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    • br Grant Support This work was supported

    2018-11-05


    Grant Support This work was supported by a research grant from the National Science Council, Taiwan and the Institute of Biomedical Sciences, Academia Sinica (IBMS-CRC103-P02).
    Conflicts of Interest
    Author Contributions
    Introduction Because of late presentation and chemotherapy resistance ovarian cancer is the deadliest amongst all gynecological malignancies. Over 80% of ovarian tumors are high-grade serous ovarian cancers (HGSOCs), which is a particularly fatal type due to its initial asymptomatic but aggressive growth behavior. Current methods of detection have been successfully implemented for detection and possible reduction of mortality from ovarian cancer (Menon et al., 2015; Drescher et al., 2013). However, such methods are only capable of the detection of established invasive cancers. Understanding the natural history of the disease and the discovery of novel markers for detection at a premalignant stage will enable the effective control of ovarian cancer. In this work, we prospectively analyzed the genomic composition of a single tumor over a three-year period to identify driver mutations that may have contributed to the initiation of the tumor. We identified non-coding mutations that cluster near genes involved in stem cell regulation. We established that one mutation is located in a previously unrecognized repressor element of SOX2, an important stem cell gene, and is associated with induction of SOX2 expression. We demonstrate that the expansion of SOX2-expressing glucokinase within the fallopian tube epithelium is a common feature of HGSOCs, a crucial finding that opens new avenues for early disease detection prior to clinical presentation.
    Materials and Methods
    Results
    Discussion Less than a third of ovarian cancer patients are diagnosed at an early, hence potentially curable, stage. The currently available detection options are patient driven symptom awareness and screening using combination of a serum marker (CA125) and imaging by ultrasound methods. Advances have been made to divert from the single threshold rule for CA125 to more complex algorithms in order to improve performance and facilitate early treatment. Jacobs et al. (2016) recently reported results of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), a study in which over 200,000 postmenopausal women were enrolled to assess whether screening is effective for improving early ovarian cancer diagnosis and survival. Results indicated a limited mortality reduction in the primary analysis (Jacobs et al., 2016). This, again, underscores the need for effective biomarkers for early detection. Recent work strongly suggests that the FTE is a common site of a large fraction of high-grade serous pelvic cancers (Perets et al., 2013). Inducing mutations in TP53, BRCA1-BRCA2, and PTEN in secretory cells in the FTE of mice resulted in the development of HGSOCs (Perets et al., 2013). However, there continues to be a need for novel molecular markers of premalignant transformation that could be used for early detection. Current screening methods only enable the detection of established invasive ovarian cancers. Mathematical modeling of tumor occurrence in BRCA1-BRCA2 mutations carriers suggests that tumors remain occult for up to four years (Brown and Palmer, 2009). This duration represents an unutilized opportunity for premalignant or early stage disease detection because of the limitations of existing markers. In addition, patients with a family history of ovarian cancer who don\'t have affected living relatives are not eligible for BRCA1-BRCA2 mutation testing. Furthermore, in many cases of familial ovarian malignancies BRCA testing is negative. Subsequently, these patients are ineligible for risk-reducing salpingo-oophorectomy. Lack of specificity of TP53 overexpression (the so called p53 signature) in the fallopian tube (Lee et al., 2007) undermines its potential use in early detection. In contrast, we have shown that SOX2 overexpression has high specificity and sensitivity as evidenced by the high AUC in our ROC analysis. In addition, unlike the p53 signature which only involves a limited number of cells, SOX2 overexpression occupies a large surface area of the fallopian tube. This makes SOX2 overexpression amenable for detection. Safe screening methods that exploit such feature would need to be developed in both BRCA mutation carriers and patients with HGSOC. The use of cell-penetrating peptides or antibodies that specifically recognize SOX2 could be labeled with PET imaging tracers to enable early, non-invasive detection in patients. In addition, fallopian tube catheterization for obtaining cytobrush specimens for quantifying SOX2 expression is also possible. Such methods could be tested in clinical trials for early detection in young women with BRCA1-BRCA2 mutations who do not wish to undergo prophylactic excision of both tubes and ovaries. Finally, as SOX2 is a potent transcription factor, it is highly likely that its aberrant expression is associated with co-expression of secreted proteins. The future discovery of such proteins could enable biomarker screening using blood sampling.