Metastatický kolorektální karcinom je heterogenní onemocnění, kde je léčba individuálně volena dle znalosti molekulárních vlastností nádoru. S přibývajícími poznatky o molekulární biologii onemocnění roste současně počet potenciálních cílů pro specifickou terapii. V posledních letech je novou možností pro pacienty s metastatickým kolorektálním karcinomem s prokázanou KRAS G12C mutací terapie KRAS G12C inhibitory. Cílem článku je poskytnout přehled současných možností léčby této jednotky.

Metastatic colorectal cancer is a heterogeneous disease where treatment is individually selected according to the knowledge of the molecular characteristics of the tumour. As the knowledge of the molecular biology of the disease increases, the number of potential targets for specific therapies increases. In recent years, KRAS G12C inhibitor therapy has become a new treatment option for patients with metastatic colorectal cancer with a proven KRAS G12C mutation. The aim of this article is to provide an overview of current treatment options for this entity.

• Klíčová slova
• KRAS G12C,
• MeSH
• erbB receptory antagonisté a inhibitory   MeSH
• klinická studie jako téma MeSH
• klinické zkoušky jako téma MeSH
• kolorektální nádory * farmakoterapie   MeSH
• kombinovaná farmakoterapie metody   MeSH
• lidé MeSH
• mutace MeSH
• piperaziny aplikace a dávkování   MeSH
• protinádorové látky aplikace a dávkování   MeSH
• pyrimidiny aplikace a dávkování   MeSH
• Ras proteiny antagonisté a inhibitory   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

The RAS pathway is among the most frequently activated signaling nodes in cancer. However, the mechanisms that alter RAS activity in human pathologies are not entirely understood. The most prevalent post-translational modification within the GTPase core domain of NRAS and KRAS is ubiquitination at lysine 128 (K128), which is significantly decreased in cancer samples compared to normal tissue. Here, we found that K128 ubiquitination creates an additional binding interface for RAS GTPase-activating proteins (GAPs), NF1 and RASA1, thus increasing RAS binding to GAP proteins and promoting GAP-mediated GTP hydrolysis. Stimulation of cultured cancer cells with growth factors or cytokines transiently induces K128 ubiquitination and restricts the extent of wild-type RAS activation in a GAP-dependent manner. In KRAS mutant cells, K128 ubiquitination limits tumor growth by restricting RAL/ TBK1 signaling and negatively regulating the autocrine circuit induced by mutant KRAS. Reduction of K128 ubiquitination activates both wild-type and mutant RAS signaling and elicits a senescence-associated secretory phenotype, promoting RAS-driven pancreatic tumorigenesis.

• MeSH
• GTP-fosfohydrolasy metabolismus   genetika   MeSH
• lidé MeSH
• lysin metabolismus   MeSH
• membránové proteiny metabolismus   genetika   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• neurofibromin 1 MeSH
• protein aktivující GTPasu p120 metabolismus   genetika   MeSH
• protein-serin-threoninkinasy metabolismus   genetika   MeSH
• protoonkogenní proteiny p21(ras) * metabolismus   genetika   MeSH
• Ras proteiny metabolismus   genetika   MeSH
• signální transdukce MeSH
• ubikvitinace * MeSH
• vazba proteinů * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

• MeSH
• dítě MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genová přestavba * MeSH
• gliom klasifikace   genetika   patologie   MeSH
• kohortové studie MeSH
• kojenec MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy genetika   MeSH
• mladiství MeSH
• mutace * MeSH
• nádorové biomarkery genetika   MeSH
• nádory mozku klasifikace   genetika   patologie   MeSH
• neurofibromin 1 genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• protoonkogenní proteiny B-raf genetika   MeSH
• ras proteiny genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• stanovení celkové genové exprese MeSH
• variabilita počtu kopií segmentů DNA * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Head and neck squamous cell carcinomas (HNSCC) are a highly heterogenous disease which can be induced by two main carcinogens – tobacco and/or alcohol, or by HR HPV infection. This work examined 60 paraffin-embedded biopsies of head and neck carcinomas after histological verification. HPV infection, including its specific types in various HNSCC areas, was studied using multiplex qPCR. Expression levels of p16INK4A and p53 were detected by subsequent IHC analysis as being potential diagnostic markers. Based on the assumption that patients with HNSCC could benefit from anti-EGFR therapy (cetuximab), but the predictors are not yet defined, analyses of point mutations of ras genes (Kras, Nras) were carried out using multiplex qPCR and sequence analysis of the Braf gene. All statistical data were processed by Chí-x2 test. HPV infection was detected in 23.34 % of cases with HNSCC, of which 100 % were HPV 16, which is the most frequently infection found in the oropharyngeal region. Using IHC analysis, a positive expression of P16INK4A was detected in 100 % of HPV-positive HNSCC while this expression was discovered to be highly correlated with HPV infection. Furthermore, a correlation between p53 and HPV-negative HNSCC was proved. The mutation incidence was the highest in the Kras gene (codon 12 and codon 146), Nras (codon 12) and Braf. A correlation between tumor location in the oropharyngeal region and Kras mutations was proved. The HPV infection correlated with Kras mutations in case of codon 146 but on the grounds of low amount of output data, these figures could be irrelevant. In one case, c.1808 G>A, protein 603 Arg>Gln mutation was found in the Braf gene but its correlation with head and neck carcinomas has not been described yet (Tab. 2, Fig. 2, Ref. 24).

• MeSH
• biopsie metody   MeSH
• dlaždicobuněčné karcinomy hlavy a krku * genetika   imunologie   MeSH
• genetické testování metody   MeSH
• imunohistochemie * metody   MeSH
• infekce papilomavirem * komplikace   patologie   MeSH
• inhibitor p16 cyklin-dependentní kinasy analýza   škodlivé účinky   MeSH
• klinická studie jako téma metody   MeSH
• lidé MeSH
• nádorové biomarkery analýza   MeSH
• nádorový supresorový protein p53 analýza   škodlivé účinky   MeSH
• nádory hlavy a krku genetika   imunologie   patologie   MeSH
• onkogenní proteiny imunologie   škodlivé účinky   MeSH
• prognóza MeSH
• Ras proteiny analýza   genetika   MeSH
• Check Tag
• lidé MeSH

Background: : Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patients and methods: Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. Results: RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). Conclusions: In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant. ClinicalTrials.gov number: NCT01183780.

• MeSH
• cetuximab aplikace a dávkování   MeSH
• fluoruracil aplikace a dávkování   MeSH
• humanizované monoklonální protilátky aplikace a dávkování   MeSH
• kamptothecin aplikace a dávkování   MeSH
• kolorektální nádory farmakoterapie   genetika   metabolismus   patologie   MeSH
• leukovorin aplikace a dávkování   MeSH
• lidé MeSH
• metastázy nádorů MeSH
• míra přežití MeSH
• mutace * MeSH
• nádorové biomarkery analýza   MeSH
• následné studie MeSH
• patologická angiogeneze * MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• protoonkogenní proteiny c-raf genetika   MeSH
• ras proteiny genetika   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10(-11)) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.

• MeSH
• faciální stigmatizace MeSH
• fenotyp MeSH
• genotyp MeSH
• guanosindifosfát metabolismus   MeSH
• guanosintrifosfát metabolismus   MeSH
• interakční proteinové domény a motivy genetika   MeSH
• konformace proteinů MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• missense mutace MeSH
• mitochondriální proteiny chemie   genetika   MeSH
• molekulární modely MeSH
• mutace * MeSH
• ral proteiny vázající GTP chemie   genetika   MeSH
• ras proteiny chemie   genetika   MeSH
• vývojové poruchy u dětí genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Genome-wide association studies (GWAs) focused on cardiovascular diseases reveal variants within genes which have not been analyzed through the pre-GWAs era, and whose function is often unknown. One of them is variant rs9818870 at the MRAS gene locus. OBJECTIVES: To analyze if MRAS polymorphism is associated with acute coronary syndrome (ACS) risk in a Czech population and with mortality in male patients after myocardial infarction. MATERIAL AND METHODS: 1,779 male patients with ACS (aged 55.3 ±7.9 years) and 673 female patients with ACS (aged 64.0 ±8.1 years) were genotyped for rs9818870 polymorphism using the PCR-RFLP method. In a subset of 1,221 patients, detailed diagnoses (901 subjects with STEMI, 280 subjects with NSTEMI, 40 cases with unstable angina pectoris) were recorded. In 1,614 males, records about total and cardiovascular mortality were available. RESULTS: Whether the entire populations or males and females have been analyzed separately or not, we have not confirmed the described association between DNA marker rs9818870 and ACS in Czechs (30.4% vs 29.4% carriers of the minor T allele [recessive model], p = 0.54; OR 1.05; 95% CI 0.89-1.24 for males and 32.1% vs 29.7% carriers of the minor T allele, p = 0.28; OR 1.12; 95% CI 0.91-1.37 for females). Types of the ACS (STEMI and NSTEMI) or mortality (in males only) were not associated with the analyzed polymorphism (all p > 0.34). CONCLUSIONS: The rs9818870 variant is not associated with ACS or mortality in ACS patients in the Czech Slavonic population.

• MeSH
• akutní koronární syndrom genetika   mortalita   MeSH
• celogenomová asociační studie MeSH
• dospělí MeSH
• genetické markery MeSH
• lidé středního věku MeSH
• lidé MeSH
• polymorfismus genetický * MeSH
• ras proteiny genetika   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in 35-45 % of colorectal cancer (CRC) cases. Although the association between the RAS signaling and angiogenesis is well known, the negative predictive value of KRAS mutation has not been established in patients treated with bevacizumab. The aim of this study was to evaluate the association between specific KRAS mutation types and outcome of patients with metastatic CRC treated with bevacizumab. The study included 404 patients with metastatic CRC (mCRC) treated with bevacizumab. Clinical data obtained from the clinical registry CORECT were retrospectively analyzed. The shortest survival was observed in patients with tumors harboring G12V or G12A KRAS mutation (G12V/A). The median progression-free survival (PFS) and overall survival (OS) for patients with tumors harboring G12V/A KRAS mutation was 6.6 and 16.8 compared to 11.6 and 26.3 months for patients with tumors harboring other KRAS mutation type (p < 0.001 and p < 0.001), while the survival of patients harboring other KRAS mutation types was comparable to those with tumors harboring wild-type KRAS gene. In the Cox multivariable analysis, KRAS G12V/A mutation type remains a significant factor predicting both PFS (HR = 2.18, p < 0.001) and OS (HR = 2.58, p < 0.001). In conclusion, the results of the present study indicate that there is a significant difference in biological behavior between tumors harboring G12V/A and other KRAS mutations. Moreover, comparison of the survival of patients with tumors harboring G12V/A KRAS mutations with those harboring wild-type KRAS gene revealed that G12V/A KRAS mutations are prognostic biomarker for inferior PFS and OS in patients with mCRC treated with bevacizumab in univariate as well as multivariable analyses.

• MeSH
• alely * MeSH
• bevacizumab terapeutické užití   MeSH
• dospělí MeSH
• Kaplanův-Meierův odhad MeSH
• kodon MeSH
• kolorektální nádory farmakoterapie   genetika   mortalita   patologie   MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• mutace * MeSH
• opakovaná terapie MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• ras proteiny genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours.

• MeSH
• ATM protein genetika   metabolismus   MeSH
• benzamidy farmakologie   MeSH
• difenylamin analogy a deriváty   farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• močovina analogy a deriváty   farmakologie   MeSH
• mutace * MeSH
• myši nahé MeSH
• nádorové buněčné linie MeSH
• nádory plic genetika   metabolismus   prevence a kontrola   MeSH
• proliferace buněk účinky léků   genetika   MeSH
• protoonkogenní proteiny B-raf genetika   metabolismus   MeSH
• pyridony farmakologie   MeSH
• pyrimidinony farmakologie   MeSH
• ras proteiny genetika   metabolismus   MeSH
• RNA interference MeSH
• thiofeny farmakologie   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We performed the genetic analysis of Rasopathy syndromes in patients from Central European by direct sequencing followed by next generation sequencing of genes associated with Rasopathies. All 51 patients harboured the typical features of Rasopathy syndromes. Thirty-five mutations were identified in the examined patients (22 in PTPN11, two in SOS1, one in RIT1, one in SHOC2, two in HRAS, three in BRAF, two in MAP2K1 and two in the NF1 gene). Two of them (p.Gly392Glu in the BRAF gene and p.Gln164Lys in the MAP2K1 gene) were novel with a potentially pathogenic effect on the structure of these proteins. Statistically significant differences in the presence of pulmonary stenosis (63.64% vs. 23.81%, P = 0.013897) and cryptorchidism (76.47% vs. 30%, P = 0.040224) were identified as the result of comparison of the prevalence of phenotypic features in patients with the phenotype of Noonan syndrome and mutation in the PTPN11 gene, with the prevalence of the same features in patients without PTPN11 mutation. Cryptorchidism as a statistically significant feature in our patients with PTPN11 mutation was not reported as significant in other European countries (Germany, Italy and Greece). The majority of mutations were clustered in exons 3 (45.45%), 8 (22.73%), and 13 (22.73%) of the PTPN11 gene.

• MeSH
• běloši genetika   MeSH
• dítě MeSH
• dospělí MeSH
• ektodermální dysplazie genetika   MeSH
• exony MeSH
• faciální stigmatizace MeSH
• fenotyp MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• kojenec MeSH
• kryptorchismus genetika   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutační analýza DNA * MeSH
• neprospívání genetika   MeSH
• Noonanové syndrom genetika   MeSH
• předškolní dítě MeSH
• protein SOS1 genetika   MeSH
• ras proteiny genetika   MeSH
• stenóza pulmonální chlopně genetika   MeSH
• tyrosinfosfatasa nereceptorového typu 11 genetika   MeSH
• vrozené srdeční vady genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH