Publications by authors named "Danhui Zhao"

21 Publications

  • Page 1 of 1

TOPK: A new predictor of the therapeutic response to neoadjuvant chemotherapy and prognosis in triple-negative breast cancer.

Pathol Res Pract 2021 Aug 28;226:153603. Epub 2021 Aug 28.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Air Force Medical University, Xi'an, China. Electronic address:

Background: Triple-negative breast cancer (TNBC) has a high probability of relapse and poor overall survival. Neoadjuvant chemotherapy (NACT) is currently a routine treatment strategy for TNBC, but some patients do not respond well. T-LAK cell-originated protein kinase (TOPK) is highly expressed in breast cancer cells and contributes to cancer cell proliferation. The present study aimed to investigate the correlation of TOPK expression with NACT treatment response and prognosis in TNBC.

Methods: We collected 66 pairs of TNBC samples before and after NACT with docetaxel+ epirubicin+ cyclophosphamide (TEC). The Miller-Payne (MP) system was used to assess the therapeutic response to NACT in TNBC patients.

Results: Immunohistochemistry analysis showed that TNBC patients with high TOPK expression before NACT had a poor treatment response and a poor prognosis. The expression of TOPK after NACT was significantly higher than that before NACT in patients with MP grade 1-3. In contrast, patients with MP grade 4-5 had significantly lower TOPK expression after NACT than before NACT, and the expression change in Ki-67 in patients with MP grade 4-5 exhibited the same trend. Survival analysis revealed that patients with TNBC accompanied by elevated TOPK expression before NACT had a worse prognosis than those with lower TOPK expression.

Conclusion: TOPK may be a novel predictor for the therapeutic response to NACT and prognosis for patients with TNBC.
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http://dx.doi.org/10.1016/j.prp.2021.153603DOI Listing
August 2021

Some pleomorphic adenomas of the breast share PLAG1 rearrangements with the analogous tumour of the salivary glands.

Histopathology 2021 Jul 22. Epub 2021 Jul 22.

Department of Pathology, The Basic Medicine Science and the First Affiliated Hospital of the Air Force Military Medical University, Xi'an, Shaan Xi Province, China.

Aims: Pleomorphic adenoma (PA) of the breast, and especially its malignant transformation, is extremely rare and represents a diagnostic pitfall. Molecular alterations in this entity have not been investigated. We aimed to examine the clinicopathological features of our breast PAs and perform molecular analysis.

Methods And Results: Seven cases of breast PA, including two cases of carcinoma ex PA, were analysed. PLAG1 and HMGA2 gene rearrangements were assayed by fluorescence in-situ hybridisation (FISH) and RNA sequencing (RNA-Seq), respectively. Reverse transcription-polymerase chain reaction (RT-PCR) and Sanger sequencing were used to verify RNA sequencing results. All seven cases of breast PA occurred in women. The histological features were similar to the analogous tumour in salivary glands, including a dual epithelial-myoepithelial component and negativity of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) by immunohistochemistry. Of the two cases with carcinoma ex PA, one demonstrated minimal invasion and one was extensively invasive. PLAG1 rearrangements were identified in two cases (28.6%), but no rearrangements of HMG2A were found. A novel fusion product in PAs, TRPS1-PLAG1, was identified in one case. No patients had recurrence or metastasis with a follow-up period of 6-158 months.

Conclusions: Breast PA is rare, but it is an important differential diagnosis of breast pathology with the potential to develop carcinoma ex PA. We report a novel TRPS1-PLAG1 fusion gene in breast PA.
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http://dx.doi.org/10.1111/his.14461DOI Listing
July 2021

QuantifyPoly(A): reshaping alternative polyadenylation landscapes of eukaryotes with weighted density peak clustering.

Brief Bioinform 2021 Jul 13. Epub 2021 Jul 13.

Key Laboratory of the Ministry of Education for Coastal and Wetland Ecosystems, College of the Environment and Ecology, Xiamen University, Xiamen, Fujian 361102, China.

The dynamic choice of different polyadenylation sites in a gene is referred to as alternative polyadenylation, which functions in many important biological processes. Large-scale messenger RNA 3' end sequencing has revealed that cleavage sites for polyadenylation are presented with microheterogeneity. To date, the conventional determination of polyadenylation site clusters is subjective and arbitrary, leading to inaccurate annotations. Here, we present a weighted density peak clustering method, QuantifyPoly(A), to accurately quantify genome-wide polyadenylation choices. Applying QuantifyPoly(A) on published 3' end sequencing datasets from both animals and plants, their polyadenylation profiles are reshaped into myriads of novel polyadenylation site clusters. Most of these novel polyadenylation site clusters show significantly dynamic usage across different biological samples or associate with binding sites of trans-acting factors. Upstream sequences of these clusters are enriched with polyadenylation signals UGUA, UAAA and/or AAUAAA in a species-dependent manner. Polyadenylation site clusters also exhibit species specificity, while plants ones generally show higher microheterogeneity than that of animals. QuantifyPoly(A) is broadly applicable to any types of 3' end sequencing data and species for accurate quantification and construction of the complex and dynamic polyadenylation landscape and enables us to decode alternative polyadenylation events invisible to conventional methods at a much higher resolution.
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http://dx.doi.org/10.1093/bib/bbab268DOI Listing
July 2021

Tumor Immune Microenvironment Components and Checkpoint Molecules in Anaplastic Variant of Diffuse Large B-Cell Lymphoma.

Front Oncol 2021 16;11:638154. Epub 2021 Jun 16.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Air Force Medical University, Xi'an, China.

Background: Anaplastic diffuse large B-cell lymphoma(A-DLBCL) is a rare morphological subtype characterized by the presence of polygonal, bizarre-shaped tumor cells. Our previous research found that A-DLBCL displays many genetic alterations and biological features that differ greatly from those of ordinary DLBCL. However, the status of tumor immune microenvironment components and checkpoint molecules in A-DLBCL remains unclear.

Methods: Thirty A-DLBCL patients were enrolled to study tumor immune microenvironment components and checkpoint molecules and their associations with clinicopathological features and prognosis.

Results: Patients with A-DLBCL presented higher expression of PD-L1 (40% 10%, P=0.004) than patients with ordinary DLBCL. FISH analysis showed that extra copies of PD-L1 were more frequent in A-DLBCL cases than in ordinary DLBCL cases (23.3% 4.0%, P=0.001). The numbers of PD-1 TILs (tumor infiltrating lymphocytes) and CD8T cells were significantly lower in A-DLBCL versus ordinary DLBCL. In contrast, the numbers of GATA3 Th2 cells, FOXP3 Tregs and CD33 myeloid-derived suppressor cells (MDSCs) were significantly higher in A-DLBCL than in ordinary DLBCL. The associations between clinicopathological features and tumor immune microenvironment cell frequency were analyzed in A-DLBCL patients. Briefly, the number of PD-1 TILs was lower and the number of CD33 MDSCs was higher in patients with mutated compared to those with wild-type . The number of FOXP3 Tregs was much lower in patients with a noncomplete response (CR) to chemotherapy than in those with a complete response. The number of CD8 T cells showed a decreasing trend in patients with high International Prognostic Index (IPI) scores and in those with concurrent MYC and BCL2 and/or BCL6 abnormalities. Univariate survival analysis showed that patients with PD-L1, mPD-L1(PD-L1 nonmalignant stromal cells) or mPD-L1 status had a significantly poorer overall survival (OS) than those with PD-L1 status. An increase in the number of CD3 T cells, FOXP3 Treg cells and T-bet Th1 cells was significantly associated with prolonged OS in patients with A-DLBCL.

Conclusion: Our study suggests that A-DLBCL displays a distinct pattern of tumor immune microenvironment components and checkpoint molecules that distinguish it from ordinary DLBCL. The analysis of tumor immune microenvironment components and checkpoint molecules could help in predicting the prognosis of A-DLBCL patients and determining therapeutic strategies targeting the tumor immune microenvironment.
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http://dx.doi.org/10.3389/fonc.2021.638154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242181PMC
June 2021

Cell-Seeded Acellular Artery for Reconstruction of Long Urethral Defects in a Canine Model.

Stem Cells Int 2021 4;2021:8854479. Epub 2021 Jun 4.

Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Peking Union Medical College Hospital, Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, Beijing Key Laboratory (No.BZO381), Beijing 100010, China.

The management of urethral stricture remains a major therapeutic challenge in clinics. Herein, we explored the feasibility of reconstructing a relatively long segment of the urethra by the cell-seeded acellular artery in a canine model. The acellular arterial matrix was obtained from the excised carotid artery of donor dogs. Autologous adipose-derived stem cells (ADSCs) from 6 male dogs were grown and seeded onto the premade acellular arterial matrix. A 3 cm long segment of the urethra was resected in 12 male dogs. Urethroplasty was performed with the acellular arterial matrix seeded with ADSCs in 6 animals and without cells in 6. Serial urethrography was performed at 1 and 3 months postoperatively. Wide urethral calibers without any signs of strictures were confirmed in all 6 animals in the experimental group. In contrast, urethral stricture was demonstrated in 3 animals in the control group. The graft was highly epithelialized and smooth in the experimental group, while graft contracture and scar formation were showed in the control group. Histologic analysis of the cell-seeded arterial matrix at 1 month confirmed the presence of multilayered urothelium and muscle. The levels of tissue formation developed over time with a progressive increase in muscle content. In contrast, extensive fibrosis and sparse smooth muscle were seen in animals treated with matrix without ADSCs. This study provides preclinical evidence that the ADSC-seeded arterial matrix can be used as a tubularized scaffold in the reconstruction of 3 cm long urethral defect in a male canine model. The ADSC-seeded arterial matrix remodels and regenerates normal-appearing urethral tissue layers over time.
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http://dx.doi.org/10.1155/2021/8854479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203373PMC
June 2021

Differential proteomic analysis of tibial subchondral bone from male and female guinea pigs with spontaneous osteoarthritis.

Exp Ther Med 2021 Jun 15;21(6):633. Epub 2021 Apr 15.

Department of Spine Surgery, Beijing Jishuitan Hospital, Beijing 100035, P.R. China.

A proteomic study on the tibial subchondral bone in guinea pigs with spontaneous osteoarthritis was performed to investigate the molecular alterations that occur in early osteoarthritis. A total of 132 healthy Hartley guinea pigs (aged 1 month; 66 female and 66 male) were randomly divided into 11 groups of six. Changes in articular cartilage and tibial subchondral bone were assessed using macroscopic examinations and micro-computed tomography. iTRAQ-integrated liquid chromatography-tandem mass spectrometry was used to identify differentially altered proteins in the tibial subchondral bone between 1- and 3-month-old guinea pigs, which were then validated using western blotting. A gradual progression of cartilage degeneration was observed in the knee joints of the subject animals from 5-11 months. With aging, the tibial subchondral trabecular bone acquired more plate-like and less anisotropic properties, with increased bone mineral density, bone volume, trabecular thickness and numbers. The proteomic study identified 138 and 113 proteins significantly differentially expressed between 3- and 1-month old guinea pigs in both the male and female animals, respectively. Western blotting confirmed the increased expression of osteoblast-associated protein S100 calcium-binding protein A8 (S100A8) and the deregulated expression of osteoclast-associated proteins coronin 1A (CORO1A) and T-cell immune regulator 1 (TCIRG1) in the 3-month old guinea pigs in comparison to the 1-month old guinea pigs. Spontaneous cartilage degeneration in the knee joints of male Hartley guinea pigs tended to be more serious compared with the females during the development of osteoarthritis. Together, the results suggest that osteoblast-associated protein S100A8 and osteoclast-associated proteins CORO1A and TCIRG1 are potentially key regulators of early osteoarthritic development in tibial subchondral bone.
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http://dx.doi.org/10.3892/etm.2021.10065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097192PMC
June 2021

Genomic Mutation Profile of Primary Gastrointestinal Diffuse Large B-Cell Lymphoma.

Front Oncol 2021 5;11:622648. Epub 2021 Mar 5.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, China.

Primary gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common gastrointestinal lymphoma, but its genetic features are poorly understood. We performed whole-exome sequencing of 25 primary tumor samples from patients with GI-DLBCL and 23 matched normal tissue samples. Oncogenic mutations were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Twenty-five patients with GI-DLBCL were enrolled in the genetic mutation analysis with a median of 184 (range 79-382) protein-altering variants per patient. We identified recurrent oncogenic mutations in GI-DLBCL, including those in , and . Compared with nodal DLBCL, GI-DLBCL exhibited an increased mutation frequency of and reduced mutation frequencies of , and . Moreover, GI-DLBCL exhibited fewer and mutations than DLBCL in the testis and central nervous system. GI-DLBCLs with , and mutations exhibited a tendency toward a high proliferation index. and mutations often occurred in tumors with early clinical staging. Our data provide a comprehensive understanding of the landscape of mutations in a small subset of GI-DLBCLs. The genetic mutation profiles of GI-DLBCL differ from those of nodal DLBCL and DLBCL in immune-privileged sites. The different mutated genes are related to the NF-κB and JAK-STAT pathways, and the different pathogenetic mechanisms leading to the development of DLBCL may be influenced by the tissue microenvironment. Differences in genetic alterations might influence the clinicopathological characteristics of GI-DLBCL.
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http://dx.doi.org/10.3389/fonc.2021.622648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973209PMC
March 2021

Decreased infiltration of CD4 Th1 cells indicates a good response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis.

Pathol Res Pract 2021 Jan 16;217:153291. Epub 2020 Nov 16.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China. Electronic address:

Background: Primary biliary cholangitis (PBC) is characterized by nonsuppurative destructive cholangitis and is thought to be an autoimmune disorder. Currently, ursodeoxycholic acid (UDCA) is the only FDA approved first-line therapy for PBC, but up to nearly one-third of patients do not achieve a complete response to this treatment. Adaptive immune cells, including T cells and B cells, have been found in the portal tracts and the bile duct epithelium and play a role in the pathogenesis of PBC, but the importance of these cells for evaluating the therapeutic response to UDCA in PBC has not yet been studied.

Methods: In this study, we collected liver puncture biopsy specimens from 34 matched patients with PBC before and after UDCA treatment and investigated the relationship between the infiltration of adaptive immune cells and the treatment response to UDCA. The extent of immune cell infiltration was determined by immunohistochemical analysis. Responses were defined based on Paris-I criteria.

Results: After 1 year of treatment, 25/34 patients responded to UDCA treatment according to Paris-I criteria (responders), and 9/34 patients were nonresponders. Immunohistochemical analysis showed that UDCA responders exhibited significantly less CD4 T cell infiltration after UDCA treatment than before (50.4 ± 7.5/HPF vs 30.0 ± 7.9/HPF, P = 0.002). In contrast, UDCA nonresponders exhibited significantly more CD4 T cell infiltration after UDCA treatment than before (32.2 ± 8.0/HPF vs 75.0 ± 13.9/HPF, P = 0.045). Moreover, patients who exhibited a reduction in CD4 T cell infiltration after UDCA treatment had a higher response rate than those that exhibited an increase in CD4 T cell infiltration (85.7 % vs 53.8 %, P = 0.041). However, CD3 T cell, CD8 T cell, and CD20 B cell infiltration was not significantly different before and after treatment in either UDCA responders or nonresponders. Furthermore, we found that the number of infiltrating T-bet Th1 cells was much lower after UDCA treatment than before in responders (10.5 ± 5.7/HPF vs. 5.16 ± 4.0/HPF, P = 0.0214) but much higher in nonresponders after treatment than before (1.89±1.2/HPF vs. 12.3±5.4/HPF, P = 0.043). However, there was no difference in the extent of GATA3 Th2 or FOXP3 Treg infiltration before and after treatment in either UDCA responders or nonresponders.

Conclusion: Collectively, our results suggest that a decrease in the number of liver-infiltrating CD4 Th1 cells is associated with a good response of PBC patients to UDCA treatment. Immunohistochemical analysis of CD4 and T-bet in PBC liver specimens may be a potential approach for evaluating the therapeutic response to UDCA.
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http://dx.doi.org/10.1016/j.prp.2020.153291DOI Listing
January 2021

The clinicopathological and molecular features of sinusoidal large B-cell lymphoma.

Mod Pathol 2021 05 24;34(5):922-933. Epub 2020 Sep 24.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.

We report 17 cases of sinusoidal large B-cell lymphoma (SLBCL). Clinical, morphologic, immunophenotypic, and molecular features were detected and analyzed. All cases showed an obvious sinusoidal growth pattern, usually associated with residual atrophic lymphoid tissue. All tumors contained large pleomorphic lymphoid cells and one or more prominent nucleoli, with abundant amphophilic cytoplasms; 15/17 cases showed anaplastic morphologic features. The patient age ranged from 43 to 80 years (median 57 years), and 7 males and 10 females were included. Eleven of 15 (73.3%) patients had Ann Arbor stage III or IV disease, and 10/15 (66.6%) patients had an International Prognostic Index (IPI) score ≥3. Immunophenotypically, 16/17 (94.1%) cases displayed a nongerminal center B-cell (non-GCB) immunophenotype. Furthermore, 16/17 (94.1%) cases were positive for CD30, and p53 was expressed in 10/16 (62.5%) cases. In total, 12/14 (85.7%) cases expressed BCL2 and MYC simultaneously (double expression), and 11/14 (78.6%) cases showed PD-L1 positivity (6/11 had a PD-L1 tumor proportion score ≥50%). Cytogenetically, concurrent MYC and BCL2 and/or BCL6 abnormalities (break-apart or extra copy) were detected in 10/15 cases, and 7/13 (53.8%) cases harbored a PD-L1/L2 amplification. TP53 mutation was found in 7/13 (53.8%) cases by Sanger sequencing. Whole-exome and large-panel sequencing results revealed high mutation frequencies of TP53 (4/7), MYD88 (3/7), KMT2D (3/7), CREBBP (3/7), and PIM1 (3/7). Among the 13 patients with SLBCL treated with aggressive chemotherapy regimens, the median overall survival (OS) was 18 months, and the 2-year OS rate was 34.6%. The OS of patients with SLBCL was markedly worse than that of 35 control group patients with common diffuse large B-cell lymphoma (DLBCL) without sinusoidal features (P < 0.001). SLBCL may represent a specific type of DLBCL that has characteristic pathologic features. The cancer is aggressive in most clinical cases, and outcomes are poor. SLBCL and anaplastic DLBCL (A-DLBCL) have many overlapping clinicopathological and molecular features.
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http://dx.doi.org/10.1038/s41379-020-00685-7DOI Listing
May 2021

Expression of RSK4, CD44 and MMP-9 is upregulated and positively correlated in metastatic ccRCC.

Diagn Pathol 2020 Mar 24;15(1):28. Epub 2020 Mar 24.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Changle West Road #169, Xi'an, 710032, Shaan Xi Province, China.

Background: To investigate the expression and function of RSK4, MMP-9 and CD44 in primary clear cell renal cell carcinoma (primary ccRCC) and metastatic clear cell renal cell carcinoma (metastatic ccRCC), as well as the correlation with clinicopathological features of patients.

Method: The expression levels of RSK4, CD44 and MMP-9 in 52 primary ccRCC samples and 48 metastatic ccRCC samples were detected by immunohistochemistry, and the relationship between RSK4, CD44 and MMP-9 expression and clinicopathological features as well as prognosis of metastatic ccRCC patients was statistically analysed. Ectopic RSK4 expression in ccRCC cell lines was performed to determine its effect on cell cycle regulation, tumour invasiveness, and metastatic capability.

Results: The positive rates of RSK4, MMP-9 and CD44 expression in metastatic ccRCC tissues were 75, 68.75 and 91.7%, respectively, while the rates in primary ccRCC tissues were 44.2, 34.6 and 69.2%, respectively. Thus, the positive rates in metastatic ccRCC were higher than those in primary ccRCC (P = 0. 002; P = 0. 002; P = 0. 001). However, the expression of RSK4, CD44 and MMP-9 was unrelated to age, gender, or metastatic sites (P > 0.05) but was related to WHO/ISUP nucleolar grade (P = 0.019; P = 0.026; P = 0.049). In metastatic ccRCC, expression among the three proteins showed a positive correlation (P = 0.008). Moreover, expression between RSK4 and CD44 (P = 0.019) and MMP-9 and CD44 (P = 0.05) also showed positive correlations, whereas RSK4 and MMP-9 showed no significant correlation (P = 1.00). Molecular studies showed that overexpression of RSK4 could enhance the invasive and migratory abilities of ccRCC cell lines through the regulation of CD44 and MMP-9 expression and vice versa.

Conclusions: The overexpression of RSK4, MMP-9 and CD44 is associated with the invasion and metastasis of ccRCC, indicating that they could be potential prognostic factors and serve as new potential therapeutic targets for ccRCC.
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http://dx.doi.org/10.1186/s13000-020-00948-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093975PMC
March 2020

Progress in triple negative breast carcinoma pathophysiology: Potential therapeutic targets.

Pathol Res Pract 2020 Apr 13;216(4):152874. Epub 2020 Feb 13.

State Key Laboratory of Tumor Biology, Department of Pathology, Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province,710032, China. Electronic address:

Triple-negative breast carcinoma (TNBC) is a subtype of breast carcinoma defined by negativity for estrogen receptor (ER) or progesterone receptor (PR) by immunohistochemical analysis and negativity for human epidermal growth factor receptor (Her2) by immunohistochemistry or in situ hybridization. TNBC is clinically marked by its high aggressiveness, particularly poor outcomes including a low survival rate, and the lack of specific and effective treatments. Therefore, new potential targets for the treatment of TNBC must be identified. This review summarizes recent evidence supporting novel targets and possible therapeutic regimens in the treatment of TNBC.
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http://dx.doi.org/10.1016/j.prp.2020.152874DOI Listing
April 2020

Genetic alterations in cell cycle regulation-associated genes may promote primary progression of gastrointestinal stromal tumors.

Lab Invest 2020 03 30;100(3):426-437. Epub 2019 Sep 30.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaan Xi, China.

Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumor types and usually contain KIT or PDGFRA mutations. GISTs with concomitant low- and high-grade components are seen in clinical practice. Herein, we retrospectively analyzed the histological characteristics and immunohistochemical results of 22 GIST cases with concomitant low- and high-grade tumors. Whole-exome sequencing (WES) was performed on ten pairs of high-grade GIST specimens and matched low-grade samples. Differential oncogenes mutated only in high-grade GISTs were identified, which were confirmed by Sanger sequencing. Fluorescence in situ hybridization was employed to detect MYC copy number variation. High-grade GISTs were more likely to have lower CD34 expression and a higher Ki-67 proliferation index compared to the matched low-grade tumors. WES identified 30 differential cancer-associated genes mutated only in high-grade GISTs; Sanger sequencing confirmed ten relevant differential oncogenic mutations in nine genes (MGA, ARID1A, LATS2, MAX, PIK3CA, RB1, RPS6KB2, SDHA, and SETD2). Two patients had MGA mutations, whereas other gene mutations occurred in only one patient. Most of the differential cancer-associated genes are mainly involved in cell cycle control. MYC copy number gain was a common genetic variation. High-grade GISTs revealed more MYC copy number gains than matched low-grade tumors, and low-grade GISTs with coexisting high-grade components showed more MYC copy number gains than pure low-grade GISTs. Moreover, MYC copy number gain was positively correlated with the mitotic index and Ki-67 proliferation index. Alterations in cell cycle regulation-associated genes, such as genetic mutations and MYC copy number gain, may promote primary progression from low-grade GISTs to high-grade tumors by regulating tumor cell proliferation.
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http://dx.doi.org/10.1038/s41374-019-0322-xDOI Listing
March 2020

Lineage-negative lymphoma with a helper innate lymphoid cell phenotype.

Virchows Arch 2020 Feb 14;476(2):285-293. Epub 2019 Sep 14.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.

Helper innate lymphoid cells (ILCs) were recently recognized as lineage-negative lymphoid cells that do not express rearranged receptors and have important effector and regulatory functions in innate immunity. However, to our knowledge, no cases of hematological malignancies arising from helper ILCs have ever been reported in the literature. Here, we report a case of a 17-year-old man with multiple lymphadenopathy who was diagnosed with lineage-negative lymphoma that displayed a helper ILC phenotype. Histological examination showed large monomorphic atypical lymphoid cells with prominent nucleoli and abundant eosinophilic cytoplasms with scattered and patchy distributions. Large amounts of histiocytes and infiltrating lymphocytes were observed in the background. Immunostaining revealed positive LCA and CD79a expression but negative expression of all lineage markers. IG and TCR rearrangement analysis showed no clonal rearrangements. Tumor cells strongly expressed helper ILC phenotypic markers, such as CD127, IL-1R, GATA3, ST2, IL-17Rβ, and RANKL, and helper ILC-produced cytokines, such as IL-4 and GM-CSF. PD-L1/PD-L2-positive histiocytes and FOXP3-positive Tregs were observed in the tumor microenvironment. Flow cytometry of bone marrow at recurrence was positive for IL-1R and negative for T, B, NK, and myelogenous lineage markers. TP53 sequencing showed that exon 5 was replaced with an intergenic sequence of chromosome 21. Next-generation sequencing demonstrated a novel IGLV2-14/IGLL5 fusion and mutations or deletions of tumor suppressor genes, such as PTPRB, PPP2CB, and UPK1A. This tumor was very aggressive, resistant to chemotherapy, recurred with bone marrow involvement, and caused the death of the patient within 6 months. To our knowledge, this is the first report of a hematological malignancy potentially arising from helper ILCs. We propose negativity for lineage markers and positivity for CD127/IL-1R in combination with specific transcription factor expression as markers of this tumor. This finding represents a novel addition to the growing spectrum of hematological malignancies.
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http://dx.doi.org/10.1007/s00428-019-02658-xDOI Listing
February 2020

Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next-generation sequencing.

Histopathology 2019 Dec 13;75(6):890-899. Epub 2019 Oct 13.

Department of Pathology, Molecular Pathology Research Centre, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

Aims: To characterise the mutational profiles of poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) and to identify markers with potential diagnostic, prognostic and therapeutic significance.

Methods And Results: Targeted next-generation sequencing with a panel of 18 thyroid carcinoma-related genes was performed on tissue samples from 41 PDTC and 25 ATC patients. Genetic alterations and their correlations with clinicopathological factors, including survival outcomes, were also analysed. Our results showed that ATC had significantly higher mutation rates of BRAF, TP53, TERT and PIK3CA than PDTC (P = 0.005, P = 0.007, P = 0.005, and P = 0.033, respectively). Nine (69%) ATC cases with papillary thyroid carcinoma (PTC) components harboured BRAF mutations, all of which coexisted with a late mutation event (TP53, TERT, or PIK3CA). Nine cases with oncogenic fusion (six RET cases, one NTRK1 case, one ALK case, and one PPARG case) were identified in 41 PDTCs, whereas only one case with oncogenic fusion (NTRK1) was found among 25 ATCs. Moreover, all six cases of RET fusion were found in PDTC with PTC components, accounting for 33%. In PDTC/ATC patients, concurrent TERT and PIK3CA mutations were associated with poor overall survival after adjustment for TNM stage (P = 0.001).

Conclusions: ATC with PTC components is typically characterised by a BRAF mutation with a late mutation event, whereas PDTC with PTC components is more closely correlated with RET fusion. TERT and concurrent PIK3CA mutations predict worse overall survival in PDTC/ATC patients.
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http://dx.doi.org/10.1111/his.13942DOI Listing
December 2019

transcription factors FoxA and SAGE divergently regulate the expression of wing cuticle protein gene 4 during metamorphosis.

J Biol Chem 2019 01 14;294(2):632-643. Epub 2018 Nov 14.

From the Guangzhou Key Laboratory of Insect Development Regulation and Application Research, Institute of Insect Science and Technology and School of Life Sciences, South China Normal University, Guangzhou 510631, China and

Stage-specific gene expression governs metamorphosis of the silkworm, wing cuticle protein gene 4 () is an essential gene for wing disc development expressed specifically during pupation. transcription is suppressed at the larval stage by unknown mechanisms, which we sought to elucidate here. Bioinformatics analysis predicted seven potential Forkhead box (Fox) -regulatory elements (CREs) in the promoter region, and we found that Fox CRE6 contributes to suppression of expression. Electrophoretic mobility shift (EMSA) and DNA pull-down assays revealed that BmFoxA suppressed activity at the promoter by specifically binding to the Fox CRE6. The expression level of BmFoxA in the wing discs was higher during the larval stage than at the pupal stage. In contrast, expression of another transcription factor, BmSAGE, increased over the course of development. Of note, the hormone 20-hydroxyecdysone (20E), which governs molting in insects, suppressed expression in the wing discs and up-regulated that of EMSA and cell co-transfection assays indicated that BmSAGE interacted with BmFoxA and suppressed its binding to the Fox CRE6, thereby releasing BmFoxA-mediated suppression of In summary, higher BmFoxA expression during the larval stage suppresses expression by binding to the Fox CRE6 on the promoter. During metamorphosis, BmSAGE forms a complex with BmFoxA to relieve this repression, initiating expression. Taken together, this study reveals a switchlike role for BmFoxA in regulating expression and provides new insights into the regulatory regulation of wing disc development in insects.
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http://dx.doi.org/10.1074/jbc.RA118.004395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333878PMC
January 2019

Autophagy defects and related genetic variations in renal cell carcinoma with eosinophilic cytoplasmic inclusions.

Sci Rep 2018 07 2;8(1):9972. Epub 2018 Jul 2.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.

The relationship between autophagy and tumour is well studied, but tumour cell morphological changes associated with autophagy defects are rarely reported, especially in renal cell carcinoma (RCC). We collected 10 renal tumour samples with characteristic eosinophilic cytoplasmic inclusions (ECIs) and found that the ECIs were majorly composed of sequestosome 1/P62, neighbor of BRCA1 gene 1 (NBR1), PEX14, and CATALASE1 (CAT1). Further, transmission electron microscopy analysis revealed that ECIs were aggregates of proteinaceous material and peroxisomes. These results confirmed that ECIs in RCCs were the products of autophagy defects. The presence of ECIs was correlated with high Fuhrman grade components of RCCs. Whole-exome sequencing (WES) and Sanger sequencing confirmed that tumours with ECIs showed somatic mutations or high frequency of genetic variations in autophagy-related (ATG) genes, such as ATG7, ATG5, and ATG10. These results indicate that nucleotide changes in ATG genes are associated with autophagy defect, ECI formation, and even tumour grade in RCCs.
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http://dx.doi.org/10.1038/s41598-018-28369-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028630PMC
July 2018

Cervical small cell carcinoma frequently presented in multiple high risk HPV infection and often associated with other type of epithelial tumors.

Diagn Pathol 2018 May 22;13(1):31. Epub 2018 May 22.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, The Fourth Military Medical University, Changle West Road #169, Xi'an, 710032, Shaan Xi Province, China.

Background: Small cell carcinoma of the uterine cervix is a rare and highly malignant tumor, and its etiopathogenesis is strongly related to high-risk HPV infections.

Methods: The clinicopathological data of 30 cases of cervical primary small cell carcinoma were retrospectively analyzed. In situ hybridization, polymerase chain reaction and reverse dot-blot hybridization were employed to detect HPV DNA in both small cell carcinoma and other coexisting epithelial tumors. Immunohistochemistry was used to detect the protein expression of p16 and p53.

Results: Amongst 30 patients with cervical primary small cell carcinoma, 15 patients simultaneously exhibited other types of epithelial tumors, including squamous cell carcinoma, adenocarcinoma, squamous cell carcinoma in situ, and adenocarcinoma in situ. Most tumor cells infected with HPV presented integrated patterns in the nuclei by in situ hybridization. HPV DNA was detected in every small cell carcinoma case (100%) by polymerase chain reaction and reverse dot blot hybridization. 27 cases (90%) harbored type 18, and 15 (50%) displayed multiple HPV18 and 16 infections. The prevalence of HPV 18 infection in small cell carcinoma was higher than in cervical squamous and glandular epithelial neoplasms (P = 0.002). However, similar infection rates of HPV 16 were detected in both tumors (P = 0.383). Both small cell carcinoma and other types of epithelial tumors exhibited strong nuclear and cytoplasmic staining for p16 in all cases. Three cases of small cell carcinoma revealed completely negative p53 immunohistochemical expression in 15 cases of composite tumors, which suggested TP53 nonsense mutation pattern. The pure small cell carcinoma of uterine cervix had similar mutation or wild type pattern for TP53 compared with composite tumor (P = 0.224).

Conclusions: Cervical small cell carcinomas are often associated with squamous or glandular epithelial tumors, which might result from multiple HPV infections, especially HPV 16 infection. Multiple HPV infections were not correlated with tumor stage, size, lymphovascular invasion, lymph node metastasis, or prognosis. Furthermore, careful observation of specimens is very important in finding little proportion of small cell carcinoma in the composite lesions, specifically in cervical biopsy specimens, in order to avoid the missed diagnosis of small cell carcinoma.
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http://dx.doi.org/10.1186/s13000-018-0709-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964718PMC
May 2018

Primary Astrocytic Tumours and Paired Recurrences have Similar Biological Features in IDH1, TP53 and TERTp Mutation and MGMT, ATRX Loss.

Sci Rep 2017 10 12;7(1):13038. Epub 2017 Oct 12.

State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital; and School of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaan Xi Province, China.

Astrocytic tumours are the most common type of primary malignant brain tumour. Most astrocytic tumours will recur at some point after surgery. Currently, the combination of radiotherapy and chemotherapy does not prevent the recurrence of astrocytic tumours. In this study, we investigated the consistency in isocitrate dehydrogenase 1 (IDH1), tumour protein p53 (TP53) and telomerase reverse transcriptase promoter (TERTp) mutations during astrocytic tumour recurrence. We also evaluated the protein loss of O-6-methylguanine-DNA methyltransferase (MGMT) and alpha-thalassemia/mental retardation, X-linked (ATRX) during disease recurrence. We then determined the prognostic significance of these findings in terms of progression-free survival (PFS) using Kaplan-Meier analysis and Cox regression models. Our results showed that in most cases, IDH1, TP53 and TERTp mutation status and MGMT and ATRX protein expression levels were stable during recurrence, which may indicate that these alterations occurred early in astrocytic tumour development. Furthermore, in IDH1 wild type group, the patients who were negative for MGMT and had a low Ki67 index showed a longer PFS. Therefore, we suggest that IDH1 mutation combined with MGMT expression level and Ki67 index might be an effective biomarker panel for evaluating the PFS of patients with astrocytic tumours.
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http://dx.doi.org/10.1038/s41598-017-13272-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638900PMC
October 2017

EZH2 overexpression in primary gastrointestinal diffuse large B-cell lymphoma and its association with the clinicopathological features.

Hum Pathol 2017 06 22;64:213-221. Epub 2017 Apr 22.

State Key Laboratory of Tumor Biology, Department of Pathology, the Basic Medicine Science and Xi Jing Hospital, the Fourth Military Medical University, Xi'an, Shaan Xi Province, 710032, China. Electronic address:

Gastrointestinal diffuse large B-cell lymphoma (GI DLBCL) is the most common gastrointestinal lymphoma. Enhancer of zeste homolog 2 (EZH2) has been implicated in the pathogenesis of several cancers. However, EZH2 has not been studied in GI DLBCL. Thus, we investigated EZH2 expression and EZH2 Y641 mutation in 100 GI DLBCL specimens by immunohistochemistry and sequencing. In addition, trimethylated H3K27 (H3K27me3), BCL2, c-MYC, and Ki-67 expression and Helicobacter pylori infection were detected, and BCL2 and c-MYC gene translocation was assessed. EZH2 was overexpressed in 50% of cases. EZH2 overexpression was significantly associated with higher stage (P = .014), higher International Prognostic Index score (P = .003), reduced overall survival rate (P = .030), and H3K27me3 (P = .001) and c-MYC expression (P = .008). We detected EZH2 mutations in 1 of 33 (3.0%) DLBCLs with a germinal center immunophenotype. The frequency of EZH2 Y641 mutation in GI DLBCL was significantly lower than that in patients with DLBCL without gastrointestinal features (P = .022). BCL2 and c-MYC translocation was detected in 6.5% and 5.1% of cases, respectively. BCL2 translocation was detected exclusively in the germinal center B-cell-like subtype. Chronic gastroenteritis was present in all cases, and 36.4% of gastric DLBCL cases had H pylori infection. The data indicate that primary GI DLBCL is closely related with chronic inflammation and has a low frequency of molecular abnormality, and EZH2 overexpression is significantly associated with inferior outcome in patients with primary GI DLBCL; evaluating EZH2 expression has therapeutic implications.
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http://dx.doi.org/10.1016/j.humpath.2017.04.011DOI Listing
June 2017

Synchronous ganglioneuroma and schwannoma of the vagal inferior ganglion.

Clin Neuropathol 2017 Jul/Aug;36(4):183-187

Neurogenic neoplasms resulting from autonomic nerves are considerably rare. In this paper, we report a case of a 41-year-old woman with composite tumor of synchronous ganglioneuroma and schwannoma in the vagal inferior ganglion. Ultrasonography and computed tomography showed a well-defined mass, which extruded from the internal and external carotid arteries. Two tumors were closely attached but with an evident boundary. The small tumor was composed of spindle cells and numerous mature ganglion cells, and the large one consisted entirely of differentiated neoplastic Schwann cells. Results showed that these tumors were a schwannoma arising in a ganglioneuroma of the vagal inferior ganglion. Our case is the first to demonstrate the occurrence of schwannoma in benign ganglioneuroma. We also provided clinical and pathological evidence that such transformation can occur spontaneously.
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http://dx.doi.org/10.5414/NP301014DOI Listing
August 2018

Population-Stratified Analysis of Bone Mineral Density Distribution in Cervical and Lumbar Vertebrae of Chinese from Quantitative Computed Tomography.

Korean J Radiol 2016 Sep-Oct;17(5):581-9. Epub 2016 Aug 23.

Department of Spine Surgery, The Fourth Clinical Medical College of Peking University, Beijing Jishuitan Hospital, Beijing 100035, China.

Objective: To investigate the bone mineral density (BMD) of cervical vertebrae in a population-stratified manner and correlate with that of the lumbar vertebrae.

Materials And Methods: Five hundred and ninety-eight healthy volunteers (254 males, 344 females), ranging from 20 to 64 years of age, were recruited for volumetric BMD (vBMD) measurements by quantitative computed tomography. Basic information (age, height, weight, waistline, and hipline), and vBMD of the cervical and lumbar vertebrae (C2-7 and L2-4) were recorded. Comparisons among sex, age groups and different levels of vertebrae were analyzed using analysis of variance. Linear regression was performed for relevance of different vertebral levels.

Results: The vBMD of cervical and lumbar vertebrae was higher in females than males in each age group. The vBMD of the cervical and lumbar vertebrae in males and the vBMD of lumbar vertebrae in females decreased with aging. In each age group, the vBMD of the cervical vertebrae was higher than that of the lumbar vertebrae with gradual decreases from C2 to C7 except for C3; moreover, the vBMD of C6 and C7 was significantly different from that of C2-5. Correlations of vBMD among different cervical vertebrae (females: r = 0.62-0.94; males: r = 0.63-0.94) and lumbar vertebrae (males: r = 0.93-0.98; females: r = 0.82-0.97) were statistically significant at each age group.

Conclusion: The present study provided normative data of cervical vertebrae in an age- and sex-stratified manner. Sex differences in vBMD prominently vary with age, which can be helpful to design a more comprehensive pre-operative surgical plan.
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http://dx.doi.org/10.3348/kjr.2016.17.5.581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007385PMC
August 2017
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