Journal of Pathology Clinical Research最新文献

{"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":"9 5","pages":"423-435"},"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":"9 5","pages":"367-377"},"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":"9 4","pages":"313-321"},"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}

{"title":"Cell-by-cell quantification of the androgen receptor in benign and malignant prostate leads to a better understanding of changes linked to cancer initiation and progression","authors":"Seta Derderian,&nbsp;Tarik Benidir,&nbsp;Eleonora Scarlata,&nbsp;Turki Altaylouni,&nbsp;Lucie Hamel,&nbsp;Fatima Zahra Zouanat,&nbsp;Fadi Brimo,&nbsp;Armen Aprikian,&nbsp;Simone Chevalier","doi":"10.1002/cjp2.319","DOIUrl":"10.1002/cjp2.319","url":null,"abstract":"<p>The androgen receptor (AR) plays a crucial role in the development and homeostasis of the prostate and is a key therapeutic target in prostate cancer (PCa). The gold standard therapy for advanced PCa is androgen deprivation therapy (ADT), which targets androgen production and AR signaling. However, resistance to ADT develops via AR-dependent and AR-independent mechanisms. As reports on AR expression patterns in PCa have been conflicting, we performed cell-by-cell AR quantification by immunohistochemistry in the benign and malignant prostate to monitor changes with disease development, progression, and hormonal treatment. Prostates from radical prostatectomy (RP) cases, both hormone-naïve and hormone-treated, prostate tissues from patients on palliative ADT, and bone metastases were included. In the normal prostate, AR is expressed in &gt;99% of luminal cells, 51% of basal cells, and 61% of fibroblasts. An increase in the percentage of AR negative (%AR−) cancer cells along with a gradual loss of fibroblastic AR were observed with increasing Gleason grade and hormonal treatment. This was accompanied by a parallel increase in staining intensity of AR positive (AR+) cells under ADT. Staining AR with N- and C-terminal antibodies yielded similar results. The combination of %AR− cancer cells, %AR− fibroblasts, and AR intensity score led to the definition of an AR index, which was predictive of biochemical recurrence in the RP cohort and further stratified patients of intermediate risk. Lastly, androgen receptor variant 7 (ARV7)+ cells and AR− cells expressing neuroendocrine and stem markers were interspersed among a majority of AR+ cells in ADT cases. Altogether, the comprehensive quantification of AR expression in the prostate reveals concomitant changes in tumor cell subtypes and fibroblasts, emphasizing the significance of AR− cells with disease progression and palliative ADT.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 4","pages":"285-301"},"PeriodicalIF":4.1,"publicationDate":"2023-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/91/88/CJP2-9-285.PMC10240153.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9997095","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":"Explainability and causability in digital pathology","authors":"Markus Plass,&nbsp;Michaela Kargl,&nbsp;Tim-Rasmus Kiehl,&nbsp;Peter Regitnig,&nbsp;Christian Geißler,&nbsp;Theodore Evans,&nbsp;Norman Zerbe,&nbsp;Rita Carvalho,&nbsp;Andreas Holzinger,&nbsp;Heimo Müller","doi":"10.1002/cjp2.322","DOIUrl":"10.1002/cjp2.322","url":null,"abstract":"<p>The current move towards digital pathology enables pathologists to use artificial intelligence (AI)-based computer programmes for the advanced analysis of whole slide images. However, currently, the best-performing AI algorithms for image analysis are deemed black boxes since it remains – even to their developers – often unclear why the algorithm delivered a particular result. Especially in medicine, a better understanding of algorithmic decisions is essential to avoid mistakes and adverse effects on patients. This review article aims to provide medical experts with insights on the issue of explainability in digital pathology. A short introduction to the relevant underlying core concepts of machine learning shall nurture the reader's understanding of why explainability is a specific issue in this field. Addressing this issue of explainability, the rapidly evolving research field of explainable AI (XAI) has developed many techniques and methods to make black-box machine-learning systems more transparent. These XAI methods are a first step towards making black-box AI systems understandable by humans. However, we argue that an explanation interface must complement these explainable models to make their results useful to human stakeholders and achieve a high level of causability, i.e. a high level of causal understanding by the user. This is especially relevant in the medical field since explainability and causability play a crucial role also for compliance with regulatory requirements. We conclude by promoting the need for novel user interfaces for AI applications in pathology, which enable contextual understanding and allow the medical expert to ask interactive ‘what-if’-questions. In pathology, such user interfaces will not only be important to achieve a high level of causability. They will also be crucial for keeping the human-in-the-loop and bringing medical experts' experience and conceptual knowledge to AI processes.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 4","pages":"251-260"},"PeriodicalIF":4.1,"publicationDate":"2023-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.322","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9622160","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":"Altered cytoplasmic and nuclear ADP-ribosylation levels analyzed with an improved ADP-ribose binder are a prognostic factor in renal cell carcinoma","authors":"Peter Schraml,&nbsp;Fabio Aimi,&nbsp;Martin Zoche,&nbsp;Domingo Aguilera-Garcia,&nbsp;Fabian Arnold,&nbsp;Holger Moch,&nbsp;Michael O Hottiger","doi":"10.1002/cjp2.320","DOIUrl":"10.1002/cjp2.320","url":null,"abstract":"<p>ADP-ribosylation (ADPR) of proteins is catalyzed by ADP-ribosyltransferases, which are targeted by inhibitors (i.e. poly(ADP-ribose) polymerase inhibitors [PARPi]). Although renal cell carcinoma (RCC) cells are sensitive <i>in vitro</i> to PARPi, studies on the association between ADPR levels and somatic loss of function mutations in DNA damage repair genes are currently missing. Here we observed, in two clear cell RCC (ccRCC) patient cohorts (<i>n</i> = 257 and <i>n</i> = 241) stained with an engineered ADP-ribose binding macrodomain (eAf1521), that decreased cytoplasmic ADPR (cyADPR) levels significantly correlated with late tumor stage, high-ISUP (the International Society of Urological Pathology) grade, presence of necrosis, dense lymphocyte infiltration, and worse patient survival (<i>p</i> &lt; 0.01 each). cyADPR proved to be an independent prognostic factor (<i>p</i> = 0.001). Comparably, absence of nuclear ADPR staining in ccRCC correlated with absence of PARP1 staining (<i>p</i> &lt; 0.01) and worse patient outcome (<i>p</i> &lt; 0.05). In papillary RCC the absence of cyADPR was also significantly associated with tumor progression and worse patient outcome (<i>p</i> &lt; 0.05 each). To interrogate whether the ADPR status could be associated with genetic alterations in DNA repair, chromatin remodeling, and histone modulation, we performed DNA sequence analysis and identified a significant association of increased <i>ARID1A</i> mutations in ccRCC^{cyADPR+++/PARP1+} compared with ccRCC^{cyADPR−/PARP1−} (31% versus 4%; <i>p</i> &lt; 0.05). Collectively, our data suggest the prognostic value of nuclear and cytoplasmic ADPR levels in RCC that might be further influenced by genetic alterations.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 4","pages":"273-284"},"PeriodicalIF":4.1,"publicationDate":"2023-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/42/02/CJP2-9-273.PMC10240151.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9996631","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":"KRAS mutations and endometriosis burden of disease","authors":"Natasha L Orr,&nbsp;Arianne Albert,&nbsp;Yang Doris Liu,&nbsp;Amy Lum,&nbsp;JooYoon Hong,&nbsp;Catalina L Ionescu,&nbsp;Janine Senz,&nbsp;Tayyebeh M Nazeran,&nbsp;Anna F Lee,&nbsp;Heather Noga,&nbsp;Kate Lawrenson,&nbsp;Catherine Allaire,&nbsp;Christina Williams,&nbsp;Mohamed A Bedaiwy,&nbsp;Michael S Anglesio,&nbsp;Paul J Yong","doi":"10.1002/cjp2.317","DOIUrl":"10.1002/cjp2.317","url":null,"abstract":"<p>The clinical phenotype of somatic mutations in endometriosis is unknown. The objective was to determine whether somatic <i>KRAS</i> mutations were associated with greater disease burden in endometriosis (i.e. more severe subtypes and higher stage). This prospective longitudinal cohort study included 122 subjects undergoing endometriosis surgery at a tertiary referral center between 2013 and 2017, with 5–9 years of follow-up. Somatic activating <i>KRAS</i> codon 12 mutations were detected in endometriosis lesions using droplet digital PCR. <i>KRAS</i> mutation status for each subject was coded as present (<i>KRAS</i> mutation in at least one endometriosis sample in a subject) or absent. Standardized clinical phenotyping for each subject was carried out via linkage to a prospective registry. Primary outcome was anatomic disease burden, based on distribution of subtypes (deep infiltrating endometriosis, ovarian endometrioma, and superficial peritoneal endometriosis) and surgical staging (Stages I–IV). Secondary outcomes were markers of surgical difficulty, demographics, pain scores, and risk of re-operation. <i>KRAS</i> mutation presence was higher in subjects with deep infiltrating endometriosis or endometrioma lesions only (57.9%; 11/19) and subjects with mixed subtypes (60.6%; 40/66), compared with those with superficial endometriosis only (35.1%; 13/37) (<i>p</i> = 0.04). <i>KRAS</i> mutation was present in 27.6% (8/29) of Stage I cases, in comparison to 65.0% (13/20) of Stage II, 63.0% (17/27) of Stage III, and 58.1% (25/43) of Stage IV cases (<i>p</i> = 0.02). <i>KRAS</i> mutation was also associated with greater surgical difficulty (ureterolysis) (relative risk [RR] = 1.47, 95% CI: 1.02–2.11) and non-Caucasian ethnicity (RR = 0.64, 95% CI: 0.47–0.89). Pain severities did not differ based on <i>KRAS</i> mutation status, at either baseline or follow-up. Re-operation rates were low overall, occurring in 17.2% with <i>KRAS</i> mutation compared with 10.3% without (RR = 1.66, 95% CI: 0.66–4.21). In conclusion, <i>KRAS</i> mutations were associated with greater anatomic severity of endometriosis, resulting in increased surgical difficulty. Somatic cancer-driver mutations may inform a future molecular classification of endometriosis.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 4","pages":"302-312"},"PeriodicalIF":4.1,"publicationDate":"2023-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.317","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9624779","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 effectiveness of neoadjuvant chemoradiotherapy in oesophageal adenocarcinoma with presence of extracellular mucin, signet-ring cells, and/or poorly cohesive cells","authors":"Maria J Valkema,&nbsp;Anne-Marie Vos,&nbsp;Rachel S van der Post,&nbsp;Ariadne HAG Ooms,&nbsp;Lindsey Oudijk,&nbsp;Ben M Eyck,&nbsp;Sjoerd M Lagarde,&nbsp;Bas PL Wijnhoven,&nbsp;Bastiaan R Klarenbeek,&nbsp;Camiel Rosman,&nbsp;J Jan B van Lanschot,&nbsp;Michail Doukas","doi":"10.1002/cjp2.321","DOIUrl":"10.1002/cjp2.321","url":null,"abstract":"<p>Oesophageal adenocarcinomas may show different histopathological patterns, including excessive acellular mucin pools, signet-ring cells (SRCs), and poorly cohesive cells (PCCs). These components have been suggested to correlate with poor outcomes after neoadjuvant chemoradiotherapy (nCRT), which might influence patient management. However, these factors have not been studied independently of each other with adjustment for tumour differentiation grade (i.e. the presence of well-formed glands), which is a possible confounder. We studied the pre- and post-treatment presence of extracellular mucin, SRCs, and/or PCCs in relation to pathological response and prognosis after nCRT in patients with oesophageal or oesophagogastric junction adenocarcinoma. A total of 325 patients were retrospectively identified from institutional databases of two university hospitals. All patients were scheduled for ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) nCRT and oesophagectomy between 2001 and 2019. Percentages of well-formed glands, extracellular mucin, SRCs, and PCCs were scored in pre-treatment biopsies and post-treatment resection specimens. The association between histopathological factors (≥1 and &gt;10%) and tumour regression grade 3–4 (i.e. &gt;10% residual tumour), overall survival, and disease-free survival (DFS) was evaluated, adjusted for tumour differentiation grade amongst other clinicopathological variables. In pre-treatment biopsies, ≥1% extracellular mucin was present in 66 of 325 patients (20%); ≥1% SRCs in 43 of 325 (13%), and ≥1% PCCs in 126 of 325 (39%). We show that pre-treatment histopathological factors were unrelated to tumour regression grade. Pre-treatment presence of &gt;10% PCCs was associated with lower DFS (hazard ratio [HR] 1.73, 95% CI 1.19–2.53). Patients with post-treatment presence of ≥1% SRCs had higher risk of death (HR 1.81, 95% CI 1.10–2.99). In conclusion, pre-treatment presence of extracellular mucin, SRCs, and/or PCCs is unrelated to pathological response. The presence of these factors should not be an argument to refrain from CROSS. At least 10% PCCs pre-treatment and any SRCs post-treatment, irrespective of the tumour differentiation grade, seem indicative of inferior prognosis, but require further validation in larger cohorts.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 4","pages":"322-335"},"PeriodicalIF":4.1,"publicationDate":"2023-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a6/c6/CJP2-9-322.PMC10240149.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9677889","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":"Identification and validation of NFIA as a novel prognostic marker in renal cell carcinoma","authors":"Roger de Alwis,&nbsp;Sarah Schoch,&nbsp;Mazharul Islam,&nbsp;Christina Möller,&nbsp;Börje Ljungberg,&nbsp;Håkan Axelson","doi":"10.1002/cjp2.316","DOIUrl":"10.1002/cjp2.316","url":null,"abstract":"<p>Prognostic tools are an essential component of the clinical management of patients with renal cell carcinoma (RCC). Although tumour stage and grade can provide important information, they fail to consider patient- and tumour-specific biology. In this study, we set out to find a novel molecular marker of RCC by using hepatocyte nuclear factor 4A (HNF4A), a transcription factor implicated in RCC progression and malignancy, as a blueprint. Through transcriptomic analyses, we show that the nuclear factor I A (NFIA)-driven transcription network is active in primary RCC and that higher levels of NFIA confer a survival benefit. We validate our findings using immunohistochemical staining and analysis of a 363-patient tissue microarray (TMA), showing for the first time that NFIA can independently predict poor cancer-specific survival in clear cell RCC (ccRCC) patients (hazard ratio = 0.46, 95% CI = 0.24–0.85, <i>p</i> value = 0.014). Furthermore, we confirm the association of HNF4A with higher grades and stages in ccRCC in our TMA cohort. We present novel data that show HNF4A protein expression does not confer favourable prognosis in papillary RCC, confirming our survival analysis with publicly available <i>HNF4A</i> RNA expression data. Further work is required to elucidate the functional role of NFIA in RCC as well as the testing of these markers on patient material from diverse multi-centre cohorts, to establish their value for the prognostication of RCC.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 4","pages":"261-272"},"PeriodicalIF":4.1,"publicationDate":"2023-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c0/26/CJP2-9-261.PMC10240150.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9627298","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":"p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study","authors":"Martin Köbel,&nbsp;Eun-Young Kang,&nbsp;Ashley Weir,&nbsp;Peter F Rambau,&nbsp;Cheng-Han Lee,&nbsp;Gregg S Nelson,&nbsp;Prafull Ghatage,&nbsp;Nicola S Meagher,&nbsp;Marjorie J Riggan,&nbsp;Jennifer Alsop,&nbsp;Michael S Anglesio,&nbsp;Matthias W Beckmann,&nbsp;Christiani Bisinotto,&nbsp;Michelle Boisen,&nbsp;Jessica Boros,&nbsp;Alison H Brand,&nbsp;Angela Brooks-Wilson,&nbsp;Michael E Carney,&nbsp;Penny Coulson,&nbsp;Madeleine Courtney-Brooks,&nbsp;Kara L Cushing-Haugen,&nbsp;Cezary Cybulski,&nbsp;Suha Deen,&nbsp;Mona A El-Bahrawy,&nbsp;Esther Elishaev,&nbsp;Ramona Erber,&nbsp;Sian Fereday,&nbsp;AOCS Group,&nbsp;Anna Fischer,&nbsp;Simon A Gayther,&nbsp;Arantzazu Barquin-Garcia,&nbsp;Aleksandra Gentry-Maharaj,&nbsp;C Blake Gilks,&nbsp;Helena Gronwald,&nbsp;Marcel Grube,&nbsp;Paul R Harnett,&nbsp;Holly R Harris,&nbsp;Andreas D Hartkopf,&nbsp;Arndt Hartmann,&nbsp;Alexander Hein,&nbsp;Joy Hendley,&nbsp;Brenda Y Hernandez,&nbsp;Yajue Huang,&nbsp;Anna Jakubowska,&nbsp;Mercedes Jimenez-Linan,&nbsp;Michael E Jones,&nbsp;Catherine J Kennedy,&nbsp;Tomasz Kluz,&nbsp;Jennifer M Koziak,&nbsp;Jaime Lesnock,&nbsp;Jenny Lester,&nbsp;Jan Lubiński,&nbsp;Teri A Longacre,&nbsp;Maria Lycke,&nbsp;Constantina Mateoiu,&nbsp;Bryan M McCauley,&nbsp;Valerie McGuire,&nbsp;Britta Ney,&nbsp;Alexander Olawaiye,&nbsp;Sandra Orsulic,&nbsp;Ana Osorio,&nbsp;Luis Paz-Ares,&nbsp;Teresa Ramón y Cajal,&nbsp;Joseph H Rothstein,&nbsp;Matthias Ruebner,&nbsp;Minouk J Schoemaker,&nbsp;Mitul Shah,&nbsp;Raghwa Sharma,&nbsp;Mark E Sherman,&nbsp;Yurii B Shvetsov,&nbsp;Naveena Singh,&nbsp;Helen Steed,&nbsp;Sarah J Storr,&nbsp;Aline Talhouk,&nbsp;Nadia Traficante,&nbsp;Chen Wang,&nbsp;Alice S Whittemore,&nbsp;Martin Widschwendter,&nbsp;Lynne R Wilkens,&nbsp;Stacey J Winham,&nbsp;Javier Benitez,&nbsp;Andrew Berchuck,&nbsp;David D Bowtell,&nbsp;Francisco J Candido dos Reis,&nbsp;Ian Campbell,&nbsp;Linda S Cook,&nbsp;Anna DeFazio,&nbsp;Jennifer A Doherty,&nbsp;Peter A Fasching,&nbsp;Renée T Fortner,&nbsp;María J García,&nbsp;Marc T Goodman,&nbsp;Ellen L Goode,&nbsp;Jacek Gronwald,&nbsp;David G Huntsman,&nbsp;Beth Y Karlan,&nbsp;Linda E Kelemen,&nbsp;Stefan Kommoss,&nbsp;Nhu D Le,&nbsp;Stewart G Martin,&nbsp;Usha Menon,&nbsp;Francesmary Modugno,&nbsp;Paul DP Pharoah,&nbsp;Joellen M Schildkraut,&nbsp;Weiva Sieh,&nbsp;Annette Staebler,&nbsp;Karin Sundfeldt,&nbsp;Anthony J Swerdlow,&nbsp;Susan J Ramus,&nbsp;James D Brenton","doi":"10.1002/cjp2.311","DOIUrl":"10.1002/cjp2.311","url":null,"abstract":"<p>Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of <i>TP53</i> mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, <i>p</i> = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, <i>p</i> = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of <i>TP53</i> mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.</p>","PeriodicalId":48612,"journal":{"name":"Journal of Pathology Clinical Research","volume":"9 3","pages":"208-222"},"PeriodicalIF":4.1,"publicationDate":"2023-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pathsocjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cjp2.311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9760515","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}