A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to identify novel CRC susceptibility genes, we whole-exome sequenced germline DNA from nine persons with a double primary CRC and a family history of CRC. The detected variants were processed by bioinformatics filtering and prioritization, including STRING protein-protein interaction and pathway analysis. A total of 150 missense, 19 stop-gain, 22 frameshift and 13 canonical splice site variants fulfilled our filtering criteria. The STRING analysis identified 20 DNA repair/cell cycle proteins as the main cluster, related to genes CHEK2, EXO1, FAAP24, FANCI, MCPH1, POLL, PRC1, RECQL, RECQL5, RRM2, SHCBP1, SMC2, XRCC1, in addition to CDK18, ENDOV, ZW10 and the known mismatch repair genes. Another STRING network included extracellular matrix genes and TGFβ signaling genes. In the nine whole-exome sequenced patients, eight harbored at least two candidate DNA repair/cell cycle/TGFβ signaling gene variants. The number of families is too small to provide evidence for individual variants but, considering the known role of DNA repair/cell cycle genes in CRC, the clustering of multiple deleterious variants in the present families suggests that these, perhaps jointly, contributed to CRC development in these families.
- MeSH
- Adult MeSH
- Genetic Predisposition to Disease * MeSH
- Colorectal Neoplasms * genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- DNA Repair genetics MeSH
- Pedigree MeSH
- Exome Sequencing * methods MeSH
- Aged MeSH
- Germ-Line Mutation * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.
- MeSH
- Azoxymethane toxicity MeSH
- Chronic Disease MeSH
- Indoles pharmacology therapeutic use MeSH
- Colitis drug therapy chemically induced metabolism pathology MeSH
- Colorectal Neoplasms * drug therapy metabolism pathology MeSH
- Disease Models, Animal * MeSH
- Molecular Mimicry MeSH
- Mice, Inbred C57BL * MeSH
- Mice MeSH
- Colitis-Associated Neoplasms pathology drug therapy metabolism MeSH
- Dextran Sulfate toxicity MeSH
- Inflammation drug therapy metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Prognostic value of T-cells between primary colorectal cancer (pCRC) and its paired synchronous and metachronous liver metastasis (LM) is underinvestigated and is the subject of the present study. We enrolled into this retrospective cohort study patients, who underwent resection of both pCRC and synchronous LM (N = 55) or metachronous LM (N = 44). After immunohistochemical staining for CD3+, CD8+, and CD45R0+ whole slides were scanned and T-cell densities were quantified using QuPath software in tumor center (TC), inner margin (IM), outer margin (OM), and peritumor zone (PT) of pCRC and LM. High densities of CD8+ T-cells in TC, OM and PT of synchronous LM were associated with longer disease-free survival (DFS). Greater densities of CD3+ T-cells in IM and PT and CD8+ T-cells in IM, OM and PT in synchronous LM over pCRC were associated with longer DFS. Greater densities of CD8+ T-cells in the TC and IM and CD3+ T-cells in the IM of pCRC were found in the metachronous over synchronous group. The first novel finding demonstrated that high density of CD8+ T cells in synchronous LM were associated with favorable outcome. The second finding of high CD8+ cell density in pCRC in metachronous over synchronous CRC may provide a mechanistic basis for the delay of metastatic spread. Both findings could be applied clinically with own reference values.
- MeSH
- CD8-Positive T-Lymphocytes immunology MeSH
- Adult MeSH
- Colorectal Neoplasms * pathology immunology MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasms, Multiple Primary pathology immunology MeSH
- Liver Neoplasms * secondary immunology pathology MeSH
- Disease-Free Survival MeSH
- Prognosis MeSH
- Retrospective Studies MeSH
- Neoplasms, Second Primary pathology MeSH
- Aged MeSH
- T-Lymphocytes immunology pathology MeSH
- Lymphocytes, Tumor-Infiltrating immunology pathology MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure. METHODS: Using resources from CRC consortia, including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score, including 141 variants associated with CRC risk. RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking (RERI = 0.24, 95% confidence interval [CI] = 0.13, 0.36), ever smoking (0.11 [0.05, 0.16]), high body mass index (female 0.09 [0.05, 0.13], male 0.10 [0.05, 0.14]), or high red meat intake (highest versus lowest quartile 0.18 [0.09, 0.27]) was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/nonsteroidal anti-inflammatory drugs use (-0.16 [-0.20, -0.11]) or higher intake of fruit, fiber, or calcium (highest quartile versus lowest quartile -0.12 [-0.18, -0.050]; -0.16 [-0.23, -0.09]; -0.11 [-0.18, -0.05], respectively) than those with average genetic susceptibility. CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.
- MeSH
- Diet MeSH
- Adult MeSH
- Genetic Predisposition to Disease * MeSH
- Body Mass Index MeSH
- Gene-Environment Interaction * MeSH
- Polymorphism, Single Nucleotide MeSH
- Colorectal Neoplasms * genetics epidemiology MeSH
- Smoking adverse effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Logistic Models MeSH
- Alcohol Drinking MeSH
- Risk Factors MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Doporučená léčba první a druhé linie metastazujícího kolorektálního karcinomu (metastatic coiorectai cancer, mCRC) zahrnuje chemoterapii na bázi fluorouracilu, oxaliplatiny, irinotekanu; terapii založenou na antiangiogenní léčbě bevacizumabem s účinkem na vaskulární endoteliální růstový faktor (vascular endothelial growth factor, VEGF) a terapii cílenou na receptor epidermálního růstového faktoru (epidermal growth factor receptor, EGFR) podle mutační stavu RAS a BRAF. Studie SUNLIGHT prokázala ve třetí linii léčby mCRC, že podání trifluridin/tipiracilu v kombinaci s bevacizumabem má významný přínos pro přežití a je nyní doporučeným režimem třetí linie u pacientů s refrakterním mCRC, bez ohledu na mutační stav RAS a předchozí léčbu anti-VEGF. Zvláště u mladších pacientů dlouhodobě v dobrém celkovém stavu je vhodné indikovat třetí nebo i vyšší linii léčby, možnosti systémové léčby jsou však velmi omezené.
The recommended firstand second-line treatment of metastatic coiorectai cancer (mCRC) includes fluorouracii, oxaiipiatin, and irinotecan-based chemotherapy; antiangiogenic therapy based on bevacizumab with an effect on vascular endothelial growth factor (VEGF) receptor and therapy targeting epidermal growth factor receptor (EGFR) according to RAS and BRAF mutational status. The SUNLIGHT study demonstrated in third-iine mCRC that administration of trifluridine/tipiracii in combination with bevacizumab has a significant survival benefit and is now the recommended third-iine regimen for patients with refractory mCRC, regardless of RAS mutational status and prior anti-VEGF therapy. Particularly in younger patients in long-term good general condition, third-line or even higher-line therapy is indicated, but systemic treatment options are very limited.
The intertumoral and intratumoral heterogeneity of colorectal adenocarcinoma (CRC) at the morphologic level is poorly understood. Previously, we identified morphological patterns associated with CRC molecular subtypes and their distinct molecular motifs. Here we aimed to evaluate the heterogeneity of these patterns across CRC. Three pathologists evaluated dominant, secondary, and tertiary morphology on four sections from four different FFPE blocks per tumor in a pilot set of 22 CRCs. An AI-based image analysis tool was trained on these tumors to evaluate the morphologic heterogeneity on an extended set of 161 stage I-IV primary CRCs (n = 644 H&E sections). We found that most tumors had two or three different dominant morphotypes and the complex tubular (CT) morphotype was the most common. The CT morphotype showed no combinatorial preferences. Desmoplastic (DE) morphotype was rarely dominant and rarely combined with other dominant morphotypes. Mucinous (MU) morphotype was mostly combined with solid/trabecular (TB) and papillary (PP) morphotypes. Most tumors showed medium or high heterogeneity, but no associations were found between heterogeneity and clinical parameters. A higher proportion of DE morphotype was associated with higher T-stage, N-stage, distant metastases, AJCC stage, and shorter overall survival (OS) and relapse-free survival (RFS). A higher proportion of MU morphotype was associated with higher grade, right side, and microsatellite instability (MSI). PP morphotype was associated with earlier T- and N-stage, absence of metastases, and improved OS and RFS. CT was linked to left side, lower grade, and better survival in stage I-III patients. MSI tumors showed higher proportions of MU and TB, and lower CT and PP morphotypes. These findings suggest that morphological shifts accompany tumor progression and highlight the need for extensive sampling and AI-based analysis. In conclusion, we observed unexpectedly high intratumoral morphological heterogeneity of CRC and found that it is not heterogeneity per se, but the proportions of morphologies that are associated with clinical outcomes.
- MeSH
- Adenocarcinoma * pathology genetics mortality MeSH
- Adult MeSH
- Colorectal Neoplasms * pathology genetics mortality MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Neoplasm Staging MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Emerging evidence suggests that tumour morphological heterogeneity may influence mutational profiles relevant to therapy response. In this pilot study, we aimed to assess whether mutations identified within specific morphological patterns or at the invasion front correlate with shorter time to progression after anti-EGFR therapy, as compared to whole-tissue analysis. METHODS: We investigated genetic mutations in 142 samples from primary tumours of 39 KRAS wild-type metastatic colorectal cancer (CRC) patients receiving anti-EGFR therapy. Deep next-generation sequencing was performed on whole-tumour sections and six morphology-defined tumour regions. RESULTS: Mutations in genes linked to anti-EGFR therapy response (KRAS, BRAF, NRAS, PTEN and PI3KCA) were found uniquely in the non-responder group, with substantial variability across morphological sub-regions. BRAF mutations were aligned with serrated and mucinous morphologies, while KRAS mutations (p.Lys147Glu and p.Ala146Thr) were associated with mucinous and desmoplastic morphologies. In all cases, the cumulative mutational profile from sub-regions provided more details than that of the whole-tumour profile. CONCLUSION: Our findings highlight that comprehensive analysis, considering morphological heterogeneity, is crucial for personalised CRC treatment strategies.
- MeSH
- Drug Resistance, Neoplasm * genetics MeSH
- Adult MeSH
- ErbB Receptors antagonists & inhibitors MeSH
- PTEN Phosphohydrolase genetics MeSH
- GTP Phosphohydrolases genetics MeSH
- Protein Kinase Inhibitors * therapeutic use MeSH
- Colorectal Neoplasms * genetics drug therapy pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Mutation * MeSH
- DNA Mutational Analysis MeSH
- Pilot Projects MeSH
- Antineoplastic Agents * therapeutic use MeSH
- Proto-Oncogene Proteins B-raf genetics MeSH
- Proto-Oncogene Proteins p21(ras) genetics MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- High-Throughput Nucleotide Sequencing MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Gastrointestinal Neoplasms * pathology therapy MeSH
- Carcinoma, Hepatocellular pathology therapy MeSH
- Antibodies, Monoclonal, Humanized administration & dosage therapeutic use MeSH
- Clinical Studies as Topic MeSH
- Colorectal Neoplasms genetics pathology therapy MeSH
- Humans MeSH
- Esophageal Neoplasms pathology therapy MeSH
- Pancreatic Neoplasms genetics pathology therapy MeSH
- Stomach Neoplasms genetics pathology therapy MeSH
- Antineoplastic Agents, Immunological administration & dosage adverse effects therapeutic use MeSH
- Antineoplastic Agents administration & dosage adverse effects therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols administration & dosage adverse effects therapeutic use MeSH
- Antineoplastic Protocols MeSH
- Check Tag
- Humans MeSH
- Publication type
- News MeSH
Fruchintinib je perorální inhibitor tyrosinkináz VEGFR-1, -2 a -3, který je registrován pro léčbu pacientů s refrakterním metastatickým kolorektálním karcinomem (mCRC). Lék představuje důležitou alternativu k dostupným terapiím ve 3. a 4. linii léčby. Podkladem pro evropskou registraci fruchintinibu byly výsledky studie FRESCO-2. V této mezinárodní randomizované dvojitě zaslepené placebem kontrolované studii III. fáze dosáhl medián celkového přežití 7,4 měsíce ve skupině s fruchintinibem oproti 4,8 měsíce v placebové skupině. Fruchintinib je novou, relativně netoxickou možností léčby u předléčených nemocných s mCRC.
Fruquintinib is an oral inhibitor of VEGFR-1, -2 and -3 tyrosine kinases and is registered for the treatment of patients with refractory metastatic colorectal cancer (mCRC). The drug represents an important alternative to available therapies in the 3rd and 4th line of treatment. The basis for the European registration of fruquintinib was the FRESCO-2 study. In this international randomized, double- -blind, placebo-controlled phase III study, the median overall survival was 7.4 months in the fruquintinib group compared to 4.8 months in the placebo group. Fruquintinib is a new, relatively non-toxic treatment option for previously treated patients with mCRC.
- Keywords
- fruchintinib,
- MeSH
- Benzofurans MeSH
- Quinazolines MeSH
- Tyrosine Kinase Inhibitors immunology therapeutic use MeSH
- Clinical Studies as Topic MeSH
- Colorectal Neoplasms * diagnosis drug therapy pathology MeSH
- Humans MeSH
- Antineoplastic Agents pharmacokinetics pharmacology therapeutic use MeSH
- Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors MeSH
- Vascular Endothelial Growth Factors MeSH
- Check Tag
- Humans MeSH
