Altogether we have shown the presence

Altogether we have shown the presence of fully methylated DAPK fragments in serum of ovarian cancer patients but also of women with uterine leiomyoma. This indicates the prerequisite for the analysis of not only healthy controls but also of women with other frequent non-cancer disease for the validation of methylation markers in serum. Due to the presence of hypermethylated DAPK in malignancies of different entities such as bladder, lung, colorectum, cervix uteri, NAD+ and lymphocytes [29], [31], [32], [33] this finding is of general interest for serum-based analyses.
Conflict of interest statement
Introduction Cervical cancer, premalignant cervical lesions and non-neoplastic HPV infections, i.e. atypical cells of undetermined significance (ASCUS) and cervical intraepithelial neoplasia (CIN), are diagnosed by cytology (Papanicolaou test, Pap test), colposcopic inspection, and histological examination of biopsies. These tests and procedures are successful at decreasing the incidence of cervical cancer, but their rate of false diagnoses is a matter of concern (Nanda et al., 2000, Stoler and Schiffman, 2001). Detection of the DNA of high-risk human papillomavirus (HPV) types (Munoz et al., 2003, Bernard et al., 2010), the primary cause of cervical cancer, has become a powerful criterion to amend these procedures, and has greatly increased the sensitivity of screening (Bulkmans et al., 2007, Mayrand et al., 2007, Naucler et al., 2007). However, since the fraction of women being infected by HPVs at some time of their lives (>80%) vastly exceed the incidence rate of cervical cancer (about 1%), and since a positive HPV DNA test often indicates a transient infection rather than a developing cervical cancer, HPV DNA diagnosis alone is not sufficient to distinguish women with benign infections from those requiring intensive management. In order to prevent unnecessary procedures on patients with abnormal Pap smears who are not at risk for developing cervical cancer, gynecologic practice needs tests that are sensitive and specific to detect high-risk patients. Numerous attempts have been made to measure markers that change as the result of HPV-dependent carcinogenesis, but these tests are still of limited benefit (von Knebel Doeberitz, 2002). The molecular mechanisms involved in the progression of asymptomatic or low-grade HPV infections to cervical cancer are yet poorly understood, but include the methylation of many of those cellular genes that are also epigenetically affected in cancers of other organ sites and without an HPV etiology. The search of clinically useful epigenetic biomarkers of cervical cancer that may allow risk stratification in patients began relatively recently, but this field of research expanded rapidly, and a review (Wentzensen et al., 2009) compared studies of more than 60 cellular genes. Unfortunately, this meta-analysis came to the conclusion that there is currently no single methylation marker that that has the appropriate performance to serve as cervical cancer biomarker. The reviewed studies point only to few genes, notably DAPK (death associated protein kinase 1) and RARB (retinoic acid receptor beta), which might be attractive targets of further evaluations. Notably, these two markers stood out in a large epidemiological study comparing a panel of twenty cellular methylation targets (Feng et al., 2005).