PURPOSE: Due to the lack of effective screening approaches and early detection biomarkers, ovarian cancer has the highest mortality rates among gynecologic cancers. Herein, we undertook a systematic biomarker discovery and validation approach to identify microRNA (miRNA) biomarkers for the early detection of ovarian cancer. EXPERIMENTAL DESIGN: During the discovery phase, we performed small RNA sequencing in stage I high-grade serous ovarian cancer (n = 31), which was subsequently validated in multiple, independent data sets (TCGA, n = 543; GSE65819, n = 87). Subsequently, we performed multivariate logistic regression-based training in a serum data set (GSE106817, n = 640), followed by its independent validation in three retrospective data sets (GSE31568, n = 85; GSE113486, n = 140; Czech Republic cohort, n = 192) and one prospective serum cohort (n = 95). In addition, we evaluated the specificity of OCaMIR, by comparing its performance in several other cancers (GSE31568 cohort, n = 369). RESULTS: The OCaMIR demonstrated a robust diagnostic accuracy in the stage I high-grade serous ovarian cancer patients in the discovery cohort (AUC = 0.99), which was consistently reproducible in both stage I (AUC = 0.96) and all stage patients (AUC = 0.89) in the TCGA cohort. Logistic regression-based training and validation of OCaMIR achieved AUC values of 0.89 (GSE106817), 0.85 (GSE31568), 0.86 (GSE113486), and 0.82 (Czech Republic cohort) in the retrospective serum validation cohorts, as well as prospective validation cohort (AUC = 0.92). More importantly, OCaMIR demonstrated a significantly superior diagnostic performance compared with CA125 levels, even in stage I patients, and was more cost-effective, highlighting its potential role for screening and early detection of ovarian cancer. CONCLUSIONS: Small RNA sequencing identified a robust noninvasive miRNA signature for early-stage serous ovarian cancer detection.
- MeSH
- časná detekce nádoru metody MeSH
- dospělí MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA analýza MeSH
- nádorové biomarkery analýza MeSH
- nádory vaječníků chemie diagnóza patologie MeSH
- prospektivní studie MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- serózní cystadenokarcinom chemie diagnóza patologie MeSH
- staging nádorů MeSH
- stupeň nádoru MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- validační studie MeSH
RATIONALE: Development of therapy-resistant cancer is a major problem in clinical oncology, and there is an urgent need for novel markers identifying development of the resistant phenotype. Lipidomics represents a promising approach to discriminate lipid profiles of malignant phenotype cells. Alterations in phospholipid distribution or chemical composition have been reported in various pathologies including cancer. Here we were curious whether quantitative differences in phospholipid composition between cisplatin-resistant and -sensitive model cancer cell lines could be revealed by mass spectrometric means. METHODS: The phospholipid contents of cell membranes of the cancer cell lines CCRF-CEM and A2780, both responsive and resistant to cisplatin, were analyzed by solid-phase extraction (SPE) and electrospray ionization mass spectrometry (ESI-MS and tandem mass spectrometry (MS/MS)). Extracts were obtained by disruption of cells with a dounce tissue grinder set followed by centrifugation. To minimize the enzymatic activity, phospholipids were extracted from cell extracts by SPE immediately after the cell lysis and analyzed by MS. Both supernatant and pellet fractions of cell extracts were analyzed. RESULTS: A phospholipid profile specific for cell lines and their phenotypes was revealed. We have documented by quantitative analysis that phosphocholines PC P-34:0, PC 34:1, PC 20:2_16:0, LPC 18:1 and LPC 16:0 PLs were present in the 200-400 μM concentration range in CCRF-CEM cisplatin-responsive cells, but absent in their cisplatin-resistant cells. Similarly, PC 34:1, LPC 18:1 and LPC 16:0 were increased in cisplatin-responsive A2780 cells, and PC 20:2_16:0 was downregulated in cisplatin-resistant A2780 cells. CONCLUSIONS: In this work we showed that the ESI-MS analysis of the lipid content of the therapy-resistant and -sensitive cells can clearly distinguish the phenotypic pattern and determine the potential tumor response to cytotoxic therapy. Lipid entities revealed by mass spectrometry and associated with development of therapy resistance can thus support molecular diagnosis and provide a potential complementary cancer biomarker.
- MeSH
- chemorezistence * MeSH
- cisplatina farmakologie MeSH
- extrakce na pevné fázi MeSH
- fosfolipidy analýza chemie MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
- lidé MeSH
- lymfoblastická leukemie-lymfom z prekurzorových T-buněk farmakoterapie patologie MeSH
- nádorové buněčné linie MeSH
- nádory vaječníků chemie farmakoterapie patologie MeSH
- protinádorové látky farmakologie MeSH
- tandemová hmotnostní spektrometrie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Glypican 3 is a membrane-bound heparan sulfate proteoglycan, which has recently been identified as a marker for liver cancer and germ cell malignancies. Individuals with loss-of-function mutations for the glypican 3 gene exhibit Simpson-Golabi-Behmel syndrome, a rare X-linked overgrowth disorder. Expression of glypican 3 mRNA and protein is normally silenced in most adult organs and may reappear during malignant transformation. In the past few years, immunohistochemical and molecular characteristics of glypican 3 in hepatocellular carcinoma have been elucidated. More recently, glypican 3 has been emerging as a new diagnostic marker for germ cell tumors and especially testicular and ovarian yolk sac tumors. However, in other tumors such as renal cell carcinomas, squamous cell carcinomas, and melanomas, studies disagree on the level of glypican 3 expression. Finally, there is the controversial notion of glypican 3 as a tumor suppressor gene. In this review article, we update current knowledge on glypican 3 expression in normal and neoplastic tissues, evaluate its utility as a tumor marker in clinical practice, and explore its role as a novel oncofetal protein with clinical implications. Our focus is on the diagnostic value of glypican 3 in germ cell tumors and other neoplasms in addition to hepatocellular carcinoma. In conclusion, glypican 3 has been proven to be a useful immunohistochemical marker in distinguishing yolk sac tumors, choriocarcinomas, and Wilms tumors from other malignancies histologically mimicking these primitive tumors. Clinically, we recommend that glypican 3 be used as part of a panel of markers in subtyping testicular germ cell tumors.
- MeSH
- biopsie MeSH
- genetické testování MeSH
- germinální a embryonální nádory krev chemie diagnóza genetika patologie MeSH
- glypikany * analýza krev genetika MeSH
- hepatocelulární karcinom krev chemie diagnóza genetika patologie MeSH
- imunohistochemie MeSH
- lidé MeSH
- nádorové biomarkery * analýza krev genetika MeSH
- nádory jater krev chemie diagnóza genetika patologie MeSH
- nádory vaječníků krev chemie diagnóza genetika patologie MeSH
- prediktivní hodnota testů MeSH
- prognóza MeSH
- testikulární nádory krev chemie diagnóza genetika patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Sklerozující stromální tumor (SST) je vzácný benigní tumor ovaria patřící mezi nádory gonadostromální, který se typicky vyskytuje u mladých žen (obvykle mladších 30 let). Histologicky je typický svou buněčnou heterogenitou, nápadnou vaskularizací a pseudolobulárním uspořádáním se střídáním buněčných a hypocelulárních okrsků. Prezentujeme případ SST ovaria u 17leté dívky. Publikován je klinický, mikroskopický, imunohistochemický, elektronmikroskopický obraz a diferenciální diagnóza.
Sclerosing stromal tumor (SST) is a rare benign ovarian neoplasm of the sex cord-stromal category occurring predominantly in young women (usually younger than 30 years of age). Histologically, the tumor is characterized by cellular heterogenity, prominent vascularisation, and a pseudolobular appearance composed of cellular and hypocellular areas. We report a case of the ovarian SST in a 17-year-old girl. Clinical, microscopic, immunohistochemical, ultrastructural findings and differential diagnosis are disscussed.
Cíl studie: Zhodnocení rozdílu hladin lysofosfatidové kyseliny (LPA) a jejich podtypů v plazmě u pacientek s karcinomem ovaria a žen bez patologie na ovariích. Typ studie: Prospektivní epidemiologická studie. Název a sídlo pracoviště: Gynekologicko-porodnická klinika, LF UK a FN Hradec Králové. Metodika: Pomocí vysokoúčinné kapilární elektroforézy s nepřímou UV detekcí jsme stanovili hodnoty lysofosfatidové kyseliny a jejich podtypů v plazmě celkem u 103 pacientek - 60 pacientek s ovariálním karcinomem, 43 pacientek bez patologie na ovariích. Výsledky: Zjistili jsme statisticky významně vyšší hodnoty sumy lysofosfatidové kyseliny i všech podtypů u pacientek s ovariálním karcinomem (Σ LPA med 16,99 μmol/l, min 4,53 μmol/l, max 43,21 μmol/l) v porovnání s ženami bez patologie na obou ovariích (n=35) (Σ LPA med 2,92 μmol/l, min 0,94 μmol/l, max 22,93 μmol/l, p<0,001). Elevaci LPA jsme prokázali i v časných stadiích ovariálního karcinomu. Závěr: Stanovení lysofosfatidové kyseliny v plazmě umožní zefektivnění diagnostiky ovariálního karcinomu.
Objective: To compare plasma lysophosphatidic acid (LPA) level in ovarian cancer patients and women without ovarian pathology. Design: Prospective study. Setting: Department of Gynecology and Obstetrics, University Hospital, Hradec Králové. Methods: The method for LPA level analyze with its specification by capillary electrophoresis using indirect ultraviolet detection has been implementated. Since the beginning of this project venous blood samples from 103 patients (60 patients with ovarian cancer, 43 patients without ovarian pathology) have been obtained. Results: Plasma LPA levels were elevated in ovarian cancer patients (Σ LPA Med 19.9 μmol/l, Range 4.5 – 42.7 μmol/l). Patients without ovarian pathology (n=35) (Σ LPA Med 2.6 μmol/l, Range 0.9 – 22.9 μmol/l, P<0,001) had statistically significant lower plasma LPA level compared with ovarian cancer patients. Conclusion: Lysophosphatidic acid appears useful as diagnostic marker of ovarian cancer.
- MeSH
- epidemiologické studie MeSH
- finanční podpora výzkumu jako téma MeSH
- lidé MeSH
- lysofosfolipidy analýza diagnostické užití krev MeSH
- nádorové biomarkery diagnostické užití krev normy MeSH
- nádory vaječníků diagnóza chemie krev MeSH
- prospektivní studie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- srovnávací studie MeSH
