Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

• MeSH
• autofagie * genetika   MeSH
• běloši genetika   MeSH
• duktální karcinom slinivky břišní * genetika   patologie   MeSH
• forkhead transkripční faktory MeSH
• genetická predispozice k nemoci * MeSH
• hepatocytární jaderný faktor 3-alfa genetika   metabolismus   MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• lidé MeSH
• nádorové biomarkery * genetika   MeSH
• nádorové supresorové proteiny * genetika   MeSH
• nádory slinivky břišní * genetika   patologie   MeSH
• studie případů a kontrol MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

BACKGROUND AND OBJECTIVE: Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is a rare variant of malignant pancreatic tumor. There is still no standardized treatment for this uncommon subtype, as surgical resection with lymphadenectomy is the only potentially curative treatment so far. In this paper, we describe the current knowledge of this very rare specific subtype of pancreatic cancer (PC) as a narrative review. METHODS: For this review, we did not specify the time range of studies referred to due to limited data availability. Our inclusion criteria comprised previous studies, which specifically focused on the rare UCOGC subtype of PC as a confirmed histopathology, either pure or present together with other subtypes. We disregarded the studies involving any other PC subtype but not UCOGC, including undifferentiated and anaplastic carcinomas without osteoclast-like giant cell components. KEY CONTENT AND FINDINGS: The limited available data precludes a definitive assessment of the efficacy of both neoadjuvant and adjuvant chemotherapy in the treatment of UCOGC. Monoclonal antibody pembrolizumab has been proven to be effective in metastatic cases. Multiple cases demonstrate a better overall survival rate for patients with UCOGC only versus those having UCOGC as a component with a pancreatic ductal adenocarcinoma (PDAC) histopathological subtype. The same conclusion can be also drawn comparing the survival rate of patients having pure UCOGC versus UCOGC with associated PDAC. Programmed cell death ligand-1 expression has been shown to be an important determinant, which shortens the survival period of patients diagnosed with UCOGC. CONCLUSIONS: The rarity of UCOGC limits data for clinical courses and treatment plans. We need more data to better understand the relationship between pathogenic mutations, histological subtypes, and prognosis in PC, including UCOGC. Understanding UCOGC's molecular, clinical, radiological, and pathological characteristics can lead to earlier, more accurate diagnoses and better management.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Search for molecular biomarkers enabling prediction of cancer treatment efficacy and establishment of optimal method for their assessment represent major opportunities, but also challenges in translational research. This project aims to explore feasibility of the next generation sequencing method for discovery of Czech population-specific genetic biomarkers for stratification of cancer patients into prognostically meaningful groups. Genetic background of patients treated with adjuvant chemotherapy regimens based on nucleoside analogs, taxanes and platinum derivatives will be explored by whole exome profiling method in cancer patients of Czech origin for the first time. Results will be compared with data in publicly available databases as TCGA and ICGC and with data from Czech NCGM genetic variability project. Panel of germline variants and somatically relevant genes for prognostication of patients will subsequently be validated and its cost efficacy and benefit will be evaluated in comparison with the whole exome approach.

Analýza molekulárních biomarkerů umožňujících predikci reakce nádorů na léčbu a zavedení optimální metody pro jejich sledování představují zásadní výzvy současného translačního výzkumu. Tento projekt má za cíl prozkoumat využitelnost metody sekvenování příští generace pro hledání genetických biomarkerů, specifických pro českou populaci, které by umožnily rozdělení pacientů se solidními nádory do prognosticky významných skupin. V rámci projektu bude studován genetický profil pacientů se solidními nádory léčenými adjuvantní terapií režimy založenými na nukleosidových analozích, taxanech a platinových derivátech. Metoda celoexomového sekvenování bude poprvé použita ke studiu tohoto fenoménu u českých pacientů s malignitami. Výsledky studie budou porovnány s daty ve veřejně dostupných databázích, např. TCGA, ICGC a s výstupy projektu NCLG, který mapuje genetickou variabilitu obecné české populace. Hlavním výstupem projektu bude validovaný panel zárodečných variant a somaticky významných genů pro další studie a analýza účinnosti panelového sekvenování, ve srovnání s celoexomovým přístupem.

• Klíčová slova
• prognosis, sekvenování nové generace, Next generation sequencing, therapy, nádor, cancer, terapie, proveditelnost, feasibility, prognoza,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

BACKGROUND: Colorectal cancer is still the second leading cause of cancer-related deaths and thus biomarkers allowing prediction of the resistance of patients to therapy and estimating their prognosis are needed. We designed a panel of 558 genes with pharmacogenomics records related to 5-fluorouracil resistance, genes important for sensitivity to other frequently used drugs, major oncodrivers, and actionable genes. We performed a target enrichment sequencing of DNA from tumors and matched blood samples of patients, and compared the results with patient prognosis stratified by systemic adjuvant chemotherapy. RESULTS: The median number of detected variants per tumor sample was 18.5 with 4 classified as having a high predicted functional effect and 14.5 moderate effect. APC, TP53, and KRAS were the most frequent mutated genes (64%, 59%, and 42% of mutated samples, respectively) followed by FAT4 (23%), FBXW7, and PIK3CA (16% for both). Patients with advanced stage III had more frequently APC, TP53, or KRAS mutations than those in stages I or II. KRAS mutation counts followed an increasing trend with grade (G1 < G2 < G3). The response to adjuvant therapy was worse in carriers of frameshift mutations in APC or 12D variant in KRAS, but none of these oncodrivers had prognostic value. Carriage of somatic mutations in any of the genes ABCA13, ANK2, COL7A1, NAV3, or UNC80 had prognostic relevance for worse overall survival (OS) of all patients. In contrast, mutations in FLG, GLI3, or UNC80 were prognostic in the same direction for patients untreated, and mutations in COL6A3, LRP1B, NAV3, RYR1, RYR3, TCHH, or TENM4 for patients treated with adjuvant therapy. The first association was externally validated. From all germline variants with high or moderate predicted functional effects (median 326 per patient), > 5% frequency and positive Manhattan plot based on 3-year RFS, rs72753407 in NFACS, rs34621071 in ERBB4, and rs2444274 in RIF1 were significantly associated with RFS, OS or both. CONCLUSIONS: The present study identified several putative somatic and germline genetic events with prognostic potential for colorectal cancer that should undergo functional characterization.

• MeSH
• chemorezistence genetika   MeSH
• dospělí MeSH
• F-Box a WD repetice obsahující protein 7 genetika   MeSH
• farmakogenetika metody   MeSH
• fluoruracil terapeutické užití   MeSH
• fosfatidylinositol-3-kinasy třídy I MeSH
• kolorektální nádory * genetika   farmakoterapie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace genetika   MeSH
• nádorové biomarkery genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• prognóza MeSH
• protein familiární adenomatózní polypózy genetika   MeSH
• protoonkogenní proteiny p21(ras) genetika   MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

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.

• 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

Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10-5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association.

• MeSH
• alely MeSH
• antigeny nádorové * genetika   MeSH
• Asijci genetika   MeSH
• běloši genetika   MeSH
• duktální karcinom slinivky břišní * genetika   MeSH
• genetická predispozice k nemoci * MeSH
• GPI-vázané proteiny * genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokus kvantitativního znaku MeSH
• metylace DNA * MeSH
• nádorové proteiny * genetika   MeSH
• nádory slinivky břišní * genetika   MeSH
• studie případů a kontrol MeSH
• vazebná nerovnováha * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• Publikační typ
• abstrakt z konference MeSH

High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological malignancies worldwide, due to late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC-related genes by high-coverage targeted DNA sequencing to identify the genetic determinants associated with resistance to platinum-based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%). Somatically, the most mutated gene was TP53 (98%), followed by CSMD1/2/3 (19/19/36%), and CFTR (23%). Results were compared with those from whole exome sequencing of a similar set of 35 HGSC patients. Somatic variants in TP53 were also validated using GENIE data of 1287 HGSC samples. Our approach showed increased prevalence of high impact somatic and germline mutations, especially those affecting splice sites of TP53, compared to validation datasets. Furthermore, nonsense TP53 somatic mutations were negatively associated with patient survival. Elevated TP53 transcript levels were associated with platinum resistance and presence of TP53 missense mutations, while decreased TP53 levels were found in tumors carrying mutations with predicted high impact, which was confirmed in The Cancer Genome Atlas data (n = 260). Targeted DNA sequencing of TP53 combined with transcript quantification may contribute to the concept of precision oncology of HGSC. Future studies should explore targeting the p53 pathway based on specific mutation types and co-analyze the expression and mutational profiles of other key cancer genes.

• MeSH
• chemorezistence * genetika   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorový supresorový protein p53 * genetika   MeSH
• nádory vaječníků * genetika   farmakoterapie   patologie   MeSH
• platina terapeutické užití   farmakologie   MeSH
• regulace genové exprese u nádorů MeSH
• sekvenování exomu metody   MeSH
• senioři MeSH
• serózní cystadenokarcinom * genetika   farmakoterapie   patologie   MeSH
• zárodečné mutace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

• MeSH
• celogenomová asociační studie MeSH
• duktální karcinom slinivky břišní * genetika   patologie   MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• nádory slinivky břišní * genetika   epidemiologie   patologie   MeSH
• regulační oblasti nukleových kyselin MeSH
• transkripční faktory genetika   metabolismus   MeSH
• vazebná místa genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Pancreatic cancer is a severe malignancy with increasing incidence and high mortality due to late diagnosis and low sensitivity to treatments. Search for the most appropriate drugs and therapeutic regimens is the most promising way to improve the treatment outcomes of the patients. This study aimed to compare (1) in vitro efficacy and (2) in vivo antitumor effects of conventional paclitaxel and the newly synthesized second (SB-T-1216) and third (SB-T-121605 and SB-T-121606) generation taxanes in KRAS wild type BxPC-3 and more aggressive KRAS G12V mutated Paca-44 pancreatic cancer cell line models. In vitro, paclitaxel efficacy was 27.6 ± 1.7 nM, while SB-Ts showed 1.7-7.4 times higher efficacy. Incorporation of SB-T-121605 and SB-T-121606 into in vivo therapeutic regimens containing paclitaxel was effective in suppressing tumor growth in Paca-44 tumor-bearing mice at small doses (≤3 mg/kg). SB-T-121605 and SB-T-121606 in combination with paclitaxel are promising candidates for the next phase of preclinical testing.

• Publikační typ
• časopisecké články MeSH