INTRODUCTION: In silico tools capable of predicting the functional consequences of genomic differences between individuals, many of which are AI-driven, have been the most effective over the past two decades for non-synonymous single nucleotide variants (nsSNVs). When appropriately selected for the purpose of the study, a high predictive performance can be expected. In this feasibility study, we investigate the distribution of nsSNVs with an allele frequency below 5%. To classify the putative functional consequence, a tier-based filtration led by AI-driven predictors and scoring system was implemented to the overall decision-making process, resulting in a list of prioritised genes. METHODS: The study has been conducted on breast cancer patients of homogeneous ethnicity. Germline rare variants have been sequenced in genes that influence pharmacokinetic parameters of anticancer drugs or molecular signalling pathways in cancer. After AI-driven functional pathogenicity classification and data mining in pharmacogenomic (PGx) databases, variants were collapsed to the gene level and ranked according to their putative deleterious role. RESULTS: In breast cancer patients, seven of the twelve genes prioritised based on the predictions were found to be associated with response to oncotherapy, histological grade, and tumour subtype. Most importantly, we showed that the group of patients with at least one rare nsSNVs in cystic fibrosis transmembrane conductance regulator (CFTR) had significantly reduced disease-free (log rank, p = 0.002) and overall survival (log rank, p = 0.006). CONCLUSION: AI-driven in silico analysis with PGx data mining provided an effective approach navigating for functional consequences across germline genetic background, which can be easily integrated into the overall decision-making process for future studies. The study revealed a statistically significant association with numerous clinicopathological parameters, including treatment response. Our study indicates that CFTR may be involved in the processes influencing the effectiveness of oncotherapy or in the malignant progression of the disease itself.

• Klíčová slova
• Breast cancer, Cystic fibrosis transmembrane conductance regulator, Gene prioritisation, Machine learning, Survival,
• MeSH
• dospělí MeSH
• frekvence genu MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu * genetika   farmakoterapie   patologie   MeSH
• protein CFTR * genetika   MeSH
• senioři MeSH
• studie proveditelnosti * MeSH
• umělá inteligence * MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CFTR protein, human MeSH Prohlížeč
• protein CFTR * MeSH

Oxysterols, oxidized derivatives of cholesterol, act in breast cancer (BC) as selective estrogen receptor modulators and affect cholesterol homeostasis, drug transport, nuclear and cell receptors, and other signaling proteins. Using data from three highly overlapping sets of patients (N = 162 in total) with early-stage estrogen-receptor-positive luminal BC-high-coverage targeted DNA sequencing (113 genes), mRNA sequencing, and full micro-RNA (miRNA) transcriptome microarrays-we describe complex oxysterol-related interaction (correlation) networks, with validation in public datasets (n = 538) and 11 databases. The ESR1-CH25H-INSIG1-ABCA9 axis was the most prominent, interconnected through miR-125b-5p, miR-99a-5p, miR-100-5p, miR-143-3p, miR-199b-5p, miR-376a-3p, and miR-376c-3p. Mutations in SC5D, CYP46A1, and its functionally linked gene set were associated with multiple differentially expressed oxysterol-related genes. STARD5 was upregulated in patients with positive lymph node status. High expression of hsa-miR-19b-3p was weakly associated with poor survival. This is the first study of oxysterol-related genes in BC that combines DNA, mRNA, and miRNA multiomics with detailed clinical data. Future studies should provide links between intratumoral oxysterol signaling depicted here, circulating oxysterol levels, and therapy outcomes, enabling eventual clinical exploitation of present findings.

• Klíčová slova
• breast cancer, integrative analysis, interaction network, multiomics, oxysterols, survival,
• MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• mikro RNA * genetika   metabolismus   MeSH
• nádory prsu * patologie   MeSH
• oxysteroly * MeSH
• transkriptom genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• messenger RNA MeSH
• mikro RNA * MeSH
• oxysteroly * MeSH

Breast cancer is the most common cancer in women in the world. The role of germline genetic variability in ATP-binding cassette (ABC) transporters in cancer chemoresistance and prognosis still needs to be elucidated. We used next-generation sequencing to assess associations of germline variants in coding and regulatory sequences of all human ABC genes with response of the patients to the neoadjuvant cytotoxic chemotherapy and disease-free survival (n = 105). A total of 43 prioritized variants associating with response or survival in the above testing phase were then analyzed by allelic discrimination in the large validation set (n = 802). Variants in ABCA4, ABCA9, ABCA12, ABCB5, ABCC5, ABCC8, ABCC11, and ABCD4 associated with response and variants in ABCA7, ABCA13, ABCC4, and ABCG8 with survival of the patients. No association passed a false discovery rate test, however, the rs17822931 (Gly180Arg) in ABCC11, associating with response, and the synonymous rs17548783 in ABCA13 (survival) have a strong support in the literature and are, thus, interesting for further research. Although replicated associations have not reached robust statistical significance, the role of ABC transporters in breast cancer should not be ruled out. Future research and careful validation of findings will be essential for assessment of genetic variation which was not in the focus of this study, e.g., non-coding sequences, copy numbers, and structural variations together with somatic mutations.

• Klíčová slova
• ABC transporter, breast cancer, competitive allele-specific PCR, disease-free survival, next-generation sequencing, therapy response,
• MeSH
• ABC transportéry genetika   MeSH
• alely MeSH
• frekvence genu MeSH
• genetická variace * MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• Kaplanův-Meierův odhad MeSH
• lidé MeSH
• lokus kvantitativního znaku MeSH
• nádorové biomarkery * MeSH
• nádory prsu diagnóza   genetika   mortalita   terapie   MeSH
• neoadjuvantní terapie MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• výsledek terapie MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry MeSH
• nádorové biomarkery * MeSH

The 12 members of the ABCA subfamily in humans are known for their ability to transport cholesterol and its derivatives, vitamins, and xenobiotics across biomembranes. Several ABCA genes are causatively linked to inborn diseases, and the role in cancer progression and metastasis is studied intensively. The regulation of translation initiation is implicated as the major mechanism in the processes of post-transcriptional modifications determining final protein levels. In the current bioinformatics study, we mapped the features of the 5' untranslated regions (5'UTR) known to have the potential to regulate translation, such as the length of 5'UTRs, upstream ATG codons, upstream open-reading frames, introns, RNA G-quadruplex-forming sequences, stem loops, and Kozak consensus motifs, in the DNA sequences of all members of the subfamily. Subsequently, the conservation of the features, correlations among them, ribosome profiling data as well as protein levels in normal human tissues were examined. The 5'UTRs of ABCA genes contain above-average numbers of upstream ATGs, open-reading frames and introns, as well as conserved ones, and these elements probably play important biological roles in this subfamily, unlike RG4s. Although we found significant correlations among the features, we did not find any correlation between the numbers of 5'UTR features and protein tissue distribution and expression scores. We showed the existence of single nucleotide variants in relation to the 5'UTR features experimentally in a cohort of 105 breast cancer patients. 5'UTR features presumably prepare a complex playground, in which the other elements such as RNA binding proteins and non-coding RNAs play the major role in the fine-tuning of protein expression.

• Klíčová slova
• 5′ untranslated region, ABC transporters, ABCA subfamily, bioinformatics, cis-acting elements,
• MeSH
• 5' nepřekládaná oblast genetika   MeSH
• ABC transportér, podrodina A klasifikace   genetika   metabolismus   MeSH
• biologický transport genetika   MeSH
• cholesterol metabolismus   MeSH
• introny genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• multigenová rodina genetika   MeSH
• otevřené čtecí rámce genetika   MeSH
• proteosyntéza genetika   MeSH
• ribozomy genetika   metabolismus   MeSH
• výpočetní biologie MeSH
• xenobiotika metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 5' nepřekládaná oblast MeSH
• ABC transportér, podrodina A MeSH
• cholesterol MeSH
• xenobiotika MeSH

INTRODUCTION: Ovarian cancer (OC) represents a serious disease with high mortality and lack of efficient predictive and prognostic biomarkers. ATP-binding cassette (ABC) proteins constitute a large family dedicated to active transmembrane transport including transport of xenobiotics. MATERIALS AND METHODS: mRNA level was measured by quantitative RT-PCR in tumor tissues from OC patients. Bioinformatics analyses were applied to two gene expression datasets (60 primary tumors and 29 peritoneal metastases). Two different approaches of expression data normalization were applied in parallel, and their results were compared. Data from publically available cancer datasets were checked to further validate our conclusions. RESULTS: The results showed significant connections between ABC gene expression profiles and time to progression (TTP), chemotherapy resistance, and metastatic progression in OC. Two consensus ABC gene profiles with clinical meaning were documented. (a) Downregulation of ABCC4, ABCC10, ABCD3, ABCE1, ABCF1, ABCF2, and ABCF3 was connected with the best sensitivity to chemotherapy and TTP. (b) Oppositely, downregulation of ABCB11 and upregulation of ABCB1 and ABCG2 were connected with the worst sensitivity to chemotherapy and TTP. Results from publicly available online databases supported our conclusions. CONCLUSION: This study stressed the connection between two well-documented ABC genes and clinicopathological features-ABCB1 and ABCG2. Moreover, we showed a comparable connection also for several other ABC genes-ABCB11, ABCC4, ABCC10, ABCD3, ABCE1, ABCF1, ABCF2, and ABCF3. Our results add new clinically relevant information to this oncology field and can stimulate further exploration.

• Klíčová slova
• ABC transporters, bioinformatics, ovarian cancer, resistance, signatures,
• MeSH
• ABC transportéry genetika   MeSH
• chemorezistence genetika   MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• nádory vaječníků genetika   patologie   MeSH
• peritoneální nádory genetika   sekundární   MeSH
• regulace genové exprese u nádorů * MeSH
• transkriptom MeSH
• výpočetní biologie MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportéry MeSH
• messenger RNA MeSH

The prognosis of esophageal cancer (EC) is poor, despite considerable effort of both experimental scientists and clinicians. The tri-modality treatment consisting of neoadjuvant chemoradiation followed by surgery has remained the gold standard over decades, unfortunately, without significant progress in recent years. Suitable prognostic factors indicating which patients will benefit from this tri-modality treatment are missing. Some patients rapidly progress on the neoadjuvant chemoradiotherapy, which is thus useless and sometimes even harmful. At the same time, other patients achieve complete remission on neoadjuvant chemoradiotherapy and subsequent surgery may increase their risk of morbidity and mortality. The prognosis of patients ranges from excellent to extremely poor. Considering these differences, the role of drug metabolizing enzymes and transporters, among other factors, in the EC response to chemotherapy may be more important compared, for example, with pancreatic cancer where all patients progress on chemotherapy regardless of the treatment or disease stage. This review surveys published literature describing the potential role of ATP-binding cassette transporters, the genetic polymorphisms, epigenetic regulations, and phenotypic changes in the prognosis and therapy of EC. The review provides knowledge base for further research of potential predictive biomarkers that will allow the stratification of patients into defined groups for optimal therapeutic outcome.

• Klíčová slova
• ABC transporters, biomarker, cancer, chemotherapy, esophagus, prognosis, radiotherapy,
• MeSH
• ABC transportéry genetika   metabolismus   MeSH
• epigeneze genetická MeSH
• lidé MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádory jícnu genetika   metabolismus   terapie   MeSH
• neoadjuvantní terapie metody   MeSH
• polymorfismus genetický MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• ABC transportéry MeSH
• nádorové biomarkery MeSH

Transport of a wide variety of substrates, including xenobiotics, is one of the main functions attributed to human ATP-binding cassette (ABC) proteins. Overexpression of ABC genes is considered to be an important mechanism facilitating the development of chemoresistance. Relationships between the expression levels of ABC genes in tumor tissues and established clinicopathological features were extensively studied previously. The current study tested our hypothesis that the expression levels of ABC genes in non-neoplastic (control) tissues also provide important information in relation to the relevant tumor progression. Expression levels of all human ABC genes (48 protein coding and one pseudogene), measured by qRT-PCR, were bioinformatically analyzed. The data originated from four independently collected cohorts covering three types of tumors - breast, colorectal and pancreatic carcinomas. ABC gene expression profiles (signatures) in non-neoplastic tissues (matched to tumor samples from three different tumor types) were characteristically clustered into three main types - those with the vast majority of the genes downregulated, upregulated or heterogeneously regulated. The clusters with mostly downregulated and upregulated genes were shown to possess significant relations to good and poor prognostic markers, respectively, in pancreatic and colorectal cancers. The present findings support the theory that the expression of ABC genes in non-neoplastic tissues can significantly contribute to tumor pathogenesis. Suggested multi-gene panels, consisting of the reduced number of ABC genes, have the potential to be implemented as new prognostic markers, which are especially urgent in pancreatic cancer. The results can also stimulate further primary research in carcinogenesis.

• Klíčová slova
• ABC transporters, ATP-binding cassette, cancer, gene expression, profiles,
• Publikační typ
• časopisecké články MeSH