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Cancers May 2024AT-rich interaction domain 1A (ARID1A) has been proposed as a new biomarker for predicting response to immune checkpoint inhibitors (ICIs). The predictive value of...
BACKGROUND
AT-rich interaction domain 1A (ARID1A) has been proposed as a new biomarker for predicting response to immune checkpoint inhibitors (ICIs). The predictive value of ARID1A for predicting ICI effectiveness has not been reported for endometrial cancer. Therefore, we investigated whether ARID1A negativity predicts ICI effectiveness for endometrial cancer treatment.
METHODS
We evaluated ARID1A expression, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1/PD-1) by immunostaining endometrial samples from patients with endometrial cancer. Samples in which any of the four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) were determined to be negative via immunostaining were excluded. In the ARID1A-negative group, microsatellite instability (MSI) status was confirmed via MSI analysis.
RESULTS
Of the 102 samples investigated, 25 (24.5%) were ARID1A-negative. CD8 and PD-1 expression did not differ significantly between the ARID1A-negative group and the ARID1A-positive group; however, the ARID1A-negative group showed significantly lower PD-L1 expression. Only three samples (14.2%) in the ARID1A-negative group showed high MSI. Sanger sequencing detected three cases of pathological mutation in the MSH2-binding regions. We also established an ARID1A-knockout human ovarian endometriotic epithelial cell line (HMOsisEC7 ARID1A KO), which remained microsatellite-stable after passage.
CONCLUSION
ARID1A negativity is not suitable as a biomarker for ICI effectiveness in treating endometrial cancer.
PubMed: 38893118
DOI: 10.3390/cancers16111999 -
International Journal of Molecular... Jun 2024Asexual development is the main propagation and transmission mode of and the basis of its pathogenicity. The regulation mechanism of conidiation and the key gene...
Asexual development is the main propagation and transmission mode of and the basis of its pathogenicity. The regulation mechanism of conidiation and the key gene resources for utilization are key links to improving the conidia yield and quality of . Their clarification may promote the industrialization of fungal pesticides. Here, we compared the regulation of morphology, resistance to external stress, virulence, and nutrient utilization capacity between the upstream developmental regulatory gene and the key genes , , and in the central growth and development pathway. The results showed that the Δ and Δ mutants completely lost the capacity to conidiate and that the Δ mutant had seriously reduced conidiation capacity. Although the deletion of did not reduce the conidiation ability as much as deletions of , , and , it significantly reduced the fungal response to external stress, virulence, and nutrient utilization, while the deletion of the three other genes had little effect. Via transcriptome analysis and screening the yeast nuclear system library, we found that the differentially expressed genes in the Δ mutants were concentrated in the signaling pathways of ABC transporters, propionate metabolism, tryptophan metabolism, DNA replication, mismatch repair, and fatty acid metabolism. FluG directly acted on 40 proteins that were involved in various signaling pathways such as metabolism, oxidative stress, and cell homeostasis. The analysis indicated that the regulatory function of was mainly involved in DNA replication, cell homeostasis, fungal growth and metabolism, and the response to external stress. Our results revealed the biological function of in asexual development and the responses to several environmental stresses as well as its influence on the asexual development regulatory network in .
Topics: Beauveria; Gene Expression Regulation, Fungal; Fungal Proteins; Reproduction, Asexual; Spores, Fungal; Virulence; Gene Expression Profiling; Stress, Physiological; Transcriptome
PubMed: 38892450
DOI: 10.3390/ijms25116261 -
International Journal of Molecular... May 2024Endometrial cancer (EC) accounts for 90% of uterine cancer cases. It is considered not only one of the most common gynecological malignancies but also one of the most... (Review)
Review
Endometrial cancer (EC) accounts for 90% of uterine cancer cases. It is considered not only one of the most common gynecological malignancies but also one of the most frequent cancers among women overall. Nowadays, the differentiation of EC subtypes is based on immunohistochemistry and molecular techniques. It is considered that patients' prognosis and the implementation of the appropriate treatment depend on the cancer subtype. Patients with pathogenic variants in have the most favorable outcome, while those with abnormal p53 protein have the poorest. Therefore, in patients with mutation, the de-escalation of postoperative treatment may be considered, and patients with abnormal p53 protein should be subjected to intensive adjuvant therapy. Patients with a DNA mismatch repair (dMMR) deficiency are classified in the intermediate prognosis group as EC patients without a specific molecular profile. Immunotherapy has been recognized as an effective treatment method in patients with advanced or recurrent EC with a mismatch deficiency. Thus, different adjuvant therapy approaches, including targeted therapy and immunotherapy, are being proposed depending on the EC subtype, and international guidelines, such as those published by ESMO and ESGO/ESTRO/ESP, include recommendations for performing the molecular classification of all EC cases. The decision about adjuvant therapy selection has to be based not only on clinical data and histological type and stage of cancer, but, following international recommendations, has to include EC molecular subtyping. This review describes how molecular classification could support more optimal therapeutic management in endometrial cancer patients.
Topics: Humans; Endometrial Neoplasms; Female; Immunotherapy; Mutation; DNA Mismatch Repair; Prognosis; Biomarkers, Tumor
PubMed: 38892080
DOI: 10.3390/ijms25115893 -
International Journal of Molecular... May 2024Tumor recurrence and drug resistance are responsible for poor prognosis in colorectal cancer (CRC). DNA mismatch repair (MMR) deficiency or elevated interleukin-8 (IL-8)...
Tumor recurrence and drug resistance are responsible for poor prognosis in colorectal cancer (CRC). DNA mismatch repair (MMR) deficiency or elevated interleukin-8 (IL-8) levels are characteristics of CRCs, which have been independently correlated with treatment resistance to common therapies. We recently demonstrated significantly impaired therapeutical response and increased IL-8 release of CRC cell lines with reduced expression of MMR protein MLH1 as well as cytoskeletal non-erythrocytic spectrin alpha II (SPTAN1). In the present study, decreased intratumoral MLH1 and SPTAN1 expression in CRCs could be significantly correlated with enhanced serum IL-8. Furthermore, using stably reduced SPTAN1-expressing SW480, SW620 or HT-29 cell lines, the RASmediated RAFMEKERK pathway was analyzed. Here, a close connection between low SPTAN1 expression, increased IL-8 secretion, enhanced extracellular-signal-regulated kinase (ERK) phosphorylation and a mesenchymal phenotype were detected. The inhibition of ERK by U0126 led to a significant reduction in IL-8 secretion, and the combination therapy of U0126 with FOLFOX optimizes the response of corresponding cancer cell lines. Therefore, we hypothesize that the combination therapy of FOLFOX and U0126 may have great potential to improve drug efficacy on this subgroup of CRCs, showing decreased MLH1 and SPTAN1 accompanied with high serum IL-8 in affected patients.
Topics: Humans; Colorectal Neoplasms; Interleukin-8; Fluorouracil; Butadienes; Nitriles; Cell Line, Tumor; Organoplatinum Compounds; Leucovorin; Antineoplastic Combined Chemotherapy Protocols; Female; Male; Extracellular Signal-Regulated MAP Kinases; HT29 Cells; MAP Kinase Signaling System; MutL Protein Homolog 1; Middle Aged; Aged; Gene Expression Regulation, Neoplastic; Phosphorylation
PubMed: 38891846
DOI: 10.3390/ijms25115658 -
Journal of Translational Medicine Jun 2024IDH1-wildtype glioblastoma multiforme (IDHwt-GBM) is a highly heterogeneous and aggressive brain tumour characterised by a dismal prognosis and significant challenges in...
BACKGROUND
IDH1-wildtype glioblastoma multiforme (IDHwt-GBM) is a highly heterogeneous and aggressive brain tumour characterised by a dismal prognosis and significant challenges in accurately predicting patient outcomes. To address these issues and personalise treatment approaches, we aimed to develop and validate robust multiomics molecular subtypes of IDHwt-GBM. Through this, we sought to uncover the distinct molecular signatures underlying these subtypes, paving the way for improved diagnosis and targeted therapy for this challenging disease.
METHODS
To identify stable molecular subtypes among 184 IDHwt-GBM patients from TCGA, we used the consensus clustering method to consolidate the results from ten advanced multiomics clustering approaches based on mRNA, lncRNA, and mutation data. We developed subtype prediction models using the PAM and machine learning algorithms based on mRNA and MRI data for enhanced clinical utility. These models were validated in five independent datasets, and an online interactive system was created. We conducted a comprehensive assessment of the clinical impact, drug treatment response, and molecular associations of the IDHwt-GBM subtypes.
RESULTS
In the TCGA cohort, two molecular subtypes, class 1 and class 2, were identified through multiomics clustering of IDHwt-GBM patients. There was a significant difference in survival between Class 1 and Class 2 patients, with a hazard ratio (HR) of 1.68 [1.15-2.47]. This difference was validated in other datasets (CGGA: HR = 1.75[1.04, 2.94]; CPTAC: HR = 1.79[1.09-2.91]; GALSS: HR = 1.66[1.09-2.54]; UCSF: HR = 1.33[1.00-1.77]; UPENN HR = 1.29[1.04-1.58]). Additionally, class 2 was more sensitive to treatment with radiotherapy combined with temozolomide, and this sensitivity was validated in the GLASS cohort. Correspondingly, class 2 and class 1 exhibited significant differences in mutation patterns, enriched pathways, programmed cell death (PCD), and the tumour immune microenvironment. Class 2 had more mutation signatures associated with defective DNA mismatch repair (P = 0.0021). Enriched pathways of differentially expressed genes in class 1 and class 2 (P-adjust < 0.05) were mainly related to ferroptosis, the PD-1 checkpoint pathway, the JAK-STAT signalling pathway, and other programmed cell death and immune-related pathways. The different cell death modes and immune microenvironments were validated across multiple datasets. Finally, our developed survival prediction model, which integrates molecular subtypes, age, and sex, demonstrated clinical benefits based on the decision curve in the test set. We deployed the molecular subtyping prediction model and survival prediction model online, allowing interactive use and facilitating user convenience.
CONCLUSIONS
Molecular subtypes were identified and verified through multiomics clustering in IDHwt-GBM patients. These subtypes are linked to specific mutation patterns, the immune microenvironment, prognoses, and treatment responses.
Topics: Humans; Cluster Analysis; Glioblastoma; Prognosis; Brain Neoplasms; Isocitrate Dehydrogenase; RNA, Messenger; Magnetic Resonance Imaging; Male; Female; Middle Aged; Mutation; Reproducibility of Results; Cohort Studies; Treatment Outcome; Multiomics
PubMed: 38890658
DOI: 10.1186/s12967-024-05401-6 -
Nature Communications Jun 2024Technologies that generate precise combinatorial genome modifications are well suited to dissect the polygenic basis of complex phenotypes and engineer synthetic...
Technologies that generate precise combinatorial genome modifications are well suited to dissect the polygenic basis of complex phenotypes and engineer synthetic genomes. Genome modifications with engineered nucleases can lead to undesirable repair outcomes through imprecise homology-directed repair, requiring non-cleavable gene editing strategies. Eukaryotic multiplex genome engineering (eMAGE) generates precise combinatorial genome modifications in Saccharomyces cerevisiae without generating DNA breaks or using engineered nucleases. Here, we systematically optimize eMAGE to achieve 90% editing frequency, reduce workflow time, and extend editing distance to 20 kb. We further engineer an inducible dominant negative mismatch repair system, allowing for high-efficiency editing via eMAGE while suppressing the elevated background mutation rate 17-fold resulting from mismatch repair inactivation. We apply these advances to construct a library of cancer-associated mutations in the ligand-binding domains of human estrogen receptor alpha and progesterone receptor to understand their impact on ligand-independent autoactivation. We validate that this yeast model captures autoactivation mutations characterized in human breast cancer models and further leads to the discovery of several previously uncharacterized autoactivating mutations. This work demonstrates the development and optimization of a cleavage-free method of genome editing well suited for applications requiring efficient multiplex editing with minimal background mutations.
Topics: Gene Editing; Saccharomyces cerevisiae; Humans; Mutation; CRISPR-Cas Systems; Estrogen Receptor alpha; Receptors, Progesterone; DNA Mismatch Repair; Breast Neoplasms; Female
PubMed: 38890276
DOI: 10.1038/s41467-024-49365-z -
Cancer Medicine Jun 2024Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to...
BACKGROUND
Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies.
METHODS
In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics.
RESULTS
By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively).
CONCLUSIONS
Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.
Topics: Humans; Male; Female; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Aged; Colorectal Neoplasms; Fluorouracil; Immune Checkpoint Inhibitors; Pilot Projects; Bevacizumab; Antibodies, Monoclonal, Humanized; Leucovorin; DNA Mismatch Repair; Adult; Microsatellite Instability; Oxaliplatin; Neoadjuvant Therapy; Tumor Microenvironment; Organoplatinum Compounds; Programmed Cell Death 1 Receptor; Treatment Outcome
PubMed: 38888366
DOI: 10.1002/cam4.7224 -
Journal of Clinical Pathology Jun 2024Colorectal cancer (CRC) is the third most common malignancy worldwide. Accurate pathological diagnosis and predictive abilities for treatment response and prognosis are...
AIMS
Colorectal cancer (CRC) is the third most common malignancy worldwide. Accurate pathological diagnosis and predictive abilities for treatment response and prognosis are crucial for patients with CRC. This study aims to analyse the expressions of p21 and EGFR in CRC and their relationships with clinicopathological characteristics and prognosis to enhance diagnostic and prognostic evaluations.
METHODS
This study conducted a retrospective analysis of p21 and EGFR expressions in 12 319 Chinese patients with CRC using immunohistochemistry. The relationships between these expressions and clinicopathological characteristics and survival outcomes were explored through statistical and survival analyses.
RESULTS
Differential expressions of p21 and EGFR in CRC were closely related to clinicopathological characteristics and significantly impacted overall survival (OS). p21 expression was associated with the primary tumour site, mucinous subtype, lymphovascular invasion, perineural invasion, circumferential resection margin, T stage, N stage, tumour, node, metastases (TNM) stage, and mismatch repair status. EGFR expression was related to mucinous subtype, tumour differentiation, lymphovascular invasion, perineural invasion, tumour size, T stage, N stage, TNM stage and gene mutation. p21 and EGFR expressions were positively correlated (r=0.11). High p21 expression correlated with favourable OS, whereas high EGFR expression predicted poorer OS. A prognostic nomogram incorporating these biomarkers and clinical variables demonstrated robust predictive power for patient survival rates.
CONCLUSION
p21 and EGFR serve as potential indicators for pathological diagnosis, risk stratification, and predicting treatment efficacy and prognosis in patients with CRC. The study's findings provide valuable references for personalised treatment and prognosis evaluation in clinical practice.
PubMed: 38886043
DOI: 10.1136/jcp-2024-209450 -
ACG Case Reports Journal Jun 2024Therapy-associated polyposis (TAP), an acquired gastrointestinal polyposis in childhood cancer survivors, poses diagnostic challenges resembling hereditary syndromes....
Therapy-associated polyposis (TAP), an acquired gastrointestinal polyposis in childhood cancer survivors, poses diagnostic challenges resembling hereditary syndromes. Four TAP patients were studied, revealing upper gastrointestinal lesions after radiotherapy in 2 patients, managed by endoscopic resection. Two underwent total colectomy; 1 had adenocarcinoma from a polyp. Next-generation sequencing on diseased tissue revealed no alteration in mismatch repair genes with stable microsatellite status; however, there was somatic mutation in APC gene altering Wnt signaling pathway in all 3 precancerous lesions. Integrating endoscopic and surgical interventions is crucial, although ongoing studies aim to elucidate pathophysiology for potential targeted therapies in TAP management.
PubMed: 38883581
DOI: 10.14309/crj.0000000000001379 -
Translational Cancer Research May 2024The nectin adhesion molecule CD112, an important component of tumor progression, belongs to the nectin family. However, a comprehensive evaluation of its clinical...
BACKGROUND
The nectin adhesion molecule CD112, an important component of tumor progression, belongs to the nectin family. However, a comprehensive evaluation of its clinical relevance and mechanism in various cancers is yet to be conducted.
METHODS
This investigation fully examined the relationship between prognosis and CD112 expression. We clarified the function of CD112 in tumor immunity by employing The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. This involved examining its connections to tumor mutation burden (TMB), DNA methylation, tumor immune invasion, mismatch repair (MMR), microsatellite instability (MSI), and common immune checkpoint inhibitors (ICIs). Additionally, the impact of CD112 knockdown on cell function was examined in colorectal cancer (CRC) cell lines.
RESULTS
In the current study, we found malignant tissues express high levels of CD112, which was related to TMB, MMR, MSI, and DNA methylation. Survival analysis indicated that patients with high CD112 expression had an unfavorable prognosis more frequently. In addition, CD112 expression was negatively associated with infiltration levels of CD4 positive (CD4) T cells, CD8 positive (CD8) T cells, and T cells. Western blotting and pathway enrichment analysis showed that CD112 is significantly linked to epithelial-to-mesenchymal transition (EMT). Additionally, CRC cells migrate and proliferate less when CD112 was knocked down. CD112 expression was found to be negatively associated with anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) treatment outcomes in patients.
CONCLUSIONS
CD112 may act as a possible prognostic marker in immune therapy and may stimulate tumor growth by upregulating the EMT pathway.
PubMed: 38881943
DOI: 10.21037/tcr-23-2258