Year: 2013
Type: dissertation
Study design: Observational Study
Abstract: Early Diagnosis of Epithelial Ovarian Cancer - Analysis of Novel Biomarkers\nBjörg Kristjánsdóttir\nDepartment of Obstetrics & Gynecology, Institute of Clinical Sciences\nat Sahlgrenska Academy, University of Gothenburg, Sweden\nABSTRACT\nBackground: Majority of epithelial ovarian cancer (EOC) is detected in advanced stage with bad prognosis and\nhigh mortality. Reliable diagnostic markers are lacking, pre-cancerous lesions in the more aggressive tumors are\nnot clearly defined, vague or unspecific early symptoms, and the localization of the ovaries, deep in the pelvis\ncontributes to late diagnose. Heterogeneity, not only different type of histology, but also different intrinsic\nbiology and behavior characterizes ovarian cancer. Invasive surgery with histological examination is needed to\nconfirm the diagnosis. Less than 25% EOC are diagnosed early, when there is great possibility to cure and 5-year\nsurvival >90%, in contrast to 20-30% 5-year survival in late stage EOC. Thus, early detection is of utmost\nimportance. Proximal fluids, like ovarian cyst fluid, are promising in the search for early markers. Cancer\nantigen 125 (CA125), the most used biomarker since 30 years, and a promising marker human epididymis 4\n(HE4) have recently been approved by FDA to be used in the prediction of malignancy in women with a pelvic\nmass.\nAims: To explore ovarian cyst fluid as a source mining for new diagnostic biomarkers for EOC, and to validate\nthe markers found together with CA125 (Paper I-III); and to evaluate the diagnostic performance of HE4 and\nCA125, to distinguish between benign cysts and EOC, and EOC divided into slow growing type I and the\naggressive type II EOC (Paper IV-V).\nMethod: Cross sectional, observational, explorative, and diagnostic clinical studies, with prospective and\nconsecutive collection of cystic fluid, blood and tumor tissue at the time of operation and retrospective analysis.\nWomen with suspicious malignant pelvic cysts, already scheduled for operation at our clinic for tumor surgery\nwere included. High throughput proteomic analyses were used for searching for novel markers, and selected\nproteins were validated with ELISA or immunoblot. Paper I: The cyst fluid proteome was mined with surfaceenhanced\nlaser desorption/ionization time of flight (SELDI-TOF) mass spectrometry (MS) (n=192). Paper II:\nEnrichment of a selection of known cancer antigens to overcome high abundant proteins, and with focus on\ninflammation, was followed by Immunoprecipitation MS (n=38). Significantly differently expressed chemokines\nwere validated (n=256). Paper III: Serous cystadenoma (n=5) and serous adenocarcinoma (n=10) of different\nstages were analyzed with isobaric tag for relative and absolute quantification (iTRAQ), followed by\nimmunoblot validation (n=68). Paper IV-V: HE4 and CA125 levels in plasma were analyzed with ELISA and\nRisk of Ovarian Malignancy Algorithm (ROMA) was calculated (n=393). Significant differences, receiver\noperator characteristics (ROC) area under the curve (AUC), cut-off levels, sensitivity and specificity were\nestimated with regard to malignancy, grade, stage histologic subtype and type I and type II.\nResults: Paper I: Combination of Apolipoprotein CIII and Protein C inhibitor had the best AUC (0.91) in cyst\nfluid, and improved by CA125 (0.94). Abundant proteins were a problem in the cyst fluid analyses. Paper II:\nInterleukin-8 and Chemoattractant Protein-I were highly significantly increased expressed in cyst fluid.\nIncreased inflammatory response was present in early tumor development and earlier than in blood. Paper III:\nTwo of 87 differentially expressed proteins in cyst fluid, with high significance and fold change, Serum Amyloid\nA-4 (SAA4) and astacin-like metalloendopeptidase (ASTL) were validated, and SAA4 was significantly\nincreased in cyst fluid, but not in blood. Paper IV: HE4 complemented CA125 in the diagnosis of ovarian cysts,\nespecially in the premenopausal women. Sensitivity for ROMA at set specificity of 75% was highest in the\npostmenopausal cohort (87%). Paper V: HE4 and CA125 diagnosed the aggressive type II EOC most correctly\n(AUC 0.93), but the results were not acceptable in early stage type II (AUC 0.85) or in type I EOC (AUC 0.79)\nrespective early type I AUC 0.73).\nConclusion: Ovarian cyst fluid is an excellent source for the search of novel biomarkers for early diagnosis of\nEOC. Early events are found near the tumor in the early phase, like the inflammatory response and later on in the\nperipheral circulation. HE4 complements CA125 in predicting malignancy in cystic ovarian tumors. The result\nfrom this thesis support, that EOC should be looked upon as several different diseases. Finding early markers\nthat are specific for each histology subgroup will be the future challenge. Combination of such markers in a\npanel could improve the early diagnosis of EOC.\nKeywords: EOC; ovarian adenocarcinoma; ovarian cyst fluid; pelvic mass; tumor biomarker; mass\nspectrometry; SELDI-TOF MS; iTRAQ;\nISBN 978-91-628-8727-8\nhttp://hdl.handle.net/2077/33099
Author: Björg Kristjánsdóttir
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W183222169