U nádorů gastrointestinálního traktu dnes vedle stanovení histologické diagnózy, grade a stage hraje zásadní roli rovněž tzv. prediktivní testování. To slouží zejména k identifikaci molekulárních cílů pro moderní onkologickou terapii. U karcinomů jícnu a žaludku je dnes standardem vyšetření exprese a amplifikace HER2, exprese proteinů mismatch repair (MMR) systému a vyšetření exprese PD-L1. U karcinomu žaludku se v blízké budoucnosti testování rozšíří o další markery, zejména exprese claudinu 18.2 či receptoru FGFR2a. U kolorektálního karcinomu je standardem prediktivního vyšetření stanovení mutací RAS (KRAS a NRAS), BRAF a dále zhodnocení mikrosatelitní instability, jen vzácně lze nalézt rovněž terapeuticky cílitelné genové fúze. U karcinomu pankreatu se lze setkat s případy deficience MMR, mutacemi BRCA1/2, zcela raritně lze identifikovat další cílitelné aberace. U nádorů žlučníku a žlučových cest hledáme zejména mutace IDH1 a IDH2, fúze a mutace genu FGFR2, amplifikace či mutace HER2, mutace BRAF či mutace BRCA1/2. Všechny výsledky by měly být projednány v rámci molekulárního tumor boardu.
In addition to the histological diagnosis, grade and stage, predictive testing plays a crucial role in gastrointestinal tumours today. This is mainly used to identify molecular targets for modern cancer therapy. In esophageal and gastric cancers, HER2 expression and amplification, mismatch repair (MMR) system protein deficiency and PD-L1 expression are tested routinely. In colorectal cancer, it is namely detection of RAS (KRAS and NRAS) and BRAF mutations, as well as the assessment of microsatellite instability; targetable gene fusions are found rarely only. In pancreatic cancer, cases of MMR deficiency, BRCA1/2 mutations and other targetable aberrations can be identified quite rarely. In gallbladder and biliary tract cancers, we are mainly looking for IDH1 and IDH2 mutations, FGFR2 gene fusions and mutations, HER2 amplifications or mutations, as well as mutations of BRAF or BRCA1/2. All results should be discussed within the molecular tumor board.
- MeSH
- diagnostické techniky molekulární MeSH
- gastrointestinální nádory * diagnóza genetika klasifikace MeSH
- genetické testování MeSH
- lidé MeSH
- mutace genetika MeSH
- nádorové biomarkery * genetika MeSH
- prediktivní hodnota testů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Most of the organs of the digestive tract comprise secretory epithelia that require specialized molecular machines to achieve their functions. As such anterior gradient (AGR) proteins, which comprise AGR1, AGR2, and AGR3, belong to the protein disulfide isomerase family, and are involved in secretory and transmembrane protein biogenesis in the endoplasmic reticulum. They are generally expressed in epithelial cells with high levels in most of the digestive tract epithelia. To date, the vast majority of the reports concern AGR2, which has been shown to exhibit various subcellular localizations and exert pro-oncogenic functions. AGR2 overexpression has recently been associated with a poor prognosis in digestive cancers. AGR2 is also involved in epithelial homeostasis. Its deletion in mice results in severe diffuse gut inflammation, whereas in inflammatory bowel diseases, the secretion of AGR2 in the extracellular milieu participates in the reshaping of the cellular microenvironment. AGR2 thus plays a key role in inflammation and oncogenesis and may represent a therapeutic target of interest. In this review, we summarize the already known roles and mechanisms of action of the AGR family proteins in digestive diseases, their expression in the healthy digestive tract, and in digestive oncology. At last, we discuss the potential diagnostic and therapeutic implications underlying the biology of AGR proteins.
- MeSH
- gastrointestinální nádory * genetika MeSH
- karcinogeneze genetika MeSH
- mukoproteiny genetika MeSH
- myši MeSH
- nádorové mikroprostředí MeSH
- onkogenní proteiny * genetika MeSH
- proteindisulfidisomerasy MeSH
- zánět genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Recently, we have witnessed impressive diagnostic and therapeutic changes for gastrointestinal cancer patients. New challenges brought by the COVID-19 pandemic have led us to re-evaluate our work priorities. Thanks to the commendable resilience of both investigators and patients, however, clinical research never stopped. In addition to conducting cutting-edge research and serving patients' needs, as EORTC Gastrointestinal Tract Cancer Group, we are committed to pursuing educational initiatives beneficial to the entire European oncology community and beyond. In this regard, we have been providing critical discussions of new data from major international meetings. In this article, we discuss results of important selected studies presented at the 2022 ASCO Gastrointestinal Cancer Symposium, putting them in perspectives and highlighting potential implications for routine practice. With the number of in-person attendees and practice-changing/informing trials presented, this meeting represented a milestone in the return to normality as well as in the fight against cancer.
- MeSH
- COVID-19 * MeSH
- gastrointestinální nádory * diagnóza genetika terapie MeSH
- lékařská onkologie MeSH
- lidé MeSH
- pandemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: Single nucleotide polymorphisms can create a genetic microenvironment in some tumors that affects the course of treatment, resistance, etc. Whether single nucleotide polymorphisms have an impact on gastrointestinal stromal tumor (GIST) development and disease progression is not yet accurately verified. KIT SNPM541L in exon 10 correlates with a worse prognosis of many cancers. The impact of KIT SNPM541L in GISTs is relatively unknown and, therefore, its analyses could have potential in patient therapy and could provide more detailed information on tumor character, clinical presentation, or tumor behavior in treatment. AIM: The aim of the study was the analysis of the biological and clinical significance of the KIT SNPM541L polymorphism in exon 10. MATERIALS AND METHODS: Paraffin sample tissues were obtained from the National GIST Register in Martin. Retrospective samples from 177 GIST patients were divided into several groups. Detection of SNPM541L was performed by Sanger sequencing. Statisitical analyses were performed to determine the prevalence of KIT SNPM541L in the Slovak GIST cohort, to search for correlation between c-KIT status and clinicopathological, molecular and biological data. RESULTS: Overall, 29 samples out of 177 showed KIT SNPM541L polymorphism. CONCLUSION: Our results do not support the association between KIT SNPM541L and increased risk of relapse in localized primary GISTs. Additionally, we found a positive correlation between KIT SNPM541L occurrence and earlier onset of relapse in PDGFRa and WT subgroup of GISTs.
- MeSH
- dospělí MeSH
- gastrointestinální nádory epidemiologie genetika patologie MeSH
- gastrointestinální stromální tumory epidemiologie genetika patologie MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé středního věku MeSH
- lidé MeSH
- míra přežití MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádorové biomarkery genetika MeSH
- následné studie MeSH
- prognóza MeSH
- protoonkogenní proteiny c-kit genetika MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
- MeSH
- gastrointestinální nádory * diagnóza genetika MeSH
- genetické testování * metody MeSH
- kongresy jako téma MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- zprávy MeSH
- MeSH
- gastrointestinální nádory farmakoterapie genetika patologie farmakoterapie genetika imunologie MeSH
- hepatocelulární karcinom chirurgie farmakoterapie genetika MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- lidé MeSH
- nádorové biomarkery genetika MeSH
- nivolumab terapeutické užití MeSH
- protinádorové látky imunologicky aktivní farmakologie terapeutické užití MeSH
- protoonkogenní proteiny c-kit účinky léků MeSH
- tekutá biopsie metody MeSH
- tyrosinkinasové receptory účinky léků MeSH
- Check Tag
- lidé MeSH
Structural chromosome aberrations are a predictive biomarker of cancer risk. Conventional chromosome analysis widely used for these purposes detects unstable chromosome aberrations that are eliminated during cell division. Stable aberrations that may persist in the body and tend to accumulate during a lifetime can be detected by fluorescence in situ hybridization (FISH). The aim of the study was to investigate the level of chromosome damage in newly diagnosed cancer patients and control subjects by FISH. Both groups of untreated cancer patients had increased frequency of aberrant cells. However, chromosome damage affected different cytogenetic endpoints. Stable translocations and cells with complex rearrangements were elevated in breast cancer patients whereas unstable chromosome aberrations (dicentric chromosomes and acentric fragments) were elevated in gastrointestinal cancer patients. These associations observed in nonsmokers were typically not pronounced in smokers (with the exception of dicentric chromosomes in gastrointestinal patients). Exposure to tobacco smoke increased aberrations in healthy controls but not in the cancer patients. Our study suggests an association between cancer and stable chromosomal rearrangements in breast cancer patients. Unstable aberrations elevated in gastrointestinal cancer patients may be at least partly ascribed to the exposure to diagnostic X-rays.
- MeSH
- chromozomální aberace * MeSH
- gastrointestinální nádory genetika MeSH
- hybridizace in situ fluorescenční MeSH
- lidé MeSH
- lymfocyty * MeSH
- nádory prsu genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The most important findings revealing pathogenesis, molecular characteristics, genotyping and targeted therapy of gastrointestinal stromal tumors (GISTs) are activated oncogenic mutations in KIT and PDGFRA genes. Imatinib mesylate (IM), which inhibits both KIT and PDGFRA receptors, significantly improved treatment of advanced (metastatic, recurrent, and/or inoperable) GISTs. However, in a significant number of patients the treatment fails due to the primary or secondary resistance to targeted therapy. Most common cause of secondary resistance is a presence of secondary mutations. Approximately 15% of adult patients with GISTs are negative for mutations in KIT or PDGFRA genes. These so-called wild-type GISTs appear to be characterized by other oncogenetic drivers, including mutations in BRAF, RAS, NF1 genes, and subunits of succinate dehydrogenase (SDH) complex. In the present study we investigated 261 tumour specimens from 239 patients with GIST. Primary mutations were detected in 82 % tumor specimens. 66 of them were in KIT, and 16 % in PDGFRA genes. Remaining 18 % were KIT/PDGFRA wild-type. Secondary KIT mutations were detected in 10 from 133 (7 %) patients treated with IM. We examined secondary KIT mutations in exons 13 and 17 and secondary PDGFRA mutation in exon 18 in sixteen progressive tumors and/or metastasis (from overall 22 samples). We identified BRAF V600E point mutation in 4 % of KIT/PDGFRA wild-type GIST patients. Moreover, we analysed SDH complex mutations in 4 younger patients (15, 33, 37, and 45 years old) from 44 patients without KIT, PDGFRA, and BRAF mutations. Two patients (a 37-year old man, and a 33-year old woman) had defects of the SDH complex. Our findings of mutational status of the primary and secondary KIT/PDGFRA mutations in patients with GIST confirm mechanisms of primary and secondary resistance, and also intralesional and interlesional heterogeneity of secondary mutations within and between progressive lesions. Moreover, detection of V600E BRAF mutation and defects of SDH complex in KIT/PDGFRA wild-type GISTs confirm their activation and allow for a selection of targeted therapy.
- MeSH
- chemorezistence genetika MeSH
- dospělí MeSH
- gastrointestinální nádory farmakoterapie genetika patologie MeSH
- gastrointestinální stromální tumory farmakoterapie genetika patologie MeSH
- genetická heterogenita MeSH
- genetická predispozice k nemoci MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mutace * MeSH
- mutační analýza DNA MeSH
- nádorové biomarkery genetika MeSH
- protinádorové látky terapeutické užití MeSH
- protoonkogenní proteiny B-raf genetika MeSH
- protoonkogenní proteiny c-kit genetika MeSH
- růstový faktor odvozený z trombocytů - receptor alfa genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sukcinátdehydrogenasa genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- BRAF, anti-EGFR terapie, trifluridin/tipiracil,
- MeSH
- gastrointestinální nádory * farmakoterapie genetika MeSH
- kolorektální nádory farmakoterapie genetika MeSH
- kombinovaná farmakoterapie MeSH
- léková rezistence MeSH
- lidé MeSH
- mikrobiota účinky léků MeSH
- mikrosatelitní nestabilita MeSH
- mutace MeSH
- trifluridin aplikace a dávkování MeSH
- Check Tag
- lidé MeSH
- MeSH
- antigen CTLA-4 antagonisté a inhibitory MeSH
- antigeny CD274 antagonisté a inhibitory MeSH
- gastroezofageální junkce patologie účinky léků MeSH
- gastrointestinální nádory * genetika imunologie terapie MeSH
- imunoterapie trendy MeSH
- ipilimumab MeSH
- lidé MeSH
- nádorové biomarkery metabolismus MeSH
- nádorové mikroprostředí imunologie účinky léků MeSH
- nádory jícnu farmakoterapie patologie MeSH
- předoperační období MeSH
- protinádorové látky imunologicky aktivní terapeutické užití MeSH
- protokoly protinádorové léčby MeSH
- udržovací chemoterapie metody MeSH
- Check Tag
- lidé MeSH
