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BACKGROUND Cancer develops as a result of somatic mutations and evolutionary processes with a Darwinian character. Tumors evolve by dynamic clonal expansion and selection to form genetically diverse cell subpopulations adapted to different tumor microenvironmental conditions. Within cancer cells, the genome is shaped by various selective pressures. Cancer evolution often follows a branched trajectory with divergent subclones evolving simultaneously. Clonal diversity within the same tumor results in genetic, epigenetic and phenotypic variability in tumor mass, which represents a major obstacle for the development of efficient diagnostics and personalized treatment. Advances in sequencing techniques have enabled a better understanding of the growth, progression and response to cancer treatment in heterogeneous cancers. Concurrently, understanding the mechanisms involved and monitoring changes in cancer clones during disease progression may improve the efficiency of cancer therapy. AIM In this review, we summarize available data on intratumor heterogeneity. We show how intratumor heterogeneity, arising from clonal diversity, manifests itself at various levels, including at the genetic, epigenetic, and protein levels. We describe how phylogenetics, a powerful systems biology approach, can help trace clonal evolution during cancer progression and metastasis formation. We also highlight the main problems caused by intratumor heterogeneity, which hinders the development of novel diagnostics and therapies. Key words: cancer evolution - intratumor heterogeneity - cancer phylogenetics - clonal evolution The work was supported by the project MEYS - NPS I - LO1413 The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Accepted: 8. 8. 2018.

Ovarian cancer is the most lethal gynecological cancer, almost 80% of all patients succumb the disease within 5 years of diagnosis. High mortality is caused especially by nonspecific symptoms, diagnosis in late stages and the absence of a specific biomarker. Currently, the most common diagnostic biomarkers are the membrane glycoprotein Cancer Antigen 125 (CA 125), the Human Epididymal Protein 4 (HE4) and the Carcinoembryonic Antigen (CAE). None of these biomarkers is specific only for ovarian cancer and increased levels may be caused by other diseases. Therefore, current research is focused on finding new biomarkers for diagnosis and prognosis of ovarian cancer. Interesting clinical material is ascites, the fluid accumulated in abdominal cavity, which is typical for ovarian cancer and it is present in almost 90% of all cases of stage III and IV.For this study, samples of ascites from patients with benign and malignant ovarian tumors were used. For full glycomic and proteomic analysis, only 5 µL of ascites were used. Glycans were released from proteins by the enzyme PNGase F and proteins were digested to peptides by trypsin. Samples were purified and measured using a mass spectrometer.Glycan and protein profiles of patients with benign and malignant ovarian cancer were compared. In patient with a benign tumor, more simple glycans with lowm/z were increased while in the patient with a malignant tumor, higher, more complex glycans were increased. In the malignat tumor in comparison to benign tumor, 127 unique proteins were identified, especially proteins of the annexin, mucin and peroxiredoxin families.This investigation is a pilot study focused on comparison of protein and glycan composition of ascites in patients with benign and malignant ovarian cancer. Significant differences were found on both glycan and protein levels. Results will be verified on a larger set of patients and compared with a set of control samples.Key words: glycomics - proteomics - ascitic fluid - ovarian cancer This study was supported by projects of the Ministry of Education Youth and Sports - National Sustainability Program I - LO1413; Ministry of Health, Czech Republic - conceptual development of research organization (MMCI, 00209805); Czech Science Foundation 16-04496S. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 13. 3. 2017Accepted: 26. 3. 2017.

Background Epithelial ovarian carcinomas are one of the most common causes of death among gynecologic malignancies in the Czech population. This group of tumors is characterized by considerable heterogeneity in terms of its pathogenesis and response to therapy. It is questionable whether advances in the elucidation of molecular pathogenesis of various types of epithelial ovarian carcinomas can contribute to application of personalized targeted therapy. Aims This work aims to summarize current knowledge on carcinogenesis and molecular basis of epithelial ovarian cancers and point out their potential applications in clinical practice. The characterization of the epithelial ovarian carcinomas is based on a dualistic model, which divides these tumors into two groups based on their different origins and mechanisms of carcinogenesis. Type I includes low-grade serous carcinomas, endometrioid carcinomas, mucinous carcinomas and Brenner tumor. Type II then comprises high-grade serous carcinomas. Conclusion The new findings acquired by next generation sequencing revealed major differences in the genetic alterations in both groups of tumors. Differences in genetic instability between the two groups of tumors determine the mechanisms of their carcinogenesis and show new ways for application of targeted therapy. Deficient homologous recombination and high genetic instability in type II tumors is a prerequisite for efficient application of platinum cytostatics and PARP (poly-ADP ribose polymerase) inhibitors. On the other hand, carcinogenesis of the less aggressive, but often resistant type I tumous is dependent on the activation of signaling pathways PI3K/AKT and RAS/BRAF/MEK/ERK pathway. Targeted inhibition of these pathways could efficiently improve therapy of type I tumors and decrease serious adverse side effects.Key words: ovarian cancer - high-grade serous ovarian carcinoma - low-grade ovarian carcinoma - endometrioid carcinoma - mucinous carcinoma - malignant transformation - genetic instabilityWe would like to thank M.Sc. Eva Michalova for critical reading of the manuscript.This work was supported by the project MEYS - NPS I - LO1413.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 7. 8. 2016Accepted: 29. 8. 2016.