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Cancer Control : Journal of the Moffitt... 2024The present study aimed to evaluate the frequencies of , and mutations and their possible associations with clinicopathological features in 249 Moroccan patients with...
OBJECTIVES
The present study aimed to evaluate the frequencies of , and mutations and their possible associations with clinicopathological features in 249 Moroccan patients with colorectal cancer (CRC).
METHODS
A retrospective investigation of a cohort of formalin-fixed paraffin-embedded tissues of 249 patients with CRC was screened for // mutations using Idylla™ technology and pyrosequencing.
RESULTS
, and mutations were revealed in 46.6% (116/249), 5.6% (14/249), and 2.4% (6/249) of patients. exon 2 mutations were identified in 87.9% of patients (102/116). G12D and G12 C were the most frequent, at 32.8% and 12.93%, respectively. Among the patients with exon 2 wild-type (wt), 27.6% (32/116) harbored additional mutations. Concurrent mutations were identified in 9.5% (11/116); including six in codon 146 (A146P/T/V), three in codon 61 (Q61H/L/R), one in codon 12 (G12 A and Q61H), and one in codon 13 (G13D and Q61 L). Among the exon 2 wt patients, 64.3% (9/14) harbored additional mutations. Concurrent mutations were identified in 28.6% (4/14) of -mutant patients. Since 3.2% wt were identified with mutations, concomitant and mutations were identified in 2.4% (6/249) of patients. mutations were higher in the >50-year-old age-group ( = .031), and the tumor location was revealed to be significantly associated with mutations ( = .028) predominantly in left colon (27.5%) and colon (42.2%) locations. mutations were most prevalent in the left colon (42.8%) and in well-differentiated tumors (64.2%).
CONCLUSION
Detection of mutations, particularly the G12 C subtype, may be significant for patients with CRC and has possible therapeutic implications. However, rare concomitant mutations in CRC patients suggest that each individual may present distinct therapeutic responses. testing alongside the identification of other affected genes in the same patient will make the treatments even more personalized by contributing more accurately to the clinical decision process. Overall, early diagnosis using novel molecular techniques may improve the management of CRC by providing the most efficient therapies for Moroccan patients.
Topics: Humans; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Male; Female; Proto-Oncogene Proteins p21(ras); Membrane Proteins; Middle Aged; GTP Phosphohydrolases; Morocco; Mutation; Retrospective Studies; Aged; Adult; Aged, 80 and over; DNA Mutational Analysis
PubMed: 38875469
DOI: 10.1177/10732748241262179 -
Global Medical Genetics Jun 2024Anaplastic lymphoma kinase ( ) fusion events account for 3 to 7% of genetic alterations in patients with nonsmall cell lung cancer (NSCLC). This study aimed to...
Anaplastic lymphoma kinase ( ) fusion events account for 3 to 7% of genetic alterations in patients with nonsmall cell lung cancer (NSCLC). This study aimed to explore the landscape of fusion-positive and fusion-negative in a large cohort of NSCLC patients. The formalin-fixed paraffin-embedded specimens of NSCLC patients who underwent next-generation sequencing from 2020 to 2023 in Yinfeng Gene Technology Co., Ltd. Clinical laboratory were included in this study. In the current study, a total of 180 (3.20%) patients tested positive for fusions in 5,622 NSCLC samples. Within the -positive cohort, a total of 228 fusions were identified. Furthermore, five novel fusion partners, including , , , , and were identified. In cases with fusion-positive, alterations were the most prevalent (26.3%), followed by (8.4%), epidermal growth factor receptor ( , 5.6%), and (5.6%). By contrast, alterations were most prevalent (51%) in patients with fusion-negative NSCLC, followed by (42.7%), (11.6%), and (11.3%). A total of 10 cases where fusion co-occurred with mutations were also identified. Notably, the fusion positivity rate was higher in younger patients ( < 0.0001) and in female patients ( = 0.0429). Additionally, positive test results were more prevalent in patients with high programmed death-ligand 1 expression, especially when applying a 50% cutoff. Collectively, these findings offer valuable genomic insights that could inform the personalized clinical care of patients with NSCLC harboring fusions within the context of precision medicine.
PubMed: 38873557
DOI: 10.1055/s-0044-1787301 -
Scientific Reports Jun 2024The detection of copy number variations (CNVs) and somatic mutations in cancer is important for the selection of specific drugs for patients with cancer. In cancers with...
The detection of copy number variations (CNVs) and somatic mutations in cancer is important for the selection of specific drugs for patients with cancer. In cancers with sporadic tumor cells, low tumor content prevents the accurate detection of somatic alterations using targeted sequencing. To efficiently identify CNVs, we performed tumor cell enrichment using tissue suspensions of formalin-fixed paraffin-embedded (FFPE) tissue sections with low tumor cell content. Tumor-enriched and residual fractions were separated from FFPE tissue suspensions of intestinal and diffuse-type gastric cancers containing sporadic tumor cells, and targeted sequencing was performed on 225 cancer-related genes. Sequencing of a targeted panel of cancer-related genes using tumor-enriched fractions increased the number of detectable CNVs and the copy number of amplified genes. Furthermore, CNV analysis using the normal cell-enriched residual fraction as a reference for CNV scoring allowed targeted sequencing to detect CNV characteristics of diffuse-type gastric cancer with low tumor content. Our approach improves the CNV detection rate in targeted sequencing with tumor enrichment and the accuracy of CNV detection in archival samples without paired blood.
Topics: Humans; Stomach Neoplasms; DNA Copy Number Variations; Paraffin Embedding; Male; Female; High-Throughput Nucleotide Sequencing; Aged; Mutation
PubMed: 38871991
DOI: 10.1038/s41598-024-64541-3 -
Oral Surgery, Oral Medicine, Oral... Mar 2024This study aimed to analyze the clinicoradiologic features and Ki-67 proliferation indices between the histopathologic variants of ameloblastomas (ABs) for possible...
OBJECTIVES
This study aimed to analyze the clinicoradiologic features and Ki-67 proliferation indices between the histopathologic variants of ameloblastomas (ABs) for possible associations.
STUDY DESIGN
The diagnosis and histopathologic variant were confirmed for all cases by experienced Oral and Maxillofacial Pathologists. Immunohistochemistry for Ki-67 was performed on the most representative formalin-fixed paraffin-embedded tissue block. Demographic, clinical data and radiologic features were analyzed from patient records and available radiographic examinations. The investigators were blinded to the histopathologic variant and proliferation index when the clinicoradiologic features were assessed.
RESULTS
The current study included 116 cases of AB in the final sample. The indolent behavior of the unicystic variant was supported by their low proliferation index and slow growth paired with low frequencies of cortical destruction, loss of teeth, root resorption, and encroachment on anatomical structures. In contrast, the comparatively high proliferation index of the plexiform variant correlated with their fast growth and pain. Furthermore, high radiologic frequencies of cortical destruction, loss of teeth, and encroachment of surrounding anatomical structures supported their more aggressive clinical course.
CONCLUSION
Statistically significant differences were noted between certain variants and Ki-67, location, borders, locularity, and cortical destruction, providing better insight into their biological behavior.
PubMed: 38871622
DOI: 10.1016/j.oooo.2024.03.007 -
Croatian Medical Journal Jun 2024To determine variations in allele and genotype frequencies between keratoacanthoma (KA) and common warts (CW), compared with the control group, in three single...
AIM
To determine variations in allele and genotype frequencies between keratoacanthoma (KA) and common warts (CW), compared with the control group, in three single nucleotide polymorphisms (SNPs) within the TLR2, TLR3, and TLR9 genes.
METHODS
This case-control study involved samples from 161 patients with KA, 152 patients with CW, and 469 controls. DNA was isolated from formalin-fixed paraffin-embedded tissue sections. Three SNPs - rs4696480 in TLR2, rs7657186 in TLR9, and rs35213 in TLR3 - were genotyped with TaqMan Genotyping Assays on the 7500 Real-Time PCR System.
RESULTS
TLR2 rs4696480 and TLR3 rs7657186 were significantly overrepresented in KA and CW compared with controls (P<0.001). The association was stronger for CW than for KA, as evidenced by higher frequencies of the A allele and AA genotype for rs4696480. Both KA and CW patients had higher frequencies of the G allele and GG genotype for rs7657186 than controls. rs7657186 was moderately associated with KA and CW, with the G allele and GG genotype being more prevalent in CW cases, where no AA homozygotes were found.
CONCLUSION
Genetic variants in TLR2 (rs4696480) and TLR3 (rs7657186) genes may affect KA and CW development, influencing immune responses and susceptibility to these skin lesions. Further research is required to elucidate TLR expression patterns and their role in KA development.
Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Young Adult; Alleles; Case-Control Studies; Gene Frequency; Genetic Predisposition to Disease; Genotype; Keratoacanthoma; Polymorphism, Single Nucleotide; Toll-Like Receptor 2; Toll-Like Receptor 3; Warts
PubMed: 38868969
DOI: 10.3325/cmj.2024.65.232 -
Scientific Reports Jun 2024Zinc finger MIZ-type containing 1 (ZMIZ1) is a transcriptional coactivator related to the protein inhibitors of activated STATs (PIAS) family. Mounting evidence suggests...
Zinc finger MIZ-type containing 1 (ZMIZ1) is a transcriptional coactivator related to the protein inhibitors of activated STATs (PIAS) family. Mounting evidence suggests that ZMIZ1 plays a crucial role in the occurrence and development of cancers. The function of ZMIZ1 in tongue squamous cell carcinoma (TSCC) and the mechanisms underpinning its role in this disease have not been fully clarified. We performed qualitative ZMIZ1 protein expression analyses using immunohistochemistry in 20 patient-derived, paraffin-embedded TSCC tissue sections. We used RNAi to knock down ZMIZ1 expression in the CAL-27 TSCC cell line and quantified the impact of ZMIZ1 knock down on proliferation, migration and apoptosis via CCK-8, scratch assay and flow cytometry, respectively. We used qRT-PCR and western blotting to investigate the role of ZMIZ1 in this cell line. Finally, we established a model of lung metastasis in nude mice to replicate the in vitro results. ZMIZ1 protein was significantly more abundant in TSCC case tissue samples. ZMIZ1 knockdown reduced the invasion and metastases of TSCC tumor cells and promoted apoptosis. ZMIZ1 knockdown was associated with the down-regulation of Notch signaling pathway related factors Jagged1 and Notch1, and invasion and metastasis related factors MKP-1, SSBP2 and MMP7 in vitro and in vivo, at the mRNA level. In vitro and in vivo data suggest that knock down of ZMIZ1 may inhibit TSCC invasion and metastasis by modulating Notch signaling. ZMIZ1 inhibition may therefore represent a new therapeutic target for TSCC.
Topics: Animals; Female; Humans; Male; Mice; Middle Aged; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Jagged-1 Protein; Lung Neoplasms; Mice, Nude; Receptor, Notch1; Signal Transduction; Tongue Neoplasms; Transcription Factors; Xenograft Model Antitumor Assays
PubMed: 38866828
DOI: 10.1038/s41598-024-59882-y -
Indian Journal of Pathology &... Jun 2024Rspondin 1 (Rspo1), a protein family member featuring secreted furin-like domains, plays a pivotal role in cancer development and exhibits a positive correlation with...
CONTEXT
Rspondin 1 (Rspo1), a protein family member featuring secreted furin-like domains, plays a pivotal role in cancer development and exhibits a positive correlation with tumor progression. However, its expression in esophageal squamous cell carcinoma (ESCC) is still unknown.
AIMS
Here, we assessed the correlation between Rspo1 and clinicopathological features of ESCC patients, and further investigated the potential role of Rspo1 in ESCC development and clinical outcomes.
SETTINGS AND DESIGN
This was a pilot study.
MATERIALS AND METHODS
A total of 112 paraffin-embedded tumor samples from patients with ESCC, including 68 matched adjacent normal tissues, were collected post-surgery. Subsequently, tissue microarray (TMA) and immunohistochemistry (IHC) techniques were employed to assess the protein levels of Rspo1.
STATISTICAL ANALYSIS
All statistical analyses were performed with SPSS 20.0 (SPSS, Inc., Chicago, IL).
RESULTS
We found that Rspo1 expression was significantly higher in ESCC than in adjacent normal tissues (P < 0.0001). Moreover, Rspo1 was highly expressed in ESCC tumor specimens and showed a significant correlation with the T classification of ESCC (P < 0.05). Additionally, our findings indicate a positive relationship between Rspo1 and survival time in ESCC. Patients exhibiting moderate to high levels of Rspo1 expression demonstrated superior survival outcomes compared to those with low expression (P = 0.0002).
CONCLUSIONS
Our investigation has demonstrated that Rspo1 is upregulated in ESCC and exhibits a positive correlation with disease progression. Furthermore, we have observed a significant association between Rspo1 overexpression and improved patient survival rates, indicating its potential as a prognostic marker and therapeutic target for ESCC treatment.
PubMed: 38864442
DOI: 10.4103/ijpm.ijpm_452_23 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Jun 2024To investigate the characteristics of the CD8 T cells infiltration from the 4 subtypes in medulloblastoma (MB), to analyze the relationship between CD8 T cells...
OBJECTIVE
To investigate the characteristics of the CD8 T cells infiltration from the 4 subtypes in medulloblastoma (MB), to analyze the relationship between CD8 T cells infiltration and prognosis, to study the function of C-X-C motif chemokine ligand 11 (CXCL11) and its receptor in CD8 T cells infiltration into tumors and to explore the potential mechanism, and to provide the necessary clinicopathological basis for exploring the immunotherapy of MB.
METHODS
In the study, 48 clinical MB samples (12 cases in each of 4 subtypes) were selected from the multiple medical center from 2012 to 2019. The transcriptomics analysis for the tumor of 48 clinical samples was conducted on the NanoString PanCancer IO360 Panel (NanoString Technologies). Immunohistochemistry (IHC) staining of formalin-fixed, paraffin-embedded sections from MB was carried out using CD8 primary antibody to analyze diffe-rential quantities of CD8 T cells in the MB four subtypes. Through bioinformatics analysis, the relationship between CD8T cells infiltration and prognosis of the patients and the expression differences of various chemokines in the different subtypes of MB were investigated. The expression of CXCR3 receptor on the surface of CD8T cells in MB was verified by double immunofluorescence staining, and the underlying molecular mechanism of CD8T cells infiltration into the tumor was explored.
RESULTS
The characteristic index of CD8T cells in the WNT subtype of MB was relatively high, suggesting that the number of CD8T cells in the WNT subtype was significantly higher than that in the other three subtypes, which was confirmed by CD8 immunohistochemical staining and Gene Expression Omnibus (GEO) database analysis by using R2 online data analysis platform. And the increase of CD8T cells infiltration was positively correlated with the patient survival. The expression level of CXCL11 in the WNT subtype MB was significantly higher than that of the other three subtypes. Immunofluorescence staining showed the presence of CXCL11 receptor, CXCR3, on the surface of CD8T cells, suggesting that the CD8T cells might be attracted to the MB microenvironment by CXCL11 through CXCR3.
CONCLUSION
The CD8T cells infiltrate more in the WNT subtype MB than other subtypes. The mechanism may be related to the activation of CXCL11-CXCR3 chemokine system, and the patients with more infiltration of CD8T cells in tumor have better prognosis. This finding may provide the necessary clinicopathological basis for the regulatory mechanism of CD8T cells infiltration in MB, and give a new potential therapeutic target for the future immunotherapy of MB.
Topics: Humans; CD8-Positive T-Lymphocytes; Medulloblastoma; Receptors, CXCR3; Chemokine CXCL11; Prognosis; Lymphocytes, Tumor-Infiltrating; Cerebellar Neoplasms; Male; Female
PubMed: 38864138
DOI: 10.19723/j.issn.1671-167X.2024.03.019 -
BMC Cancer Jun 2024Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression caused by erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (AMP) by...
BACKGROUND
Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression caused by erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (AMP) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is essential for treating unresectable metastatic gastric cancer (GC). A targeted tumour sequencing test enables comprehensive assessment of alterations in cancer-related genes, including ERBB2. This study aimed to evaluate the concordance between the targeted tumour sequencing test and IHC/FISH for detecting HER2-positive GC and to clarify the significance of ERBB2 AMP and concomitant genetic alterations in HER2 downstream pathways (DPs) in anti-HER2 therapy for unresectable metastatic GC patients.
METHODS
ERBB2 copy number alteration (CNA) was examined via a targeted tumour sequencing test in 152 formalin-fixed paraffin-embedded (FFPE) GC tissues. ERBB2 CNA was compared to HER2 status evaluated by IHC/FISH in FFPE block sections, which were identical to those subjected to the targeted tumour sequencing test. Treatment outcomes of anti-HER2 therapy in 11 patients with unresectable metastatic GC was evaluated.
RESULTS
ERBB2 AMP (≥ 2.5-fold change) was detected by the targeted tumour sequencing test in 15 patients (9.9%), and HER2 positivity (IHC 3 + or IHC 2+/FISH positive) was detected in 21 patients (13.8%). The overall percent agreement, positive percent agreement, negative percent agreement and Cohen's kappa between ERBB2 CNA and HER2 status were 94.7%, 66.7%, 99.2% and 0.75, respectively. Progression-free survival for trastuzumab therapy in patients with ERBB2 AMP was significantly longer than that in patients with no ERBB2 AMP detected by the targeted tumour sequencing test (median 14 months vs. 4 months, P = 0.007). Treatment response to trastuzumab therapy was reduced in patients with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs. One patient with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs achieved a durable response to trastuzumab deruxtecan as fourth-line therapy.
CONCLUSIONS
A targeted tumour sequencing test is a reliable modality for identifying HER2-positive GC. ERBB2 AMP and concomitant genetic alterations detected through the targeted tumour sequencing test are potential indicators of treatment response to trastuzumab therapy. The targeted tumour sequencing test has emerged as a plausible candidate for companion diagnostics to determine indications for anti-HER2 therapy in the era of precision medicine for GC.
Topics: Humans; Stomach Neoplasms; Receptor, ErbB-2; Female; Male; Gene Amplification; Aged; Middle Aged; In Situ Hybridization, Fluorescence; Adult; Aged, 80 and over; Immunohistochemistry; Trastuzumab; DNA Copy Number Variations; Biomarkers, Tumor
PubMed: 38862927
DOI: 10.1186/s12885-024-12482-5 -
Scientific Reports Jun 2024The tumor microenvironment (TME) comprises immune-infiltrating cells that are closely linked to tumor development. By screening and analyzing genes associated with...
The tumor microenvironment (TME) comprises immune-infiltrating cells that are closely linked to tumor development. By screening and analyzing genes associated with tumor-infiltrating M0 cells, we developed a risk model to provide therapeutic and prognostic guidance in clear cell renal cell carcinoma (ccRCC). First, the infiltration abundance of each immune cell type and its correlation with patient prognosis were analyzed. After assessing the potential link between the depth of immune cell infiltration and prognosis, we screened the infiltrating M0 cells to establish a risk model centered on three key genes (TMEN174, LRRC19, and SAA1). The correlation analysis indicated a positive correlation between the risk score and various stages of the tumor immune cycle, including B-cell recruitment. Furthermore, the risk score was positively correlated with CD8 expression and several popular immune checkpoints (ICs) (TIGIT, CTLA4, CD274, LAG3, and PDCD1). Additionally, the high-risk group (HRG) had higher scores for tumor immune dysfunction and exclusion (TIDE) and exclusion than the low-risk group (LRG). Importantly, the risk score was negatively correlated with the immunotherapy-related pathway enrichment scores, and the LRG showed a greater therapeutic benefit than the HRG. Differences in sensitivity to targeted drugs between the HRG and LRG were analyzed. For commonly used targeted drugs in RCC, including axitinib, pazopanib, temsirolimus, and sunitinib, LRG had lower IC50 values, indicating increased sensitivity. Finally, immunohistochemistry results of 66 paraffin-embedded specimens indicated that SAA1 was strongly expressed in the tumor samples and was associated with tumor metastasis, stage, and grade. SAA1 was found to have a significant pro-tumorigenic effect by experimental validation. In summary, these data confirmed that tumor-infiltrating M0 cells play a key role in the prognosis and treatment of patients with ccRCC. This discovery offers new insights and directions for the prognostic prediction and treatment of ccRCC.
Topics: Humans; Carcinoma, Renal Cell; Prognosis; Tumor Microenvironment; Kidney Neoplasms; Lymphocytes, Tumor-Infiltrating; Female; Male; Risk Assessment; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Middle Aged; Immunotherapy; Sulfonamides
PubMed: 38862642
DOI: 10.1038/s41598-024-64207-0