 (to M.E.), the Health and Science Departments of the Catalan regional government (Generalitat de Catalunya), Instituto de Salud Carlos III (ISCIII), and the Ministerio de Economía y Competitividad (MINECO).

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All authors researched data for the article, contributed to discussions of content, wrote, reviewed, and edited the manuscript before submission.

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Correspondence to Manel Esteller.

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A.M-C. has received honoraria from Ferrer International. M.E. has received grant support and is named in a patent from Ferrer International. S.M. and S.B. declare no competing interests.

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Moran, S., Martinez-Cardús, A., Boussios, S. et al. Precision medicine based on epigenomics: the paradigm of carcinoma of unknown primary. Nat Rev Clin Oncol 14, 682–694 (2017). https://doi.org/10.1038/nrclinonc.2017.97

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