Molecular biomarkers of solid tumors and their use in prognosis and prevention of cancer

Molecular biomarkers of solid tumors and their use in prognosis and prevention of cancer Molekulární biomarkery solidních nádorů a jejich využití v prognóze a prevenci nádorových onemocnění Mgr. Kateřina Elsnerová Summary Malignant tumors of ovary and breast are among the most widespread cancers in women. Despite improvements in diagnostics and in therapy, mortality is still very high. An important tool for early cancer detection, as well as for monitoring prognosis and preventing progression, are molecular biomarkers; biomarkers were the topic of this work. The aim of this work was to find out (i) whether there are differences in gene expression between tumor and non-tumor tissues, and among controls (C), primary tumors (pT) and intraperitoneal metastases (iM), respectively; (ii) whether gene expression or genetic variants (single nucleotide polymorphisms, DNA methylation, germline mutations) associate with clinical data of patients, thus being potentially relevant for prognosis. In epithelial ovarian cancer (EOC), 50 of 94 genes were deregulated in controls compared to tumors. Fifteen of 66 genes were deregulated in intraperitoneal metastases compared to primary tumors. Gene expression of ABCA7, ABCB2, ABCC3, ESR2, NH1H4 and NR1I1 was deregulated either in comparison of primary tumors and metastases, or...Molekulární biomarkery solidních nádorů a jejich využití v prognóze a prevenci nádorových onemocnění Molecular biomarkers of solid tumors and their use in prognosis and prevention of cancer Mgr. Kateřina Elsnerová Souhrn dizertační práce Zhoubné nádory vaječníků a prsu patří mezi nejrozšířenější nádorová onemocnění v ženské populaci. I přes pokroky v diagnostice a terapii je úmrtnost stále vysoká; výzamný nástroj nejen pro časnou detekci nádorového onemocnění, ale také pro sledování prognózy a prevenci progrese představují molekulární biomarkery, jejichž studium bylo náplní předkládané práce. Cílem práce bylo zjistit, (i) zda mezi nádorovou a nenádorovou tkání, respektive mezi kontrolami, primárními nádory a intraperitoneálními metastázami existují rozdíly v genové expresi; (ii) zda genová exprese, respektive výskyt genetických variant (jednonukleotidové polymorfismy, metylace DNA, zárodečná variabilita) asociují s klinickými daty pacientek a mají tak potenciální prognostistický význam. V případě ovariálního karcinomu (EOC, z angl. epithelial ovarian cancer) bylo ukázáno, že 50 z 94 studovaných genů je v nádorech oproti kontrolám (K) deregulováno, stejně jako 15 z 66 genů v intraperitoneálních metastázách (iM) v porovnání s primárními nádory (pT). Exprese genů ABCA7, ABCB2, ABCC3, ESR2, NH1H4 a NR1I1 byla...Mimofakultní pracovištěThird Faculty of Medicine3. lékařská fakult

Use of germline genetic variability for prediction of chemoresistance and prognosis of breast cancer patients

The aim of our study was to set up a panel for targeted sequencing of chemoresistance genes and the main transcription factors driving their expression and to evaluate their predictive and prognostic value in breast cancer patients. Coding and regulatory regions of 509 genes, selected from PharmGKB and Phenopedia, were sequenced using massive parallel sequencing in blood DNA from 105 breast cancer patients in the testing phase. In total, 18,245 variants were identified of which 2565 were novel variants (without rs number in dbSNP build 150) in the testing phase. Variants with major allele frequency over 0.05 were further prioritized for validation phase based on a newly developed decision tree. Using emerging in silico tools and pharmacogenomic databases for functional predictions and associations with response to cytotoxic therapy or disease-free survival of patients, 55 putative variants were identified and used for validation in 805 patients with clinical follow up using KASP™ technology. In conclusion, associations of rs2227291, rs2293194, and rs4376673 (located in ATP7A, KCNAB1, and DFFB genes, respectively) with response to neoadjuvant cytotoxic therapy and rs1801160 in DPYD with disease-free survival of patients treated with cytotoxic drugs were validated and should be further functionally characterized. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.Czech Medical Council [15-25618A]; Charles University [GAUK 1776218

Molecular biomarkers of solid tumors and their use in prognosis and prevention of cancer

Molecular biomarkers of solid tumors and their use in prognosis and prevention of cancer Molekulární biomarkery solidních nádorů a jejich využití v prognóze a prevenci nádorových onemocnění Mgr. Kateřina Elsnerová Summary Malignant tumors of ovary and breast are among the most widespread cancers in women. Despite improvements in diagnostics and in therapy, mortality is still very high. An important tool for early cancer detection, as well as for monitoring prognosis and preventing progression, are molecular biomarkers; biomarkers were the topic of this work. The aim of this work was to find out (i) whether there are differences in gene expression between tumor and non-tumor tissues, and among controls (C), primary tumors (pT) and intraperitoneal metastases (iM), respectively; (ii) whether gene expression or genetic variants (single nucleotide polymorphisms, DNA methylation, germline mutations) associate with clinical data of patients, thus being potentially relevant for prognosis. In epithelial ovarian cancer (EOC), 50 of 94 genes were deregulated in controls compared to tumors. Fifteen of 66 genes were deregulated in intraperitoneal metastases compared to primary tumors. Gene expression of ABCA7, ABCB2, ABCC3, ESR2, NH1H4 and NR1I1 was deregulated either in comparison of primary tumors and metastases, or..

SLC46A1 haplotype with predicted functional impact has prognostic value in breast carcinoma

Background and Objective: Membrane solute carrier transporters play an important role in the transport of a wide spectrum of substrates including anticancer drugs and cancer-related physiological substrates. This study aimed to assess the prognostic relevance of gene expression and genetic variability of selected solute carrier transporters in breast cancer. Methods: Gene expression was determined by quantitative real-time polymerase chain reaction. All SLC46A1 and SLCO1A2 exons and surrounding non-coding sequences in DNA extracted from the blood of patients with breast cancer (exploratory phase) were analyzed by next-generation sequencing technology. Common variants (minor allele frequency ≥ 5%) with in silico-predicted functional relevance were further analyzed in a large cohort of patients with breast cancer (n = 815) and their prognostic and predictive potential was estimated (validation phase). Results: A gene expression and bioinformatics analysis suggested SLC46A1 and SLCO1A2 to play a putative role in the prognosis of patients with breast cancer. In total, 135 genetic variants (20 novel) were identified in both genes in the exploratory phase. Of these variants, 130 were non-coding, three missense, and two synonymous. One common variant in SLCO1A2 and four variants in SLC46A1 were predicted to be pathogenic by in silico programs and subsequently validated. A SLC46A1 haplotype block composed of rs2239911-rs2239910-rs8079943 was significantly associated with ERBB2/HER2 status and disease-free survival of hormonally treated patients. Conclusions: This study revealed the prognostic value of a SLC46A1 haplotype block for breast cancer that should be further studied. © 2020, The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.Ministry of Health of the Czech RepublicMinistry of Health, Czech Republic [17-28470A]; National Center of Medical Genomics [CZ.02.1.01/0.0/0.0/16_ 013/0001634]; Czech Ministry of Education, Youth and Sports INTERCOST [LTC19020]; Charles University project "Center of clinical and experimental liver surgery" [UNCE/MED/006]CZ.02.1.01/0.0/0.0/16_013/0001634; Univerzita Karlova v Praze, UK: UNCE/MED/006; Grantová Agentura, Univerzita Karlova, GA, UK; Ministerstvo Školství, Mládeže a Tělovýchovy, MŠMT: LTC19020; Ministerstvo Zdravotnictví Ceské Republiky, MZCR: 17-28470