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) 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. Epigenetic and other molecularly-based diagnostic strategies have emerged to complement traditional diagnostic procedures, thereby improving the clinical management of patients with CUP. Herein, the authors present the latest data on strategies using epigenetics and other molecular biomarkers to guide therapeutic decisions involving patients with CUP, addressing a previously unmet need. 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.