Abstract
Ovarian cancer (OC) causes significant morbidity and mortality as neither detection nor screening of OC is currently feasible at an early stage. Difficulty to promptly diagnose OC in its early stage remains challenging due to non-specific symptoms in the early-stage of the disease, their presentation at an advanced stage and poor survival. Therefore, improved detection methods are urgently needed. In this article, we summarize the potential clinical utility of epigenetic signatures like DNA methylation, histone modifications, and microRNA dysregulation, which play important role in ovarian carcinogenesis and discuss its application in development of diagnostic, prognostic, and predictive biomarkers. Molecular characterization of epigenetic modification (methylation) in circulating cell free tumor DNA in body fluids offers novel, non-invasive approach for identification of potential promising cancer biomarkers, which can be performed at multiple time points and probably better reflects the prevailing molecular profile of cancer. Current status of epigenetic research in diagnosis of early OC and its management are discussed here with main focus on potential diagnostic biomarkers in tissue and body fluids. Rapid and point of care diagnostic applications of DNA methylation in liquid biopsy has been precluded as a result of cumbersome sample preparation with complicated conventional methods of isolation. New technologies which allow rapid identification of methylation signatures directly from blood will facilitate sample-to answer solutions thereby enabling next-generation point of care molecular diagnostics. To date, not a single epigenetic biomarker which could accurately detect ovarian cancer at an early stage in either tissue or body fluid has been reported. Taken together, the methodological drawbacks, heterogeneity associated with ovarian cancer and non-validation of the clinical utility of reported potential biomarkers in larger ovarian cancer populations has impeded the transition of epigenetic biomarkers from lab to clinical settings. Until addressed, clinical implementation as a diagnostic measure is a far way to go.
Highlights
Ovarian cancer, a molecularly heterogeneous disease, remains the most lethal disease among gynecological malignancies
Other biochemical markers such as lysophosphatidic acid, human epididymis protein 4 (HE4), inhibins, Mesothelin (Huang et al, 2006), Osteopontin, and YKL-40 have been reported to be elevated in sera of patients with OC amongst various studies, which could be of diagnostic significance for improved cancer detection, most likely in various combination with one another and /or with CA125 (Rosenthal et al, 2006; Moore et al, 2010)
Highest degree of promoter methylation of SFN, TMS1 and WT1 has been demonstrated in clear-cell ovarian tumors than in other histological types (Kaneuchi et al, 2004, p. 14; Terasawa et al, 2004; Kaneuchi et al, 2005; Teodoridis et al, 2005). Another finding suggests that promoter methylation of RASSF1A, APC, GSTP1, and MGMT correlates with the presence of invasive ovarian carcinomas (Makarla et al, 2005)
Summary
A molecularly heterogeneous disease, remains the most lethal disease among gynecological malignancies. Being considered as the “gold standard” biomarker for detection of OC, its clinical relevance mainly falls in evaluating disease recurrence Other biochemical markers such as lysophosphatidic acid, human epididymis protein 4 (HE4), inhibins (which are members of TGF-β subfamily), Mesothelin (associated with migration and metastasis) (Huang et al, 2006), Osteopontin, and YKL-40 have been reported to be elevated in sera of patients with OC amongst various studies, which could be of diagnostic significance for improved cancer detection, most likely in various combination with one another and /or with CA125 (Rosenthal et al, 2006; Moore et al, 2010). The sensitivity and specificity of serum based non-invasive biomarkers for improved ovarian cancer detection from various studies as well as the currently active/completed clinical trials evaluating potent biochemical markers of clinical significance for early diagnosis of EOC are summarized in Tables 2, 3 respectively. Of Serine proteases *Human KLK family: 15 members *Chromosome position: 19q13.3–4 An adhesive glycoprotein
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