Journal of Pathology Clinical Research最新文献

{"title":"DNA methylation profile discriminates sporadic giant cell granulomas of the jaws and cherubism from their giant cell-rich histological mimics","authors":"Letícia Martins Guimarães,&nbsp;Daniel Baumhoer,&nbsp;Vanghelita Andrei,&nbsp;Dennis Friedel,&nbsp;Christian Koelsche,&nbsp;Ricardo Santiago Gomez,&nbsp;Andreas von Deimling,&nbsp;Carolina Cavalieri Gomes","doi":"10.1002/cjp2.337","DOIUrl":"10.1002/cjp2.337","url":null,"abstract":"<p>Sporadic giant cell granulomas (GCGs) of the jaws and cherubism-associated giant cell lesions share histopathological features and microscopic diagnosis alone can be challenging. Additionally, GCG can morphologically closely resemble other giant cell-rich lesions, including non-ossifying fibroma (NOF), aneurysmal bone cyst (ABC), giant cell tumour of bone (GCTB), and chondroblastoma. The epigenetic basis of these giant cell-rich tumours is unclear and DNA methylation profiling has been shown to be clinically useful for the diagnosis of other tumour types. Therefore, we aimed to assess the DNA methylation profile of central and peripheral sporadic GCG and cherubism to test whether DNA methylation patterns can help to distinguish them. Additionally, we compared the DNA methylation profile of these lesions with those of other giant cell-rich mimics to investigate if the microscopic similarities extend to the epigenetic level. DNA methylation analysis was performed for central (<i>n</i> = 10) and peripheral (<i>n</i> = 10) GCG, cherubism (<i>n</i> = 6), NOF (<i>n</i> = 10), ABC (<i>n</i> = 16), GCTB (<i>n</i> = 9), and chondroblastoma (<i>n</i> = 10) using the Infinium Human Methylation EPIC Chip. Central and peripheral sporadic GCG and cherubism share a related DNA methylation pattern, with those of peripheral GCG and cherubism appearing slightly distinct, while central GCG shows overlap with both of the former. NOF, ABC, GCTB, and chondroblastoma, on the other hand, have distinct methylation patterns. The global and enhancer-associated CpG DNA methylation values showed a similar distribution pattern among central and peripheral GCG and cherubism, with cherubism showing the lowest and peripheral GCG having the highest median values. By contrast, promoter regions showed a different methylation distribution pattern, with cherubism showing the highest median values. In conclusion, DNA methylation profiling is currently not capable of clearly distinguishing sporadic and cherubism-associated giant cell lesions. Conversely, it could discriminate sporadic GCG of the jaws from their giant cell-rich mimics (NOF, ABC, GCTB, and chondroblastoma).</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/23/51/CJP2-9-464.PMC10556276.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10332289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAD51 as a biomarker for homologous recombination deficiency in high-grade serous ovarian carcinoma: robustness and interobserver variability of the RAD51 test","authors":"Claire JH Kramer,&nbsp;Alba Llop-Guevara,&nbsp;Elisa Yaniz-Galende,&nbsp;Benedetta Pellegrino,&nbsp;Natalja T ter Haar,&nbsp;Andrea Herencia-Ropero,&nbsp;Nicoletta Campanini,&nbsp;Antonino Musolino,&nbsp;Tjalling Bosse,&nbsp;Alexandra Leary,&nbsp;Violeta Serra,&nbsp;Maaike PG Vreeswijk","doi":"10.1002/cjp2.336","DOIUrl":"10.1002/cjp2.336","url":null,"abstract":"<p>The RAD51 test is emerging as a promising biomarker for the assessment of functional homologous recombination deficiency (HRD). Yet, the robustness and reproducibility of the immunofluorescence-based RAD51 test, in different academic laboratories, have not been systematically investigated. Therefore, we tested the performance of the RAD51 assay in formalin-fixed paraffin-embedded (FFPE) high-grade serous ovarian carcinoma (HGSOC) samples in four European laboratories. Here, we confirm that subtle differences in staining procedures result in low variability of RAD51 and γH2AX scores. However, substantial variability in RAD51 scoring was observed in some samples, likely due to complicating technical and biological features, such as high RAD51 signal-to-noise ratio and RAD51 heterogeneity. These results support the need to identify and perform additional quality control steps and/or automating image analysis. Altogether, resolving technical issues should be a priority, as identifying tumours with functional HRD is urgently needed to guide the individual treatment of HGSOC patients. Follow-up studies are needed to define the key tissue quality requirements to assess HRD by RAD51 in FFPE tumour samples, as this test could help in guiding the individual treatment of HGSOC patients.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/64/14/CJP2-9-442.PMC10556259.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10242543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The epigenetic modifier lysine methyltransferase 2C is frequently mutated in gastric remnant carcinoma","authors":"Bo Sun,&nbsp;Haojie Chen,&nbsp;Jiawen Lao,&nbsp;Cong Tan,&nbsp;Yue Zhang,&nbsp;Zhen Shao,&nbsp;Dazhi Xu","doi":"10.1002/cjp2.335","DOIUrl":"10.1002/cjp2.335","url":null,"abstract":"<p>Gastric remnant carcinoma (GRC), which occurs in the stomach after partial gastrectomy, is a rare and aggressive form of gastric adenocarcinoma (GAC). Comprehensive profiling of genomic mutations in GRC could provide the basis for elucidating the origin and characteristics of this cancer. Herein, whole-exome sequencing (WES) was performed on 36 matched tumor–normal samples from patients with GRC and identified recurrent mutations in epigenetic modifiers, notably <i>KMT2C</i>, <i>ARID1A</i>, <i>NSD1</i>, and <i>KMT2D</i>, in 61.11% of cases. Mutational signature analysis revealed a low frequency of microsatellite instability (MSI) in GRC, which was further identified by MSIsensor, MSI-polymerase chain reaction, and immunohistochemistry analysis. Comparative analysis demonstrated that GRC had a distinct mutation spectrum compared to that of GAC in The Cancer Genome Atlas samples, with a significantly higher mutation rate of <i>KMT2C</i>. Targeted deep sequencing (Target-seq) of an additional 25 paired tumor–normal samples verified the high mutation frequency (48%) of <i>KMT2C</i> in GRC. <i>KMT2C</i> mutations correlated with poor overall survival in both WES and Target-seq cohorts and were independent prognosticators in GRC. In addition, <i>KMT2C</i> mutations were positively correlated with favorable outcomes in immune checkpoint inhibitor-treated pan-cancer patients and associated with higher intratumoral CD3⁺, CD8⁺ tumor-infiltrating lymphocyte counts, and PD–L1 expression in GRC samples (<i>p</i> = 0.018, 0.092, 0.047, 0.010, and 0.034, respectively). Our dataset provides a platform for information and knowledge mining of the genomic characteristics of GRC and helps to frame new therapeutic approaches for this disease.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c1/7e/CJP2-9-409.PMC10397379.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9960626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-associated fibroblast expression of glutamine fructose-6-phosphate aminotransferase 2 (GFPT2) is a prognostic marker in gastric cancer","authors":"Shuo Yang,&nbsp;Guoli Li,&nbsp;Xin Yin,&nbsp;Yufei Wang,&nbsp;Xinju Jiang,&nbsp;Xiulan Bian,&nbsp;Tianyi Fang,&nbsp;Shengjie Yin,&nbsp;Lei Zhang,&nbsp;Yingwei Xue","doi":"10.1002/cjp2.333","DOIUrl":"10.1002/cjp2.333","url":null,"abstract":"<p>Glutamine fructose-6-phosphate aminotransferase 2 (GFPT2) is a rate-limiting enzyme in hexosamine biosynthesis involved in the occurrence and progress of many cancers. What role it plays in gastric cancer (GC) is still unclear. In this study, transcriptome sequencing data from the Harbin Medical University (HMU)-GC cohort and The Cancer Genome Atlas (TCGA) dataset were combined with the HMU-TCGA training cohort to analyze the biological function and clinical significance of <i>GFPT2</i>. The correlation of <i>GFPT2</i> with immune cells and stromal cells was analyzed in the GC immune microenvironment through transcriptome sequencing data and a public single-cell sequencing database. In cell lines, GC tissues, and the tissue microarray, GFPT2 protein expression was confirmed by western blotting and immunohistochemistry. The mRNA of <i>GFPT2</i> was highly expressed in the tumor (<i>p</i> &lt; 0.001), and GC cells and tumors expressed high levels of GFPT2 protein. Compared to low expression, high <i>GFPT2</i> mRNA expression was associated with higher levels of tumor invasion, higher pathological stages, and poor prognosis (<i>p</i> = 0.02) in GC patients. In a drug susceptibility analysis, <i>GFPT2</i> mRNA expression was associated with multiple chemotherapeutic drug sensitivity, including docetaxel, paclitaxel, and cisplatin. Gene enrichment analysis found that <i>GFPT2</i> was mainly primarily involved in the extracellular matrix receptor interaction pathway. The ESTIMATE, CIBERSORT, and ssGSEA algorithms showed that <i>GFPT2</i> was associated with immune cell infiltration. In addition, <i>GFPT2</i> was more likely to be expressed within cancer-associated fibroblasts (CAFs), and high levels of <i>GFPT2</i> expression were highly correlated with four CAFs scores (all <i>p</i> &lt; 0.05). Finally, a prognostic model to assess the risk of death in GC patients was constructed based on GFPT2 protein expression and lymph node metastasis rate. In conclusion, GFPT2 plays an essential role in the function of CAFs in GC. It can be used as a biomarker to assess GC prognosis and immune infiltration.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ca/d6/CJP2-9-391.PMC10397376.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9960627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosome-derived ANXA9 functions as an oncogene in breast cancer","authors":"Cuiping Lu,&nbsp;Ying Zhan,&nbsp;Yunshan Jiang,&nbsp;Jianrong Liao,&nbsp;Zidan Qiu","doi":"10.1002/cjp2.334","DOIUrl":"10.1002/cjp2.334","url":null,"abstract":"<p>Breast cancer (BCA) is one of the most prevalent cancers among women. Emerging evidence has revealed that Annexin A-9 (<i>ANXA9</i>) plays a crucial function in the development of some cancers. Notably, <i>ANXA9</i> has been reported to be a new prognostic biomarker for gastric and colorectal cancers. However, its expression and biological function in BCA have not yet been investigated. Using online bioinformatics tools such as TIMER, GEPIA, HPA, and UALCAN, we predicted <i>ANXA9</i> expression and its correlation with the clinicopathological characteristics of BCA patients. RT-qPCR and western blot were utilized to measure <i>ANXA9</i> mRNA and ANXA9 protein expression in BCA patient tissues and cells. BCA-derived exosomes were identified by transmission electron microscopy. Functional assays were employed to evaluate the biological role of <i>ANXA9</i> in BCA cell proliferation, migration, invasion, and apoptosis. A tumor xenograft <i>in vivo</i> model was utilized to assess the role of <i>ANXA9</i> in tumor growth in mice. Bioinformatics and functional screening analysis revealed that <i>ANXA9</i> was highly expressed in BCA patient tissues, with median <i>ANXA9</i> expression 1.5- to 2-fold higher than in normal tissues (<i>p</i> &lt; 0.05). RT-qPCR confirmed that <i>ANXA9</i> expression in BCA tissues was around 1.5-fold higher than the adjacent normal tissues (<i>p</i> &lt; 0.001). <i>ANXA9</i> expression in different subtypes of BCA also showed a difference, and <i>ANXA9</i> was found to be mostly significantly upregulated in luminal BCA relative to normal tissues or other histological subtypes (<i>p</i> &lt; 0.001). Moreover, <i>ANXA9</i> expression was elevated in different races, ages, clinical stages, node metastasis status, and menopause status groups relative to the normal group (<i>p</i> &lt; 0.001). Furthermore, <i>ANXA9</i> was found to be secreted by BCA tissue-derived exosomes and its expression was upregulated 1- to 7-fold in BCA cells treated with exosomes (<i>p</i> &lt; 0.001), while its expression in MCF10A cells was not significantly altered by treatment with exosomes (<i>p</i> &gt; 0.05). <i>ANXA9</i> silencing induced a significant decrease of around 30% in the colony number of BCA cells (<i>p</i> &lt; 0.01). The number of migrated and invaded BCA cells also decreased by around 65 and 68%, respectively, after silencing <i>ANXA9</i> (<i>p</i> &lt; 0.01). Tumor size was significantly reduced (nearly half) in the LV-sh-<i>ANXA9</i> group relative to the LV-NC group in the xenograft model (<i>p</i> &lt; 0.01), suggesting that <i>ANXA9</i> silencing repressed tumor progression in BCA progression <i>in vitro</i> and <i>in vivo</i>. In conclusion, exosome-derived <i>ANXA9</i> functions as an oncogene that facilitates the proliferation, migration, and invasiveness of BCA cells and enhances tumor growth in BCA development, which may provide a new prognostic and therapeutic biomarker for BCA patients.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.334","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9959583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-operative mortality and recurrence patterns in pancreatic cancer according to KRAS mutation and CDKN2A, p53, and SMAD4 expression","authors":"Yohei Masugi,&nbsp;Manabu Takamatsu,&nbsp;Mariko Tanaka,&nbsp;Kensuke Hara,&nbsp;Yosuke Inoue,&nbsp;Tsuyoshi Hamada,&nbsp;Tatsunori Suzuki,&nbsp;Junichi Arita,&nbsp;Yuki Hirose,&nbsp;Yoshikuni Kawaguchi,&nbsp;Yousuke Nakai,&nbsp;Atsushi Oba,&nbsp;Naoki Sasahira,&nbsp;Gaku Shimane,&nbsp;Tsuyoshi Takeda,&nbsp;Keisuke Tateishi,&nbsp;Sho Uemura,&nbsp;Mitsuhiro Fujishiro,&nbsp;Kiyoshi Hasegawa,&nbsp;Minoru Kitago,&nbsp;Yu Takahashi,&nbsp;Tetsuo Ushiku,&nbsp;Kengo Takeuchi,&nbsp;Michiie Sakamoto,&nbsp;for the GTK Pancreatic Cancer Study Group in Japan","doi":"10.1002/cjp2.323","DOIUrl":"10.1002/cjp2.323","url":null,"abstract":"<p>Alterations in <i>KRAS</i>, <i>CDKN2A</i> (<i>p16</i>), <i>TP53</i>, and <i>SMAD4</i> genes have been major drivers of pancreatic carcinogenesis. The clinical course of patients with pancreatic cancer in relation to these driver alterations has not been fully characterised in large populations. We hypothesised that pancreatic carcinomas with different combinations of <i>KRAS</i> mutation and aberrant expression of CDKN2A, p53, and SMAD4 might show distinctive recurrence patterns and post-operative survival outcomes. To test this hypothesis, we utilised a multi-institutional cohort of 1,146 resected pancreatic carcinomas and assessed <i>KRAS</i> mutations by droplet digital polymerase chain reaction and CDKN2A, p53, and SMAD4 expression by immunohistochemistry. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed according to each molecular alteration and the number of altered genes using the Cox regression models. Multivariable competing risks regression analyses were conducted to assess the associations of the number of altered genes with specific patterns of recurrence. Loss of SMAD4 expression was associated with short DFS (multivariable HR, 1.24; 95% CI, 1.09–1.43) and OS times (multivariable HR, 1.27; 95% CI, 1.10–1.46). Compared to cases with 0–2 altered genes, cases with three and four altered genes had multivariable HRs for OS of 1.28 (95% CI, 1.09–1.51) and 1.47 (95% CI, 1.22–1.78), respectively (<i>p</i>_trend &lt; 0.001). Patients with an increasing number of altered genes were more likely to have short DFS time (<i>p</i>_trend = 0.003) and to develop liver metastasis (<i>p</i>_trend = 0.006) rather than recurrence at local or other distant sites. In conclusion, loss of SMAD4 expression and an increasing number of altered genes were associated with unfavourable outcomes in pancreatic cancer patients. This study suggests that the accumulation of the four major driver alterations can confer a high metastatic potential to the liver, thereby impairing post-operative survival among patients with pancreatic cancer.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1b/22/CJP2-9-339.PMC10397380.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9957561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual epigenetic changes in diabetes mellitus-associated pancreatic ductal adenocarcinoma correlate with downregulation of E-cadherin and worsened prognosis","authors":"Yutaro Hara,&nbsp;Hiroki Mizukami,&nbsp;Keisuke Yamazaki,&nbsp;Takahiro Yamada,&nbsp;Akiko Igawa,&nbsp;Yuki Takeuchi,&nbsp;Takanori Sasaki,&nbsp;Hanae Kushibiki,&nbsp;Kotaro Murakami,&nbsp;Kazuhiro Kudoh,&nbsp;Keinosuke Ishido,&nbsp;Kenichi Hakamada","doi":"10.1002/cjp2.326","DOIUrl":"10.1002/cjp2.326","url":null,"abstract":"<p>Diabetes mellitus (DM) is a risk factor for pancreatic ductal adenocarcinoma (PDAC) that promotes the promoter methylation of <i>CDH1</i>. It is still unclear whether DM can exert other epigenetic effects, such as altering microRNA (miR) expression, in PDAC. The expression of miR-100-5p is known to be changed in DM patients and can suppress the expression of E-cadherin. In this study, the correlation between DM status and dual epigenetic changes was evaluated in PDAC specimens from patients who underwent radical surgical resection. A total of 132 consecutive patients with PDAC were clinicopathologically evaluated. E-cadherin and nuclear β-catenin expression was measured using immunohistochemistry. DNA and miRs were extracted from the main tumor site on formalin-fixed paraffin-embedded tissue sections. TaqMan miR assays were applied to assess miR-100-5p expression. Bisulfite modification was conducted on the extracted DNA, which was then subjected to methylation-specific polymerase chain reaction. Immunohistochemistry revealed that decreased E-cadherin expression and increased nuclear β-catenin expression were significantly associated with DM and poor tumor cell differentiation. The presence of long-duration DM (≥3 years)  was a significant factor contributing to <i>CDH1</i> promoter methylation (<i>p</i> &lt; 0.01), while miR-100-5p expression was proportionally correlated with the preoperative HbA1c level (<i>R</i> = 0.34, <i>p</i> &lt; 0.01), but not the duration of DM. The subjects with high miR-100-5p expression and <i>CDH1</i> promoter methylation showed the highest level of vessel invasion and prevalence of tumor size ≥30 mm. PDAC subjects with dual epigenetic changes showed poorer overall survival (OS) than those with a single epigenetic change. miR-100-5p expression ≥4.13 and <i>CDH1</i> promoter methylation independently predicted poor OS and disease-free survival (DFS) in the multivariate analysis. OS and DFS worsened in DM subjects with both HbA1c ≥ 6.5% and DM duration ≥3 years. Thus, DM is associated with two modes of epigenetic change by independent mechanisms and worsens prognosis.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/92/06/CJP2-9-354.PMC10397378.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9947974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KLF2 inhibits colorectal cancer progression and metastasis by inducing ferroptosis via the PI3K/AKT signaling pathway","authors":"Jia Li,&nbsp;Ji Ling Jiang,&nbsp;Yi Mei Chen,&nbsp;Wei Qi Lu","doi":"10.1002/cjp2.325","DOIUrl":"10.1002/cjp2.325","url":null,"abstract":"<p>Krüppel-like factor 2 (KLF2) belongs to the zinc finger family and is thought to be a tumor suppressor gene due to its low expression in various cancer types. However, its functional role and molecular pathway involvement in colorectal cancer (CRC) are not well defined. Herein, we investigated the potential mechanism of KLF2 in CRC cell invasion, migration, and epithelial–mesenchymal transition (EMT). We utilized the TCGA and GEPIA databases to analyze the expression of KLF2 in CRC patients and its correlation with different CRC stages and CRC prognosis. RT-PCR, western blot, and immunohistochemistry assays were used to measure KLF2 expression. Gain-of-function assays were performed to evaluate the role of KLF2 in CRC progression. Moreover, mechanistic experiments were conducted to investigate the molecular mechanism and involved signaling pathways regulated by KLF2. Additionally, we also conducted a xenograft tumor assay to evaluate the role of KLF2 in tumorigenesis. KLF2 expression was low in CRC patient tissues and cell lines, and low expression of KLF2 was associated with poor CRC prognosis. Remarkably, overexpressing KLF2 significantly inhibited the invasion, migration, and EMT capabilities of CRC cells, and tumor growth in xenografts. Mechanistically, KLF2 overexpression induced ferroptosis in CRC cells by regulating glutathione peroxidase 4 expression. Moreover, this KLF2-dependent ferroptosis in CRC cells was mediated by inhibiting the PI3K/AKT signaling pathway that resulted in the suppression of invasion, migration, and EMT of CRC cells. We report for the first time that KLF2 acts as a tumor suppressor in CRC by inducing ferroptosis via inhibiting the PI3K/AKT signaling pathway, thus providing a new direction for CRC prognosis assessment and targeted therapy.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b5/8a/CJP2-9-423.PMC10397377.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10313948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NTRK gene aberrations in triple-negative breast cancer: detection challenges using IHC, FISH, RT-PCR, and NGS","authors":"Federica Zito Marino,&nbsp;Simona Buono,&nbsp;Marco Montella,&nbsp;Rosa Giannatiempo,&nbsp;Francesco Messina,&nbsp;Giovanni Casaretta,&nbsp;Grazia Arpino,&nbsp;Giulia Vita,&nbsp;Francesco Fiorentino,&nbsp;Luigi Insabato,&nbsp;Alessandro Sgambato,&nbsp;Michele Orditura,&nbsp;Renato Franco,&nbsp;Marina Accardo","doi":"10.1002/cjp2.324","DOIUrl":"10.1002/cjp2.324","url":null,"abstract":"<p>Triple-negative breast cancer (TNBC) is usually an aggressive disease with a poor prognosis and limited treatment options. The neurotrophic tyrosine receptor kinase (NTRK) gene fusions are cancer type-agnostic emerging biomarkers approved by the Food and Drug Administration (FDA), USA, for the selection of patients for targeted therapy. The main aim of our study was to investigate the frequency of <i>NTRK</i> aberrations, i.e. fusions, gene copy number gain, and amplification, in a series of TNBC using different methods. A total of 83 TNBCs were analyzed using pan-TRK immunohistochemistry (IHC), fluorescence <i>in situ</i> hybridization (FISH), real-time polymerase chain reaction (RT-PCR), and RNA-based next-generation sequencing (NGS). Of 83 cases, 16 showed pan-TRK positivity although no cases had <i>NTRK</i>-fusions. Indeed, FISH showed four cases carrying an atypical <i>NTRK1</i> pattern consisting of one fusion signal and one/more single green signals, but all cases were negative for fusion by NGS and RT-PCR testing. In addition, FISH analysis showed six cases with <i>NTRK1</i> amplification, one case with <i>NTRK2</i> copy number gain, and five cases with <i>NTRK3</i> copy number gain, all negative for pan-TRK IHC. Our data demonstrate that IHC has a high false-positive rate for the detection of fusions and molecular testing is mandatory; there is no need to perform additional molecular tests in cases negativity for NTRK by IHC. In conclusion, the <i>NTRK</i> genes are not involved in fusions in TNBC, but both copy number gain and amplification are frequent events, suggesting a possible predictive role for other NTRK aberrations.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.324","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9956671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining triple-negative breast cancer with neuroendocrine differentiation (TNBC-NED)","authors":"Sean M Hacking,&nbsp;Evgeny Yakirevich,&nbsp;Yihong Wang","doi":"10.1002/cjp2.318","DOIUrl":"10.1002/cjp2.318","url":null,"abstract":"<p>Primary breast neuroendocrine (NE) neoplasms are uncommon, and definitions harbor controversy. We retrospectively collected 73 triple-negative breast cancers (TNBC) and evaluated NE biomarker expression along with p53 aberrant staining (which correlates with <i>TP53</i> gene mutation) and Rb protein loss by immunohistochemistry. In the study cohort, we found 11 (15%) cases of TNBC with neuroendocrine differentiation (TNBC-NED) showing positivity for one or more NE markers (synaptophysin/chromogranin/insulinoma-associated protein 1 [INSM1]). We also identified one separate small cell neuroendocrine carcinoma. Histologic types for these 11 TNBC-NED cases were as follows: 8 invasive ductal carcinoma (IDC) not otherwise specified (NOS), 2 IDC with apocrine features, 1 IDC with solid papillary features. INSM1 had the highest positivity and was seen in all 11 carcinomas. Seven (64%) cases showed p53 aberrant staining, 6 (55%) had Rb protein loss, while 6 (55%) had p53/Rb co-aberrant staining/protein loss. TNBC-NED was associated with Rb protein loss (<i>p</i> &lt; 0.001), as well as p53/Rb co-aberrant staining/protein loss (<i>p</i> &lt; 0.001). In 61 cases negative for NE markers, 37 (61%) showed p53 aberrant staining, while 5 (8%) had Rb protein loss. We also analyzed genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) PanCancer Atlas of 171 basal/TNBC patients. Transcriptomic analysis revealed mRNA expression of <i>RB1</i> to be correlated negatively with <i>SYN1</i> mRNA expression (<i>p</i> = 0.0400) and <i>INSM1</i> mRNA expression (<i>p</i> = 0.0106) in this cohort. We would like to highlight the importance of these findings. TNBC-NED is currently diagnosed as TNBC, and although it overlaps morphologically with TNBC without NED, the unique p53/Rb signature highlights a genetic overlap with NE carcinomas of the breast.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.318","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9622183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}