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Welter N, Al-Saadi R, Gravier-Dumonceau R, Furtwängler R, Graf N, Wegert J, Gessler M, Williams RD, Pritchard-Jones K, Coulomb-L'Hermine A, van den Heuvel-Eibrink MM, Verschuur AC. The Clinical Impact of Somatic Copy Number Variations in Patients With Stage IV Wilms Tumor Enrolled in the SIOP 2001 Trial and Study. Pediatr Blood Cancer 2025; 72:e31580. [PMID: 39895484 DOI: 10.1002/pbc.31580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 01/16/2025] [Accepted: 01/22/2025] [Indexed: 02/04/2025]
Abstract
BACKGROUND Recent research elucidated the prognostic significance of molecular biology in Wilms tumor (WT) by linking somatic genomic variants (such as gain of chromosome 1q) to unfavorable patient outcomes. This analysis describes the clinical impact of copy number variations (CNV) in tumor samples of WT patients with stage IV disease. METHODS Tumor samples of 55 WT patients with stage IV disease from the United Kingdom, France, and Germany enrolled in the SIOP 2001 study and treated with preoperative chemotherapy (pCHT) were examined for their CNVs of chromosome 1q and other regions of interest using multiplex ligation-dependent probe amplification (MLPA). The identified CNV were analyzed regarding their prognostic impact. RESULTS Chromosome 1q gain (1q+) and TP53 loss occurred in 38.2% and 16.4% of tumors and were associated with older patient age at diagnosis (median [months]: 65 and 64 vs. 49 each, p = 0.03 and 0.02, respectively) and poorer 5-year event-free survival (40.0% and 11.1% vs. 67.7% and 82.6%, p = 0.04 and <0.01, respectively) compared to their specific control group of tumors without the respective CNV. In patients with pulmonary-only metastasis, 1q+ was an adverse prognostic marker irrespective of remission status after pCHT with or without metastasectomy. A simultaneous MYCN gain occurred more frequently in tumors with 1q+ than in tumors without 1q+ (p = 0.03). TP53 loss was linked to high-risk histology and inferior 5-year overall survival (p < 0.001). CONCLUSIONS We confirm the prognostic relevance of 1q+ and TP53 loss in stage IV WTs and emphasize their potential utility for future treatment stratification.
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Affiliation(s)
- Nils Welter
- Department of Pediatric Oncology and Hematology, Saarland University, Homburg, Germany
| | - Reem Al-Saadi
- Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
- Department of Histopathology, Great Ormond Street Hospital for Children, London, UK
| | - Robinson Gravier-Dumonceau
- APHM, Hop Timone, BioSTIC, Biostatistique et Technologies de l'Information et de la Communication, Marseille, France
| | - Rhoikos Furtwängler
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Inselspital University Hospital, Bern, Switzerland
| | - Norbert Graf
- Department of Pediatric Oncology and Hematology, Saarland University, Homburg, Germany
| | - Jenny Wegert
- Developmental Biochemistry and Comprehensive Cancer Centre Mainfranken, Theodor-Boveri-Institute/Biocenter, University of Würzburg, Würzburg, Germany
| | - Manfred Gessler
- Developmental Biochemistry and Comprehensive Cancer Centre Mainfranken, Theodor-Boveri-Institute/Biocenter, University of Würzburg, Würzburg, Germany
| | - Richard D Williams
- Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
- Section of Genetics and Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Kathy Pritchard-Jones
- Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
| | | | | | - Arnauld C Verschuur
- Department of Pediatric Haematology-Oncology, La Timone Children's Hospital, AP-HM, Marseille, France
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Song YH, Li WL, Yang Z, Gao Y, Feng ZP. Loss of heterozygosity for chromosomes 16q in Wilms tumors predicts outcomes: A meta-analysis. World J Gastrointest Oncol 2024; 16:2159-2167. [PMID: 38764827 PMCID: PMC11099455 DOI: 10.4251/wjgo.v16.i5.2159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 02/06/2024] [Accepted: 03/12/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND The research findings suggest that the prognosis of children with Wilms tumor (WT) is affected by various factors. Some scholars have indicated that loss of heterozygosity (LOH) on chromosome 16q is associated with a poor prognosis in patients with WT. AIM To further elucidate this relationship, we conducted a meta-analysis. METHODS This meta-analysis was registered in INPLASY (INPLASY2023100060). We systematically searched databases including Embase, PubMed, Web of Science, Cochrane, and Google Scholar up to May 31, 2020, for randomized trials reporting any intrapartum fetal surveillance approach. The meta-analysis was performed within a frequentist framework, and the quality and network inconsistency of trials were assessed. Odds ratios and 95%CIs were calculated to report the relationship between event-free survival and 16q LOH in patients with WT. RESULTS Eleven cohort studies were included in this meta-analysis to estimate the relationship between event-free survival and 16q LOH in patients with WT (I2 = 25%, P < 0.001). As expected, 16q LOH can serve as an effective predictor of event-free survival in patients with WT (risk ratio = 1.95, 95%CI: 1.52-2.49, P < 0.001). CONCLUSION In pediatric patients with WT, there exists a partial correlation between 16q LOH and an unfavorable treatment prognosis. Clinical detection of 16q chromosome LOH warrants increased attention to the patient's prognosis.
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Affiliation(s)
- Yuan-Hua Song
- Department of Oncology, Kunming Children's Hospital, Kunming 650103, Yunnan Province, China
| | - Wen-Ling Li
- Department of Oncology, Kunming Children's Hospital, Kunming 650103, Yunnan Province, China
| | - Zhen Yang
- Department of Oncology, Kunming Children's Hospital, Kunming 650103, Yunnan Province, China
| | - Yan Gao
- Department of Oncology, Kunming Children's Hospital, Kunming 650103, Yunnan Province, China
| | - Zhi-Ping Feng
- Department of Nuclear Medicine, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), Kunming 650118, Yunnan Province, China
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Perotti D, Williams RD, Wegert J, Brzezinski J, Maschietto M, Ciceri S, Gisselsson D, Gadd S, Walz AL, Furtwaengler R, Drost J, Al-Saadi R, Evageliou N, Gooskens SL, Hong AL, Murphy AJ, Ortiz MV, O'Sullivan MJ, Mullen EA, van den Heuvel-Eibrink MM, Fernandez CV, Graf N, Grundy PE, Geller JI, Dome JS, Perlman EJ, Gessler M, Huff V, Pritchard-Jones K. Hallmark discoveries in the biology of Wilms tumour. Nat Rev Urol 2024; 21:158-180. [PMID: 37848532 DOI: 10.1038/s41585-023-00824-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2023] [Indexed: 10/19/2023]
Abstract
The modern study of Wilms tumour was prompted nearly 50 years ago, when Alfred Knudson proposed the 'two-hit' model of tumour development. Since then, the efforts of researchers worldwide have substantially expanded our knowledge of Wilms tumour biology, including major advances in genetics - from cloning the first Wilms tumour gene to high-throughput studies that have revealed the genetic landscape of this tumour. These discoveries improve understanding of the embryonal origin of Wilms tumour, familial occurrences and associated syndromic conditions. Many efforts have been made to find and clinically apply prognostic biomarkers to Wilms tumour, for which outcomes are generally favourable, but treatment of some affected individuals remains challenging. Challenges are also posed by the intratumoural heterogeneity of biomarkers. Furthermore, preclinical models of Wilms tumour, from cell lines to organoid cultures, have evolved. Despite these many achievements, much still remains to be discovered: further molecular understanding of relapse in Wilms tumour and of the multiple origins of bilateral Wilms tumour are two examples of areas under active investigation. International collaboration, especially when large tumour series are required to obtain robust data, will help to answer some of the remaining unresolved questions.
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Affiliation(s)
- Daniela Perotti
- Predictive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
| | - Richard D Williams
- Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
- Section of Genetics and Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Jenny Wegert
- Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Wuerzburg University, Wuerzburg, Germany
| | - Jack Brzezinski
- Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Mariana Maschietto
- Research Center, Boldrini Children's Hospital, Campinas, São Paulo, Brazil
| | - Sara Ciceri
- Predictive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - David Gisselsson
- Cancer Cell Evolution Unit, Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Clinical Genetics, Pathology and Molecular Diagnostics, Office of Medical Services, Skåne, Sweden
| | - Samantha Gadd
- Department of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Amy L Walz
- Division of Hematology,Oncology, Neuro-Oncology, and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Rhoikos Furtwaengler
- Division of Pediatric Oncology and Hematology, Department of Pediatrics, Inselspital Bern University, Bern, Switzerland
| | - Jarno Drost
- Princess Máxima Center for Paediatric Oncology, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Reem Al-Saadi
- Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
- Department of Histopathology, Great Ormond Street Hospital for Children, London, UK
| | - Nicholas Evageliou
- Divisions of Hematology and Oncology, Children's Hospital of Philadelphia, CHOP Specialty Care Center, Vorhees, NJ, USA
| | - Saskia L Gooskens
- Princess Máxima Center for Paediatric Oncology, Utrecht, Netherlands
| | - Andrew L Hong
- Aflac Cancer and Blood Disorders Center, Emory University and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Andrew J Murphy
- Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Michael V Ortiz
- Department of Paediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maureen J O'Sullivan
- Histology Laboratory, Children's Health Ireland at Crumlin, Dublin, Ireland
- Trinity Translational Medicine Institute, Trinity College, Dublin, Ireland
| | - Elizabeth A Mullen
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA
| | | | - Conrad V Fernandez
- Division of Paediatric Hematology Oncology, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada
| | - Norbert Graf
- Department of Paediatric Oncology and Hematology, Saarland University Hospital, Homburg, Germany
| | - Paul E Grundy
- Department of Paediatrics Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - James I Geller
- Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
| | - Jeffrey S Dome
- Division of Oncology, Center for Cancer and Blood Disorders, Children's National Hospital and the Department of Paediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
| | - Elizabeth J Perlman
- Department of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Manfred Gessler
- Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Wuerzburg University, Wuerzburg, Germany
- Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany
| | - Vicki Huff
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kathy Pritchard-Jones
- Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
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Zheng H, Liu J, Pan X, Cui X. Biomarkers for patients with Wilms tumor: a review. Front Oncol 2023; 13:1137346. [PMID: 37554168 PMCID: PMC10405734 DOI: 10.3389/fonc.2023.1137346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 06/27/2023] [Indexed: 08/10/2023] Open
Abstract
Wilms tumor, originating from aberrant fetal nephrogenesis, is the most common renal malignancy in childhood. The overall survival of children is approximately 90%. Although existing risk-stratification systems are helpful in identifying patients with poor prognosis, the recurrence rate of Wilms tumors remains as high as 15%. To resolve this clinical problem, diverse studies on the occurrence and progression of the disease have been conducted, and the results are encouraging. A series of molecular biomarkers have been identified with further studies on the mechanism of tumorigenesis. Some of these show prognostic value and have been introduced into clinical practice. Identification of these biomarkers can supplement the existing risk-stratification systems. In the future, more biomarkers will be discovered, and more studies are required to validate their roles in improving the detection rate of occurrence or recurrence of Wilms tumor and to enhance clinical outcomes.
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Affiliation(s)
| | | | - Xiuwu Pan
- Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xingang Cui
- Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Groenendijk A, Spreafico F, de Krijger RR, Drost J, Brok J, Perotti D, van Tinteren H, Venkatramani R, Godziński J, Rübe C, Geller JI, Graf N, van den Heuvel-Eibrink MM, Mavinkurve-Groothuis AMC. Prognostic Factors for Wilms Tumor Recurrence: A Review of the Literature. Cancers (Basel) 2021; 13:cancers13133142. [PMID: 34201787 PMCID: PMC8268923 DOI: 10.3390/cancers13133142] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/08/2021] [Accepted: 06/18/2021] [Indexed: 01/10/2023] Open
Abstract
Simple Summary A Wilms tumor is a childhood kidney tumor. In high-income countries, 90% of patients with this tumor survive. However, the tumor recurs in 15% of patients. It is important to identify the patients at risk of recurrence in order to adjust treatment in such a way that recurrence may potentially be prevented. However, we are currently unable to determine precisely which patients are at risk of recurrence. Therefore, we present an overview of factors that influence the risk of recurrence, also known as prognostic factors. These factors range from patient-, tumor- and treatment-related characteristics to geographic and socioeconomic factors. In addition to these factors, biological markers, such as genetic alterations, should be studied more intensively as these markers may be able to better identify patients at risk of tumor recurrence. Abstract In high-income countries, the overall survival of children with Wilms tumors (WT) is ~90%. However, overall, 15% of patients experience tumor recurrence. The adverse prognostic factors currently used for risk stratification (advanced stage, high risk histology, and combined loss of heterozygosity at 1p and 16q in chemotherapy-naïve WTs) are present in only one third of these cases, and the significance of these factors is prone to change with advancing knowledge and improved treatment regimens. Therefore, we present a comprehensive, updated overview of the published prognostic variables for WT recurrence, ranging from patient-, tumor- and treatment-related characteristics to geographic and socioeconomic factors. Improved first-line treatment regimens based on clinicopathological characteristics and advancing knowledge on copy number variations unveil the importance of further investigating the significance of biological markers for WT recurrence in international collaborations.
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Affiliation(s)
- Alissa Groenendijk
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (R.R.d.K.); (J.D.); (H.v.T.); (M.M.v.d.H.-E.); (A.M.C.M.-G.)
- Correspondence:
| | - Filippo Spreafico
- Department of Medical Oncology and Hematology, Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy;
| | - Ronald R. de Krijger
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (R.R.d.K.); (J.D.); (H.v.T.); (M.M.v.d.H.-E.); (A.M.C.M.-G.)
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
| | - Jarno Drost
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (R.R.d.K.); (J.D.); (H.v.T.); (M.M.v.d.H.-E.); (A.M.C.M.-G.)
- Oncode Institute, 3584 CS Utrecht, The Netherlands
| | - Jesper Brok
- Department of Pediatric Oncology and Hematology, Rigshospitalet, 2100 Copenhagen, Denmark;
- Developmental Biology and Cancer Research and Teaching Department, University College London Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
| | - Daniela Perotti
- Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy;
| | - Harm van Tinteren
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (R.R.d.K.); (J.D.); (H.v.T.); (M.M.v.d.H.-E.); (A.M.C.M.-G.)
| | | | - Jan Godziński
- Department of Pediatric Surgery, Marciniak Hospital, Fieldorfa 2, 54-049 Wroclaw, Poland;
- Department of Pediatric Traumatology and Emergency Medicine, Wroclaw Medical University, Bujwida 44a, 50-345 Wroclaw, Poland
| | - Christian Rübe
- Department of Radiation Oncology, Saarland University Medical Center and Saarland University Faculty of Medicine, D-66421 Homburg, Germany;
| | - James I. Geller
- Division of Oncology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA;
| | - Norbert Graf
- Department of Pediatric Oncology and Hematology, Saarland University Medical Center and Saarland University Faculty of Medicine, D-66421 Homburg, Germany;
| | - Marry M. van den Heuvel-Eibrink
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (R.R.d.K.); (J.D.); (H.v.T.); (M.M.v.d.H.-E.); (A.M.C.M.-G.)
| | - Annelies M. C. Mavinkurve-Groothuis
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands; (R.R.d.K.); (J.D.); (H.v.T.); (M.M.v.d.H.-E.); (A.M.C.M.-G.)
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Apple AN, Neuzil KE, Phelps HM, Li B, Lovvorn Iii HN. Race disparities in genetic alterations within Wilms tumor specimens. J Pediatr Surg 2021; 56:1135-1141. [PMID: 33745745 DOI: 10.1016/j.jpedsurg.2021.02.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 02/05/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND Wilms tumor (WT) affects Black children disproportionately. Genetic aberrations within WT specimens that contribute to this disparity have not been reported. METHODS The Therapeutically Applied Research to Generate Effective Treatments (TARGET) database was queried for WT patient and genomic features. Clinical and genetic variables were compared by race. RESULTS Within the discovery set (enriched for adverse events; N = 94 White, 19 Black, 14 Other/unreported patients), Black children were more likely to present with advanced stage disease (p = 0.019). Within the validation set (primarily a random sampling of NWTS-5; N = 360 White, 92 Black, 72 Other/Unreported), Black children appeared older at diagnosis (p = 0.050), had decreased median follow-up time (p<0.0005) and were over-represented (17.4%) relative to the concurrent U.S. Census (12.8%). Among the 37 target genes sequenced, ACTB (p = 0.030) and DICER1 (p = 0.026) mutations were more common in Black patient specimens, whereas DGCR8 (p = 0.041) mutations were more common in White patient specimens. White patient specimens were more likely to contain one or multiple targeted mutations (p = 0.026). CONCLUSION Within the TARGET database, Black children were over-represented and harbored WT specimens containing more frequent ACTB and DICER1 mutations. In contrast, WT from White children contained overall more mutations in targeted genes and specifically in DGCR8. LEVEL OF EVIDENCE III.
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Affiliation(s)
- Annie N Apple
- Vanderbilt University School of Medicine, Nashville, TN, United States; Surgical Outcomes Center for Kids, Monroe Carrell Jr. Children's Hospital, Vanderbilt University Medical Center, Nashville, TN, United States.
| | - Kevin E Neuzil
- Vanderbilt University School of Medicine, Nashville, TN, United States; Surgical Outcomes Center for Kids, Monroe Carrell Jr. Children's Hospital, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Hannah M Phelps
- Department of Surgery, Washington University at St. Louis School of Medicine, St. Louis, MO, United States
| | - Bingshan Li
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Harold N Lovvorn Iii
- Department of Pediatric Surgery, Monroe Carrell Jr. Children's Hospital, Vanderbilt University Medical Center, Nashville, TN, United States
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Kitamura E, Cowell JK, Chang CS, Hawthorn L. Variant profiles of genes mapping to chromosome 16q loss in Wilms tumors reveals link to cilia-related genes and pathways. Genes Cancer 2020; 11:137-153. [PMID: 33488951 PMCID: PMC7805536 DOI: 10.18632/genesandcancer.207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 09/08/2020] [Indexed: 11/25/2022] Open
Abstract
Background: Wilms tumor is the most common pediatric renal tumor and the fourth most common malignancy in children. Chromosome 16q deletion(del) or loss of heterozygosity (LOH) has been correlated with recurrence and overall poor prognosis, such that patients with 16qLOH and 1p allelic loss are treated with more aggressive chemotherapeutic regimens. Methods: In the present study, we have compared the variant profiles of Wilms tumors with and without 16q del/LOH using both data available from the TARGET database (42 samples) and tumors procured from our legacy collection (8 samples). Exome-Seq data was analyzed for tumor specific variants mapping to 16q. Whole exome analysis was also performed. An unbiased approach for somatic variant analysis was used to detect tumor-specific, somatic variants. Results: Of the 72 genes mapping to 16q, 42% were cilia-related genes and 28% of these were found to carry somatic variants specific to those tumors with 16qdel/LOH. Whole exome analyses further revealed that 30% of cilia-related genes across the genome carried alterations in tumors both with and without 16qdel/LOH. Additional pathway analyses revealed that many cilia-related pathway members also carried deleterious variant in these tumors including Sonic Hedgehog (SHh), Wnt, and Notch signaling pathways. Conclusions: The data suggest that cilia-related genes and pathways are compromised in Wilms tumors. The genes on chromosome 16q that carry deleterious variants in cilia-related genes may account for the more aggressive nature of tumors with 16q del/LOH.
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Affiliation(s)
- Eiko Kitamura
- Georgia Cancer Center, Augusta University, Augusta, GA, USA
| | - John K. Cowell
- Georgia Cancer Center, Augusta University, Augusta, GA, USA
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Abstract
BACKGROUND The prognostic role of copy number variation is upcoming in Wilms tumor, and its identification will help in tailored therapy for improved cure. STUDY DESIGN This was a retrospective, nested case-control, pilot study. MATERIALS AND METHODS Formalin-fixed paraffin-embedded blocks of nephrectomy specimens were retrieved for the study and control groups (children with relapse and survivors for ≥2 y). Multiplex ligand probe amplification (MRC-Holland probe-mix P 380 A1) was performed, with 3 reference samples of normal kidney DNA run for every 7 cases. RESULTS At least 1 variation was detected in 41 (97.8%) specimens. Loss of heterozygosity 1p was not observed. Loss of 16q, 1q gain, and MYCN gain were observed in 5 (11.9%), 29 (69%), and 39 (92.9%) specimens, respectively. The occurrence of copy number variations was similar in both groups: 1q gain: 15 versus 14 (P=1.0), 16q loss: 4 versus 1 (P=0.34), MYCN gain: 19 versus 20 (P=1.0). The gain of 1q, 16p loss, and MYCN gain did not differ across stage or age. CONCLUSIONS The gain of 1q, MYCN gain, and 16p loss were identified. A higher occurrence of 1q gain and MYCN gain and a lack of difference in the distribution of variations among survivors and those with a relapse suggest a different molecular profile of Wilms tumor in Indian children.
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Holl EK, Routh JC, Johnston AW, Frazier V, Rice HE, Tracy ET, Nair SK. Immune expression in children with Wilms tumor: a pilot study. J Pediatr Urol 2019; 15:441.e1-441.e8. [PMID: 30981637 DOI: 10.1016/j.jpurol.2019.03.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 03/13/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Given improvements in multimodality therapy, survival among children with Wilms tumor (WT) exceeds 90%. However, 15% of children with favorable histology and 50% of children with anaplastic WT experience recurrence or progression. Of patients with advanced disease, only 50% survive to adulthood. In adult malignancies (including renal tumors), patient survival has improved with the advent of immunotherapy. However, little is known about the immune microenvironment of WT, making the potential role of immunotherapy unclear. OBJECTIVE The objective of the study is to perform an exploratory, descriptive analysis of the immune milieu in WT. STUDY DESIGN Between 2016 and 2017, all pediatric patients with WT, some of whom received neoadjuvant chemotherapy, underwent ex vivo wedge biopsy at the time of nephrectomy. The fresh tumor tissue and peripheral blood samples were analyzed for infiltrating immune infiltrate and effector cells using flow cytometry. Immunohistochemistry was performed for CD4, CD8, and PD-L1 expression. Matched blood samples were obtained for each patient, and circulating immune cells were analyzed by flow cytometry. RESULTS A total of six patients were enrolled. One patient with neuroblastoma was excluded. The remaining five patients included the following: two with unilateral WT (resected before chemotherapy), two with bilateral WT (resected after neoadjuvant chemotherapy), and one with Denys-Drash syndrome, end-stage renal disease, and history of WT in the contralateral kidney. Immune analysis showed that WT were infiltrated by immune cells regardless of chemotherapy status. CD8 and CD4 T cells were present in the tumor tissue and exhibited an activated phenotype. Elevated levels of natural killer (NK) cells were observed in the tumors (Figure). Immune checkpoint PD-L1 was also found expressed in one of the tumors stained. DISCUSSION In this pilot study, it was found that WTs were infiltrated by immune cells (CD45+) both before and after chemotherapy. Elevated levels of NK cells infiltrating the tumor specimens, which were quantitatively increased compared with levels of NK cells circulating in the blood, were noted. T cells, particularly CD4+ and CD8+ T cells, were present in tumor specimens. Tumor-infiltrating CD4 and CD8 T cells displayed an activated phenotype as defined by increased expression of human leukocyte antigen-DR isotype (HLA-DR), programmed cell death protein 1 (PD1), and CD57. Together, these findings suggest that WT microenvironment is immune engaged and may be susceptible to immunotherapy similar to other malignancies. CONCLUSIONS These pilot data suggest an immune-engaged tumor microenvironment is present within WT. This implies that WT may be susceptible to immunotherapy similar to adult renal tumors and other adult malignancies. Follow-up studies are currently underway.
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Affiliation(s)
- E K Holl
- Division of Surgical Sciences, Dept of Surgery, Duke University School of Medicine, Durham, NC, USA.
| | - J C Routh
- Division of Pediatric Surgery, Dept of Surgery, Duke University School of Medicine, Durham, NC, USA; Division of Urologic Surgery, Dept of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - A W Johnston
- Division of Urologic Surgery, Dept of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - V Frazier
- Division of Surgical Sciences, Dept of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - H E Rice
- Division of Pediatric Surgery, Dept of Surgery, Duke University School of Medicine, Durham, NC, USA; Division of Urologic Surgery, Dept of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - E T Tracy
- Division of Pediatric Surgery, Dept of Surgery, Duke University School of Medicine, Durham, NC, USA; Division of Urologic Surgery, Dept of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - S K Nair
- Division of Surgical Sciences, Dept of Surgery, Duke University School of Medicine, Durham, NC, USA
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10
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Park JE, Noh OK, Lee Y, Choi HS, Han JW, Hahn SM, Lyu CJ, Lee JW, Yoo KH, Koo HH, Jeong SY, Sung KW. Loss of Heterozygosity at Chromosome 16q Is a Negative Prognostic Factor in Korean Pediatric Patients with Favorable Histology Wilms Tumor: A Report of the Korean Pediatric Hematology Oncology Group (K-PHOG). Cancer Res Treat 2019; 52:438-445. [PMID: 31505910 PMCID: PMC7176966 DOI: 10.4143/crt.2019.313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 09/09/2019] [Indexed: 11/21/2022] Open
Abstract
PURPOSE Loss of heterozygosity (LOH) at chromosomes 1p and 16q is a poor prognostic factor in favorable histology Wilms tumor (FHWT). This study investigated the prevalence of LOH at 1p and 16q and evaluated its prognostic value in Korean children with FHWT. MATERIALS AND METHODS We analyzed 101 FHWT patients who were diagnosed between 1996 and 2016 in Korean Society of Pediatric Hematology Oncology Group hospitals. Using paraffin-embedded kidney tissue samples sent from each center, we reviewed LOH at 1p and 16q in each patient and assessed the prognostic value of LOH status for clinical parameters affecting event-free survival (EFS). RESULTS Of the 101 patients, 12 (11.9%) experienced recurrence; the 3-year EFS was 87.6%. LOH at 1p or 16q was detected in 19 patients (18.8%), with five having LOH at both 1q and 16q. The frequency of LOH at 1p was higher among younger patients (p=0.049), but there was no difference in LOH prevalence according to tumor stage. In the multivariate analysis, LOH at 16q was a significant negative prognostic factor affecting EFS (3-year EFS, 73.7% vs. 91.1%; hazard ratio, 3.95; p=0.037), whereas LOH at 1p was not (p=0.786). CONCLUSION LOH at 16q was a significant negative prognostic factor affecting outcome in Korean pediatric FHWT patients. Due to the small sample size of this study, large-scale multicenter trials are warranted to investigate the prognostic value of LOH at 1p and 16q in Korean children with FHWT.
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Affiliation(s)
- Jun Eun Park
- Department of Pediatrics, Ajou University School of Medicine, Suwon, Korea
| | - O Kyu Noh
- Department of Radiation Oncology, Ajou University School of Medicine, Suwon, Korea
| | - Yonghee Lee
- Department of Pathology, Ajou University School of Medicine, Suwon, Korea
| | - Hyoung Soo Choi
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jung Woo Han
- Department of Pediatric Hematology and Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea
| | - Seung Min Hahn
- Department of Pediatric Hematology and Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea
| | - Chuhl Joo Lyu
- Department of Pediatric Hematology and Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea
| | - Ji Won Lee
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Keon Hee Yoo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hong Hoe Koo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seon-Yong Jeong
- Department of Medical Genetics, Ajou University School of Medicine, Suwon, Korea
| | - Ki Woong Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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11
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Haruta M, Arai Y, Okita H, Tanaka Y, Takimoto T, Sugino RP, Yamada Y, Kamijo T, Oue T, Fukuzawa M, Koshinaga T, Kaneko Y. Combined Genetic and Chromosomal Characterization of Wilms Tumors Identifies Chromosome 12 Gain as a Potential New Marker Predicting a Favorable Outcome. Neoplasia 2018; 21:117-131. [PMID: 30530054 PMCID: PMC6288985 DOI: 10.1016/j.neo.2018.10.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 10/29/2018] [Accepted: 10/29/2018] [Indexed: 11/26/2022] Open
Abstract
To identify prognostic factors, array CGH (aCGH) patterns and mutations in WT1 and 9 other genes were analyzed in 128 unilateral Wilms tumors (WTs). Twenty patients had no aCGH aberrations, and 31 had WT1 alterations [silent and WT1 types: relapse-free survival (RFS), 95% and 83%, respectively]. Seventy-seven patients had aCGH changes without WT1 alterations (nonsilent/non-WT1 type) and were subtyped into those with or without +12, 11q-, 16q-, or HACE1 loss. RFS was better for those with than those without +12 (P = .010) and worse for those with than those without 11q-, 16q-, or HACE1 loss (P = .001, .025, or 1.2E-04, respectively). Silent and WT1 type and 8 subtype tumors were integrated and classified into 3 risk groups: low risk for the silent type and +12 subgroup; high risk for the no +12 plus 11q-, 16q-, or HACE1 loss subgroup; intermediate risk for the WT1 type and no +12 plus no 11q-, 16q-, or HACE1 loss subgroup. Among the 27 WTs examined, the expression of 146 genes on chromosome 12 was stronger in +12 tumors than in no +12 tumors, while that of 10 genes on 16q was weaker in 16q- tumors than in no 16q- tumors. Overexpression in 75 out of 146 upregulated genes and underexpression in 7 out of 10 downregulated genes correlated with better and worse overall survival, respectively, based on the public database. +12 was identified as a potential new marker predicting a favorable outcome, and chromosome abnormalities may be related to altered gene expression associated with these abnormalities.
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Affiliation(s)
- Masayuki Haruta
- Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama 362-0806, Japan
| | - Yasuhito Arai
- Cancer Genomics Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Hajime Okita
- Department of Pathology, Keio University, Tokyo 157-8535, Japan
| | - Yukichi Tanaka
- Department of Pathology, Kanagawa Children's Medical Center, Kanagawa 232-8555, Japan
| | - Tetsuya Takimoto
- Clinical Research Center, National Center for Child Health and Development, Tokyo 157-8535, Japan
| | - Ryuichi P Sugino
- Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama 362-0806, Japan
| | - Yasuhiro Yamada
- Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan
| | - Takehiko Kamijo
- Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama 362-0806, Japan
| | - Takaharu Oue
- Department of Pediatric Surgery, Hyogo College of Medicine, Hyogo 663-8501, Japan
| | | | - Tsugumichi Koshinaga
- Department of Pediatric Surgery, Nihon University School of Medicine, Tokyo 173-8610, Japan
| | - Yasuhiko Kaneko
- Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama 362-0806, Japan.
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12
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Loke BN, Wong MK, Tawng KD, Kuick CH, Jain S, Lian D, Wagner E, Zou Y, Ganesan V, Sim SW, Lee YT, Chin F, Chan MY, Tan AM, Teh BT, Soh SY, Chang KT, Loh AH. Clinical, pathological and loss of heterozygosity differences in Wilms tumors between Asian and non-Asian children. Int J Cancer 2018; 144:1234-1242. [DOI: 10.1002/ijc.31946] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 09/27/2018] [Accepted: 10/10/2018] [Indexed: 01/02/2023]
Affiliation(s)
- Benjamin N. Loke
- Department of Biological Sciences; National University of Singapore; Singapore Singapore
| | - Meng Kang Wong
- VIVA-KKH Paediatric Solid Tumour Research Laboratory; KK Women's and Children's Hospital; Singapore Singapore
| | - Khawn D. Tawng
- Department of Paediatric Subspecialties Haematology/Oncology Service; KK Women's and Children's Hospital; Singapore Singapore
| | - Chick Hong Kuick
- Department of Pathology and Laboratory Medicine; KK Women's and Children's Hospital; Singapore Singapore
| | - Sudhanshi Jain
- Department of Pathology and Laboratory Medicine; KK Women's and Children's Hospital; Singapore Singapore
| | - Derrick Lian
- Department of Pathology and Laboratory Medicine; KK Women's and Children's Hospital; Singapore Singapore
| | - Elizabeth Wagner
- Institute for Genomic Medicine; Nationwide Children's Hospital; Columbus OH
| | - Yuhan Zou
- Yong Loo Lin School of Medicine; National University of Singapore; Singapore Singapore
| | - Visveswari Ganesan
- Yong Loo Lin School of Medicine; National University of Singapore; Singapore Singapore
| | - Siam Wee Sim
- Department of Paediatric Surgery; KK Women's and Children's Hospital; Singapore Singapore
| | - York Tien Lee
- Department of Paediatric Surgery; KK Women's and Children's Hospital; Singapore Singapore
| | - Francis Chin
- Division of Radiation Oncology, National Cancer Centre Singapore; Singapore Singapore
| | - Mei Yoke Chan
- Department of Paediatric Subspecialties Haematology/Oncology Service; KK Women's and Children's Hospital; Singapore Singapore
| | - Ah Moy Tan
- Department of Paediatric Subspecialties Haematology/Oncology Service; KK Women's and Children's Hospital; Singapore Singapore
| | - Bin Tean Teh
- Laboratory of Cancer Epigenome, National Cancer Centre Singapore; Singapore Singapore
| | - Shui Yen Soh
- Department of Paediatric Subspecialties Haematology/Oncology Service; KK Women's and Children's Hospital; Singapore Singapore
| | - Kenneth T.E. Chang
- VIVA-KKH Paediatric Solid Tumour Research Laboratory; KK Women's and Children's Hospital; Singapore Singapore
- Department of Pathology and Laboratory Medicine; KK Women's and Children's Hospital; Singapore Singapore
| | - Amos H.P. Loh
- VIVA-KKH Paediatric Solid Tumour Research Laboratory; KK Women's and Children's Hospital; Singapore Singapore
- Department of Paediatric Surgery; KK Women's and Children's Hospital; Singapore Singapore
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13
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Bu Q, He H, Fan D, Lyu J, Pan Z, You H. Association between loss of heterozygosity of chromosome 16q and survival in Wilms' tumor: A meta-analysis. Pathol Res Pract 2018; 214:1772-1777. [PMID: 30143352 DOI: 10.1016/j.prp.2018.08.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 07/31/2018] [Accepted: 08/08/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Wilms' tumor (WT) is the most common pediatric renal tumor. Despite its high survival rate, the potential prognostic factors should further be studied to reduce the intensity of the treatment. A few studies have found LOH of 16q is associated with worse survival in patients with WT, but it is still contradictory. This study aimed to performed a meta-analysis to clarify this. METHODS Databases including the Wanfang, PubMed, Chinese National Knowledge Infrastructure, Embase, and Cochrane Library databases were searched July 2018. The meta-analysis was done using Stata (version 14.0). Publication bias was evaluated by funnel plots, Begg's test, and Egger's test. The trim-and-fill method was applied if significant publication bias existed. Sensitivity analysis was performed to evaluate the stability of the results. RESULTS This meta-analysis identified 9 cohort studies encompassing 3266 cases. The pooled relative risk when comparing LOH of 16q groups with control groups was 2.22 [95% confidence interval (CI) = 1.64-3.00, P < 0.001], and the pooled hazard ratio was 1.92 (95%CI = 1.32-2.80, P = 0.001). The results were stable after correcting for publication bias and performing a leave-one-out sensitivity analysis. CONCLUSIONS This meta-analysis indicated that LOH of 16q was significantly associated with worse survival in WT. Further studies need to identify this conclusion because the overall quality of the included studies is not high, investigate the impact of LOH of 16q on the survival of WT patients in different subgroups and identify better treatments for WT patients with LOH of 16q in order to lengthen their survival.
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Affiliation(s)
- Qingting Bu
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; Department of Genetics, Northwest Women's and Children's Hospital, Xi'an, 710061, China
| | - Hairong He
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Di Fan
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jun Lyu
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Zhenyu Pan
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China; School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China; Department of Pharmacy, The Affiliated Children Hospital of Xi'an Jiaotong University, Xi'an, 710003, China.
| | - Haisheng You
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
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14
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Jiménez I, Chicard M, Colmet-Daage L, Clément N, Danzon A, Lapouble E, Pierron G, Bohec M, Baulande S, Berrebi D, Fréneaux P, Coulomb A, Galmiche-Rolland L, Sarnacki S, Audry G, Philippe-Chomette P, Brisse HJ, Doz F, Michon J, Delattre O, Schleiermacher G. Circulating tumor DNA analysis enables molecular characterization of pediatric renal tumors at diagnosis. Int J Cancer 2018; 144:68-79. [DOI: 10.1002/ijc.31620] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 03/27/2018] [Accepted: 05/11/2018] [Indexed: 01/05/2023]
Affiliation(s)
- Irene Jiménez
- SIREDO Oncology Center (Care, Innovation and research for children and AYA with cancer); Institut Curie; Paris France
- INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center; Institut Curie; Paris France
- SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique »; Institut Curie; Paris France
- PSL Research University; Paris France
| | - Mathieu Chicard
- SIREDO Oncology Center (Care, Innovation and research for children and AYA with cancer); Institut Curie; Paris France
- INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center; Institut Curie; Paris France
- SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique »; Institut Curie; Paris France
- PSL Research University; Paris France
| | - Léo Colmet-Daage
- SIREDO Oncology Center (Care, Innovation and research for children and AYA with cancer); Institut Curie; Paris France
- INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center; Institut Curie; Paris France
- SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique »; Institut Curie; Paris France
- PSL Research University; Paris France
| | - Nathalie Clément
- SIREDO Oncology Center (Care, Innovation and research for children and AYA with cancer); Institut Curie; Paris France
- SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique »; Institut Curie; Paris France
- PSL Research University; Paris France
| | - Adrien Danzon
- SIREDO Oncology Center (Care, Innovation and research for children and AYA with cancer); Institut Curie; Paris France
- INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center; Institut Curie; Paris France
- SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique »; Institut Curie; Paris France
- PSL Research University; Paris France
| | - Eve Lapouble
- Somatic Genetics Unit; Institut Curie; Paris France
| | | | - Mylène Bohec
- Research Center, Institut Curie; Institut Curie Genomics of Excellence (ICGex) Platform; Paris France
| | - Sylvain Baulande
- Research Center, Institut Curie; Institut Curie Genomics of Excellence (ICGex) Platform; Paris France
| | | | - Paul Fréneaux
- PSL Research University; Paris France
- Service de Pathologie; Hospital Group, Institut Curie; Paris France
| | - Aurore Coulomb
- Service de Pathologie; Hôpital Armand Trousseau, APHP; Paris France
- Université Pierre et Marie Curie; Paris France
| | | | - Sabine Sarnacki
- Département de Chirurgie Pédiatrique; Hôpital Necker, APHP; Paris France
- Université Paris Descartes; Paris France
| | - Georges Audry
- Université Pierre et Marie Curie; Paris France
- Département de Chirurgie Pédiatrique; Hôpital Armand Trousseau, APHP; Paris France
| | | | - Hervé J. Brisse
- PSL Research University; Paris France
- Département d'Imagerie; Hospital Group, Institut Curie; Paris France
| | - François Doz
- SIREDO Oncology Center (Care, Innovation and research for children and AYA with cancer); Institut Curie; Paris France
- PSL Research University; Paris France
- Université Paris Descartes; Paris France
| | - Jean Michon
- SIREDO Oncology Center (Care, Innovation and research for children and AYA with cancer); Institut Curie; Paris France
- PSL Research University; Paris France
| | - Olivier Delattre
- SIREDO Oncology Center (Care, Innovation and research for children and AYA with cancer); Institut Curie; Paris France
- INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center; Institut Curie; Paris France
- PSL Research University; Paris France
| | - Gudrun Schleiermacher
- SIREDO Oncology Center (Care, Innovation and research for children and AYA with cancer); Institut Curie; Paris France
- INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center; Institut Curie; Paris France
- SiRIC RTOP « Recherche Translationelle en Oncologie Pédiatrique »; Institut Curie; Paris France
- PSL Research University; Paris France
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15
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Pan Z, He H, Tang L, Bu Q, Cheng H, Wang A, Lyu J, You H. Loss of heterozygosity on chromosome 16q increases relapse risk in Wilms' tumor: a meta-analysis. Oncotarget 2017; 8:66467-66475. [PMID: 29029528 PMCID: PMC5630428 DOI: 10.18632/oncotarget.20191] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 08/06/2017] [Indexed: 02/05/2023] Open
Abstract
Wilms' tumor (WT) is the most frequent malignant renal tumor in children. The survival rate is lower in patients with recurrence, and the factors that influence relapse in WT are not fully understood. Loss of heterozygosity on chromosome 16q (LOH 16q) has been reported to be associated with the relapse in WT, but this remains controversial. We performed a meta-analysis to clarify this. PUBMED, EMBASE, and the Cochrane Library were searched up to March 17, 2017. Ten studies involving 3385 patients were ultimately included in the meta-analysis. The meta-analysis showed that LOH 16q was significantly associated with the relapse in WT (relative risk [RR] = 1.74, 95% confidence interval [CI] = 1.43-2.13, P < 0.00001; hazard ratio [HR] = 1.76, 95% CI = 1.38-2.24, P < 0.00001). No significant heterogeneity among studies or publication bias was found. Sensitivity analysis showed omitting one study in each turn could not change the results. Subgroup analysis based on two studies indicated LOH 16q was more effective on elevated replase risk in patients with favorable-histology WT (RR = 2.52, 95% CI = 1.68-3.78, P < 0.00001; HR = 2.99, 95% CI = 1.84-4.88, P < 0.0001) but further work are needed to confirm this. These findings confirm that LOH 16q increased the relapse risk in WT, but more studies are required to further assess the association between LOH 16q and WT relapse among different subgroups.
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Affiliation(s)
- Zhenyu Pan
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, 710061, China
- Department of Pharmacy, Xi’an Jiaotong University Affiliated Children’s Hospital, Xi’an, Shaanxi, 710003, China
| | - Hairong He
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, 710061, China
| | - Lina Tang
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, 710061, China
| | - Qingting Bu
- Department of Genetics, Northwest Women’s and Children’s Hospital, Xi’an, Shaanxi, 710061, China
| | - Hua Cheng
- Department of Pharmacy, Xi’an Jiaotong University Affiliated Children’s Hospital, Xi’an, Shaanxi, 710003, China
| | - Anmin Wang
- Department of Pharmacy, Xi’an Jiaotong University Affiliated Children’s Hospital, Xi’an, Shaanxi, 710003, China
| | - Jun Lyu
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, 710061, China
| | - Haisheng You
- Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an, Shaanxi, 710061, China
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16
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Bahrami A, Joodi M, Maftooh M, Ferns GA, M. Ahmadi M, Hassanian SM, Avan A. The genetic factors contributing to the development of Wilm's tumor and their clinical utility in its diagnosis and prognosis. J Cell Physiol 2017; 233:2882-2888. [DOI: 10.1002/jcp.26021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/19/2017] [Indexed: 12/19/2022]
Affiliation(s)
- Afsane Bahrami
- Department of Modern Sciences and Technologies; Faculty of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
- Student Research Committee; Faculty of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Marjan Joodi
- Department of Pediatric Surgery; Faculty of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
- Endoscopic and Minimally Invasive Surgery Research Center; Sarvar Children's Hospital; Mashhad Iran
| | - Mina Maftooh
- Metabolic Syndrome Research Center; Mashhad University of Medical Sciences; Mashhad Iran
| | - Gordon A. Ferns
- Division of Medical Education, Falmer, Brighton; Brighton and Sussex Medical School; Sussex UK
| | - Mehrdad M. Ahmadi
- Metabolic Syndrome Research Center; Mashhad University of Medical Sciences; Mashhad Iran
| | - Seyed M. Hassanian
- Metabolic Syndrome Research Center; Mashhad University of Medical Sciences; Mashhad Iran
| | - Amir Avan
- Metabolic Syndrome Research Center; Mashhad University of Medical Sciences; Mashhad Iran
- Cancer Research Center; Mashhad University of Medical Sciences; Mashhad Iran
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17
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Spreafico F, Ciceri S, Gamba B, Torri F, Terenziani M, Collini P, Macciardi F, Radice P, Perotti D. Chromosomal anomalies at 1q, 3, 16q, and mutations of SIX1 and DROSHA genes underlie Wilms tumor recurrences. Oncotarget 2017; 7:8908-15. [PMID: 26802027 PMCID: PMC4891013 DOI: 10.18632/oncotarget.6950] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 12/08/2015] [Indexed: 12/22/2022] Open
Abstract
Approximately half of children suffering from recurrent Wilms tumor (WT) develop resistance to salvage therapies. Hence the importance to disclose events driving tumor progression/recurrence. Future therapeutic trials, conducted in the setting of relapsing patients, will need to prioritize targets present in the recurrent lesions. Different studies identified primary tumor-specific signatures associated with poor prognosis. However, given the difficulty in recruiting specimens from recurrent WTs, little work has been done to compare the molecular profile of paired primary/recurrent diseases. We studied the genomic profile of a cohort of eight pairs of primary/recurrent WTs through whole-genome SNP arrays, and investigated known WT-associated genes, including SIX1, SIX2 and micro RNA processor genes, whose mutations have been recently proposed as associated with worse outcome. Through this approach, we sought to uncover anomalies characterizing tumor recurrence, either acquired de novo or already present in the primary disease, and to investigate whether they overlapped with known molecular prognostic signatures. Among the aberrations that we disclosed as potentially acquired de novo in recurrences, some had been already recognized in primary tumors as associated with a higher risk of relapse. These included allelic imbalances of chromosome 1q and of chromosome 3, and CN losses on chromosome 16q. In addition, we found that SIX1 and DROSHA mutations can be heterogeneous events (both spatially and temporally) within primary tumors, and that their co-occurrence might be positively selected in the progression to recurrent disease. Overall, these results provide new insights into genomic and genetic events underlying WT progression/recurrence.
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Affiliation(s)
- Filippo Spreafico
- Pediatric Unit, Department of Hematology and Pediatric Onco-Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sara Ciceri
- Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Beatrice Gamba
- Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Torri
- Genomics and Bioinformatics Unit, University of Milan-Fondazione Filarete, Milan, Italy
| | - Monica Terenziani
- Pediatric Unit, Department of Hematology and Pediatric Onco-Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paola Collini
- Department of Pathology and Laboratory Medicine Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Fabio Macciardi
- Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, CA, USA
| | - Paolo Radice
- Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Daniela Perotti
- Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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18
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Fawzy M, Bahanassy A, Samir A, Hafez H. Profiling Loss of Heterozygosity Patterns in a Cohort of Favorable Histology Nephroblastoma Egyptian Patients: What is Consistent With the Rest of the World. Pediatr Hematol Oncol 2016; 32:548-56. [PMID: 26390800 DOI: 10.3109/08880018.2015.1071902] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
According to the Fifth National Wilms Tumor Study (NWTS-5), tumor-specific loss of heterozygosity (LOH) for chromosomes 1p and 16q identifies a subset of patients with Wilms tumor (WT) who despite having favorable histology (FH) have a significantly increased risk of relapse and death. We aimed to find out 1p and 16q LOH frequencies in patients with FH-WT as well as its correlation to survival outcome and epidemiologic and clinical characteristics. Data of patients with FH-WT presenting to the National Cancer Institute, Egypt, were retrospectively analyzed. Paraffin blocks were tested for 1p and 16q LOH using polymorphic loci that span the minimal regions of LOH at this area. The study included 100 patients with a median age of 5 years. Thirty-nine patients (39%) showed LOH at 1p (n = 14), 16q (n = 13), or both (n = 12). LOH was most frequently encountered in patients above 10 years (5/5), advanced stages disease (80% of stage V and 50% of stages IV and III each). The 3-year overall survival (OS) and event-free survival (EFS) were significantly lower in patients with double LOH (75% and 50%, respectively), followed by 16q (92% and 54%), in comparison with 1p (93% each) and negative LOH (97% and 100%) cases, respectively (p = 0.001). Combined LOH (1p+16q), followed by 16q LOH alone, was predictive of poorer outcome and was associated with lower OS and EFS in patients with FH-WT. Our results showed a higher-risk disease that would suggest the need for an intensified upfront therapy in this group of patients.
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Affiliation(s)
- Mohamed Fawzy
- a Department of Pediatric Oncology , National Cancer Institute , Cairo , Egypt
| | - Abeer Bahanassy
- b Department of Pathology , National Cancer Institute , Cairo , Egypt
| | - Amr Samir
- c Department of Pediatrics , Armed Forces Hospitals , Egypt
| | - Hanafy Hafez
- a Department of Pediatric Oncology , National Cancer Institute , Cairo , Egypt
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Gratias EJ, Dome JS, Jennings LJ, Chi YY, Tian J, Anderson J, Grundy P, Mullen EA, Geller JI, Fernandez CV, Perlman EJ. Association of Chromosome 1q Gain With Inferior Survival in Favorable-Histology Wilms Tumor: A Report From the Children's Oncology Group. J Clin Oncol 2016; 34:3189-94. [PMID: 27400937 PMCID: PMC5012705 DOI: 10.1200/jco.2015.66.1140] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
PURPOSE The goal of this study was to analyze the association of copy number gain of 1q in favorable-histology Wilms tumors (FHWTs) with event-free survival (EFS) and overall survival (OS) within each tumor stage and with 1p and 16q copy number loss and/or loss of heterozygosity. METHODS Unilateral FHWTs from 1,114 patients enrolled in National Wilms Tumor Study-5 that were informative for 1p and 16q microsatellite markers (previously determined) and informative for 1q gain, 1p loss, and 16q loss using multiplex ligation-dependent probe amplification were analyzed. RESULTS Eight-year EFS was 86% (95% CI, 84% to 88%) for the entire cohort. Of 1,114 patients, 317 tumors (28%) displayed 1q gain. Eight-year EFS was 77% for those with 1q gain and 90% for those lacking 1q gain (P < .001). Eight-year OS was 88% for those with 1q gain and 96% for those lacking 1q gain (P < .001). Within each disease stage, 1q gain was associated with inferior EFS (stage I, 85% v 95%; P = .0052; stage II, 81% v 87%; P = .0775; stage III, 79% v 89%; P = .01; stage IV, 64% v 91%; P = .001). OS was significantly inferior in patients with stage I (P < .0015) and stage IV disease (P = .011). With multivariable analysis, 1q gain was associated with an increased relative risk of relapse of 2.4 (P < .001), whereas 1p loss was not, despite significance on univariable analysis. CONCLUSION Gain of 1q is associated with inferior survival in unilateral FHWTs and may be used to guide risk stratification in future studies.
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Affiliation(s)
- Eric J Gratias
- Eric J. Gratias, University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN; Jeffrey S. Dome, Children's National Health System, Washington, DC; Lawrence J. Jennings and Elizabeth J. Perlman, Northwestern University, Chicago, IL; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James Anderson, University of Nebraska Medical Center, Omaha, NE; Paul Grundy, University of Alberta, Edmonton, Alberta; Conrad V. Fernandez, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada; Elizabeth A. Mullen, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA; and James I. Geller, University of Cincinnati, Cincinnati, OH
| | - Jeffrey S Dome
- Eric J. Gratias, University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN; Jeffrey S. Dome, Children's National Health System, Washington, DC; Lawrence J. Jennings and Elizabeth J. Perlman, Northwestern University, Chicago, IL; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James Anderson, University of Nebraska Medical Center, Omaha, NE; Paul Grundy, University of Alberta, Edmonton, Alberta; Conrad V. Fernandez, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada; Elizabeth A. Mullen, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA; and James I. Geller, University of Cincinnati, Cincinnati, OH
| | - Lawrence J Jennings
- Eric J. Gratias, University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN; Jeffrey S. Dome, Children's National Health System, Washington, DC; Lawrence J. Jennings and Elizabeth J. Perlman, Northwestern University, Chicago, IL; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James Anderson, University of Nebraska Medical Center, Omaha, NE; Paul Grundy, University of Alberta, Edmonton, Alberta; Conrad V. Fernandez, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada; Elizabeth A. Mullen, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA; and James I. Geller, University of Cincinnati, Cincinnati, OH
| | - Yueh-Yun Chi
- Eric J. Gratias, University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN; Jeffrey S. Dome, Children's National Health System, Washington, DC; Lawrence J. Jennings and Elizabeth J. Perlman, Northwestern University, Chicago, IL; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James Anderson, University of Nebraska Medical Center, Omaha, NE; Paul Grundy, University of Alberta, Edmonton, Alberta; Conrad V. Fernandez, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada; Elizabeth A. Mullen, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA; and James I. Geller, University of Cincinnati, Cincinnati, OH
| | - Jing Tian
- Eric J. Gratias, University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN; Jeffrey S. Dome, Children's National Health System, Washington, DC; Lawrence J. Jennings and Elizabeth J. Perlman, Northwestern University, Chicago, IL; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James Anderson, University of Nebraska Medical Center, Omaha, NE; Paul Grundy, University of Alberta, Edmonton, Alberta; Conrad V. Fernandez, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada; Elizabeth A. Mullen, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA; and James I. Geller, University of Cincinnati, Cincinnati, OH
| | - James Anderson
- Eric J. Gratias, University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN; Jeffrey S. Dome, Children's National Health System, Washington, DC; Lawrence J. Jennings and Elizabeth J. Perlman, Northwestern University, Chicago, IL; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James Anderson, University of Nebraska Medical Center, Omaha, NE; Paul Grundy, University of Alberta, Edmonton, Alberta; Conrad V. Fernandez, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada; Elizabeth A. Mullen, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA; and James I. Geller, University of Cincinnati, Cincinnati, OH
| | - Paul Grundy
- Eric J. Gratias, University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN; Jeffrey S. Dome, Children's National Health System, Washington, DC; Lawrence J. Jennings and Elizabeth J. Perlman, Northwestern University, Chicago, IL; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James Anderson, University of Nebraska Medical Center, Omaha, NE; Paul Grundy, University of Alberta, Edmonton, Alberta; Conrad V. Fernandez, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada; Elizabeth A. Mullen, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA; and James I. Geller, University of Cincinnati, Cincinnati, OH
| | - Elizabeth A Mullen
- Eric J. Gratias, University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN; Jeffrey S. Dome, Children's National Health System, Washington, DC; Lawrence J. Jennings and Elizabeth J. Perlman, Northwestern University, Chicago, IL; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James Anderson, University of Nebraska Medical Center, Omaha, NE; Paul Grundy, University of Alberta, Edmonton, Alberta; Conrad V. Fernandez, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada; Elizabeth A. Mullen, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA; and James I. Geller, University of Cincinnati, Cincinnati, OH
| | - James I Geller
- Eric J. Gratias, University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN; Jeffrey S. Dome, Children's National Health System, Washington, DC; Lawrence J. Jennings and Elizabeth J. Perlman, Northwestern University, Chicago, IL; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James Anderson, University of Nebraska Medical Center, Omaha, NE; Paul Grundy, University of Alberta, Edmonton, Alberta; Conrad V. Fernandez, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada; Elizabeth A. Mullen, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA; and James I. Geller, University of Cincinnati, Cincinnati, OH
| | - Conrad V Fernandez
- Eric J. Gratias, University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN; Jeffrey S. Dome, Children's National Health System, Washington, DC; Lawrence J. Jennings and Elizabeth J. Perlman, Northwestern University, Chicago, IL; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James Anderson, University of Nebraska Medical Center, Omaha, NE; Paul Grundy, University of Alberta, Edmonton, Alberta; Conrad V. Fernandez, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada; Elizabeth A. Mullen, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA; and James I. Geller, University of Cincinnati, Cincinnati, OH
| | - Elizabeth J Perlman
- Eric J. Gratias, University of Tennessee College of Medicine-Chattanooga, Chattanooga, TN; Jeffrey S. Dome, Children's National Health System, Washington, DC; Lawrence J. Jennings and Elizabeth J. Perlman, Northwestern University, Chicago, IL; Yueh-Yun Chi and Jing Tian, University of Florida, Gainesville, FL; James Anderson, University of Nebraska Medical Center, Omaha, NE; Paul Grundy, University of Alberta, Edmonton, Alberta; Conrad V. Fernandez, Dalhousie University and the IWK Health Centre, Halifax, Nova Scotia, Canada; Elizabeth A. Mullen, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA; and James I. Geller, University of Cincinnati, Cincinnati, OH.
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Abstract
PURPOSE Wilms tumor is the most common childhood renal malignancy and the fourth most common childhood cancer. Many biomarkers have been studied but there has been no comprehensive summary. We systematically reviewed the literature on biomarkers in Wilms tumor to quantify the prognostic implications of the presence of individual tumor markers. MATERIALS AND METHODS We searched for English language studies from 1980 to 2015 performed in patients younger than 18 years with Wilms tumor and prognostic data. The protocol was conducted per PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Two reviewers abstracted data in duplicate using a standard evaluation form. We performed descriptive statistics, then calculated relative risks and 95% confidence intervals for markers appearing in multiple level II or III studies. RESULTS A total of 40 studies were included examining 32 biomarkers in 7,381 patients with Wilms tumor. Studies had a median of 61 patients, 24 biomarker positive patients per series and a median followup of 68.4 months. Median percentages of patients with stages 1, 2, 3, 4 and 5 tumors were 28.5%, 26.4%, 24.5%, 14.1% and 1.7%, respectively, and 10.2% had anaplasia. The strongest negative prognostic association was loss of heterozygosity at 11p15, with a risk of recurrence of 5.00, although loss of heterozygosity at 1p and gain of function at 1q were also strongly linked to increased recurrence (2.93 and 2.86, respectively). CONCLUSIONS Several tumor markers are associated with an increased risk of recurrence or a decreased risk of overall survival in patients with Wilms tumor. These data suggest targets for development of diagnostic tests and potential therapies.
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Ludwig N, Werner TV, Backes C, Trampert P, Gessler M, Keller A, Lenhof HP, Graf N, Meese E. Combining miRNA and mRNA Expression Profiles in Wilms Tumor Subtypes. Int J Mol Sci 2016; 17:475. [PMID: 27043538 PMCID: PMC4848931 DOI: 10.3390/ijms17040475] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 03/18/2016] [Accepted: 03/22/2016] [Indexed: 12/22/2022] Open
Abstract
Wilms tumor (WT) is the most common childhood renal cancer. Recent findings of mutations in microRNA (miRNA) processing proteins suggest a pivotal role of miRNAs in WT genesis. We performed miRNA expression profiling of 36 WTs of different subtypes and four normal kidney tissues using microarrays. Additionally, we determined the gene expression profile of 28 of these tumors to identify potentially correlated target genes and affected pathways. We identified 85 miRNAs and 2107 messenger RNAs (mRNA) differentially expressed in blastemal WT, and 266 miRNAs and 1267 mRNAs differentially expressed in regressive subtype. The hierarchical clustering of the samples, using either the miRNA or mRNA profile, showed the clear separation of WT from normal kidney samples, but the miRNA pattern yielded better separation of WT subtypes. A correlation analysis of the deregulated miRNA and mRNAs identified 13,026 miRNA/mRNA pairs with inversely correlated expression, of which 2844 are potential interactions of miRNA and their predicted mRNA targets. We found significant upregulation of miRNAs-183, -301a/b and -335 for the blastemal subtype, and miRNAs-181b, -223 and -630 for the regressive subtype. We found marked deregulation of miRNAs regulating epithelial to mesenchymal transition, especially in the blastemal subtype, and miRNAs influencing chemosensitivity, especially in regressive subtypes. Further research is needed to assess the influence of preoperative chemotherapy and tumor infiltrating lymphocytes on the miRNA and mRNA patterns in WT.
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Affiliation(s)
- Nicole Ludwig
- Department of Human Genetics, Saarland University, 66421 Homburg/Saar, Germany.
| | - Tamara V Werner
- Department of Human Genetics, Saarland University, 66421 Homburg/Saar, Germany.
| | - Christina Backes
- Chair for Clinical Bioinformatics, Building E2.1, 66123 Saarbruecken, Germany.
| | - Patrick Trampert
- Center for Bioinformatics, Saarland University, Building E.1.1, 66041 Saarbruecken, Germany.
| | - Manfred Gessler
- Developmental Biochemistry, Biocenter, and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, 97074 Wuerzburg, Germany.
| | - Andreas Keller
- Chair for Clinical Bioinformatics, Building E2.1, 66123 Saarbruecken, Germany.
| | - Hans-Peter Lenhof
- Center for Bioinformatics, Saarland University, Building E.1.1, 66041 Saarbruecken, Germany.
| | - Norbert Graf
- Department of Pediatric Oncology and Hematology, Medical School, Saarland University, 66421 Homburg, Germany.
| | - Eckart Meese
- Department of Human Genetics, Saarland University, 66421 Homburg/Saar, Germany.
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Deng C, Dai R, Li X, Liu F. Genetic variation frequencies in Wilms' tumor: A meta-analysis and systematic review. Cancer Sci 2016; 107:690-9. [PMID: 26892980 PMCID: PMC4970837 DOI: 10.1111/cas.12910] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 02/11/2016] [Accepted: 02/12/2016] [Indexed: 12/11/2022] Open
Abstract
Over the last few decades, numerous biomarkers in Wilms' tumor have been confirmed and shown variations in prevalence. Most of these studies were based on small sample sizes. We carried out a meta-analysis of the research published from 1992 to 2015 to obtain more precise and comprehensive outcomes for genetic tests. In the present study, 70 out of 5175 published reports were eligible for the meta-analysis, which was carried out using Stata 12.0 software. Pooled prevalence for gene mutations WT1, WTX, CTNNB1, TP53, MYCN, DROSHA, and DGCR8 was 0.141 (0.104, 0.178), 0.147 (0.110, 0.184), 0.140 (0.100, 0.190), 0.410 (0.214, 0.605), 0.071 (0.041, 0.100), 0.082 (0.048, 0.116), and 0.036 (0.026, 0.046), respectively. Pooled prevalence of loss of heterozygosity at 1p, 11p, 11q, 16q, and 22q was 0.109 (0.084, 0.133), 0.334 (0.295, 0.373), 0.199 (0.146, 0.252), 0.151 (0.129, 0.172), and 0.148 (0.108, 0.189), respectively. Pooled prevalence of 1q and chromosome 12 gain was 0.218 (0.161, 0.275) and 0.273 (0.195, 0.350), respectively. The limited prevalence of currently known genetic alterations in Wilms' tumors indicates that significant drivers of initiation and progression remain to be discovered. Subgroup analyses indicated that ethnicity may be one of the sources of heterogeneity. However, in meta-regression analyses, no study-level characteristics of indicators were found to be significant. In addition, the findings of our sensitivity analysis and possible publication bias remind us to interpret results with caution.
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Affiliation(s)
- Changkai Deng
- Department of Urology Surgery, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorder, Key Laboratory of Pediatrics in Chongqing (CSTC2009CA5002), Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.,Chengdu Women and Children's Central Hospital, Chengdu, China
| | - Rong Dai
- Chengdu Center for Disease Control and Prevention, Chengdu, China
| | - Xuliang Li
- Department of Urology Surgery, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorder, Key Laboratory of Pediatrics in Chongqing (CSTC2009CA5002), Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China
| | - Feng Liu
- Department of Urology Surgery, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorder, Key Laboratory of Pediatrics in Chongqing (CSTC2009CA5002), Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China
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Krepischi ACV, Maschietto M, Ferreira EN, Silva AG, Costa SS, da Cunha IW, Barros BDF, Grundy PE, Rosenberg C, Carraro DM. Genomic imbalances pinpoint potential oncogenes and tumor suppressors in Wilms tumors. Mol Cytogenet 2016; 9:20. [PMID: 26913079 PMCID: PMC4765068 DOI: 10.1186/s13039-016-0227-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 02/06/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Wilms tumor (WT) has a not completely elucidated pathogenesis. DNA copy number alterations (CNAs) are common in cancer, and often define key pathogenic events. The aim of this work was to investigate CNAs in order to disclose new candidate genes for Wilms tumorigenesis. RESULTS Array-CGH of 50 primary WTs without pre-chemotherapy revealed a few recurrent CNAs not previously reported, such as 7q and 20q gains, and 7p loss. Genomic amplifications were exclusively detected in 3 cases of WTs that later relapsed, which also exhibited an increased frequency of gains affecting a 16.2 Mb 1q21.1-q23.2 region, losses at 11p, 11q distal, and 16q, and WT1 deletions. Conversely, aneuploidies of chromosomes 13 and 19 were found only in WTs without further relapse. The 1q21.1-q23.2 gain associated with WT relapse harbours genes such as CHD1L, CRABP2, GJA8, MEX3A and MLLT11 that were found to be over-expressed in WTs. In addition, down-regulation of genes encompassed by focal deletions highlighted new potential tumor suppressors such as CNKSR1, MAN1C1, PAQR7 (1p36), TWIST1, SOSTDC1 (7p14.1-p12.2), BBOX and FIBIN (11p13), and PLCG2 (16q). CONCLUSION This study confirmed the presence of CNAs previously related to WT and characterized new CNAs found only in few cases. The later were found in higher frequency in relapsed cases, suggesting that they could be associated with WT progression.
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Affiliation(s)
- A. C. V. Krepischi
- />International Research Center, AC Camargo Cancer Center, São Paulo, Brazil
- />Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | - M. Maschietto
- />International Research Center, AC Camargo Cancer Center, São Paulo, Brazil
- />Brazilian Biosciences National Laboratory, National Center for Research in Energy and Materials, Campinas, São Paulo, Brazil
| | - E. N. Ferreira
- />International Research Center, AC Camargo Cancer Center, São Paulo, Brazil
| | - A. G. Silva
- />Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | - S. S. Costa
- />Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | - I. W. da Cunha
- />Department of Surgical and Investigative Pathology, AC Camargo Cancer Center, São Paulo, Brazil
| | - B. D. F. Barros
- />International Research Center, AC Camargo Cancer Center, São Paulo, Brazil
| | - P. E. Grundy
- />Alberta Health Services, Cancer Control Alberta, Alberta, Canada
| | - C. Rosenberg
- />Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | - D. M. Carraro
- />International Research Center, AC Camargo Cancer Center, São Paulo, Brazil
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Dome JS, Graf N, Geller JI, Fernandez CV, Mullen EA, Spreafico F, Van den Heuvel-Eibrink M, Pritchard-Jones K. Advances in Wilms Tumor Treatment and Biology: Progress Through International Collaboration. J Clin Oncol 2015; 33:2999-3007. [PMID: 26304882 PMCID: PMC4567702 DOI: 10.1200/jco.2015.62.1888] [Citation(s) in RCA: 260] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Clinical trials in Wilms tumor (WT) have resulted in overall survival rates of greater than 90%. This achievement is especially remarkable because improvements in disease-specific survival have occurred concurrently with a reduction of therapy for large patient subgroups. However, the outcomes for certain patient subgroups, including those with unfavorable histologic and molecular features, bilateral disease, and recurrent disease, remain well below the benchmark survival rate of 90%. Therapy for WT has been advanced in part by an increasingly complex risk-stratification system based on patient age; tumor stage, histology, and volume; response to chemotherapy; and loss of heterozygosity at chromosomes 1p and 16q. A consequence of this system has been the apportionment of patients into such small subgroups that only collaboration between large international WT study groups will support clinical trials that are sufficiently powered to answer challenging questions that move the field forward. This article gives an overview of the Children's Oncology Group and International Society of Pediatric Oncology approaches to WT and focuses on four subgroups (stage IV, initially inoperable, bilateral, and relapsed WT) for which international collaboration is pressing. In addition, biologic insights resulting from collaborative laboratory research are discussed. A coordinated expansion of international collaboration in both clinical trials and laboratory science will provide real opportunity to improve the treatment and outcomes for children with renal tumors on a global level.
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Affiliation(s)
- Jeffrey S Dome
- Jeffrey S. Dome, Children's National Health System, Washington, DC; James I. Geller, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Elizabeth A. Mullen, Dana-Farber Cancer Institute, Boston, MA; Norbert Graf, Saarland University, Homburg, Germany; Conrad V. Fernandez, IWK Health Centre, Halifax, Nova Scotia, Canada; Filippo Spreafico, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Marry Van den Heuvel-Eibrink, Princess Màxima Center for Pediatric Oncology, Utrecht, the Netherlands; and Kathy Pritchard-Jones, University College London Institute of Child Health, London, United Kingdom.
| | - Norbert Graf
- Jeffrey S. Dome, Children's National Health System, Washington, DC; James I. Geller, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Elizabeth A. Mullen, Dana-Farber Cancer Institute, Boston, MA; Norbert Graf, Saarland University, Homburg, Germany; Conrad V. Fernandez, IWK Health Centre, Halifax, Nova Scotia, Canada; Filippo Spreafico, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Marry Van den Heuvel-Eibrink, Princess Màxima Center for Pediatric Oncology, Utrecht, the Netherlands; and Kathy Pritchard-Jones, University College London Institute of Child Health, London, United Kingdom
| | - James I Geller
- Jeffrey S. Dome, Children's National Health System, Washington, DC; James I. Geller, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Elizabeth A. Mullen, Dana-Farber Cancer Institute, Boston, MA; Norbert Graf, Saarland University, Homburg, Germany; Conrad V. Fernandez, IWK Health Centre, Halifax, Nova Scotia, Canada; Filippo Spreafico, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Marry Van den Heuvel-Eibrink, Princess Màxima Center for Pediatric Oncology, Utrecht, the Netherlands; and Kathy Pritchard-Jones, University College London Institute of Child Health, London, United Kingdom
| | - Conrad V Fernandez
- Jeffrey S. Dome, Children's National Health System, Washington, DC; James I. Geller, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Elizabeth A. Mullen, Dana-Farber Cancer Institute, Boston, MA; Norbert Graf, Saarland University, Homburg, Germany; Conrad V. Fernandez, IWK Health Centre, Halifax, Nova Scotia, Canada; Filippo Spreafico, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Marry Van den Heuvel-Eibrink, Princess Màxima Center for Pediatric Oncology, Utrecht, the Netherlands; and Kathy Pritchard-Jones, University College London Institute of Child Health, London, United Kingdom
| | - Elizabeth A Mullen
- Jeffrey S. Dome, Children's National Health System, Washington, DC; James I. Geller, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Elizabeth A. Mullen, Dana-Farber Cancer Institute, Boston, MA; Norbert Graf, Saarland University, Homburg, Germany; Conrad V. Fernandez, IWK Health Centre, Halifax, Nova Scotia, Canada; Filippo Spreafico, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Marry Van den Heuvel-Eibrink, Princess Màxima Center for Pediatric Oncology, Utrecht, the Netherlands; and Kathy Pritchard-Jones, University College London Institute of Child Health, London, United Kingdom
| | - Filippo Spreafico
- Jeffrey S. Dome, Children's National Health System, Washington, DC; James I. Geller, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Elizabeth A. Mullen, Dana-Farber Cancer Institute, Boston, MA; Norbert Graf, Saarland University, Homburg, Germany; Conrad V. Fernandez, IWK Health Centre, Halifax, Nova Scotia, Canada; Filippo Spreafico, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Marry Van den Heuvel-Eibrink, Princess Màxima Center for Pediatric Oncology, Utrecht, the Netherlands; and Kathy Pritchard-Jones, University College London Institute of Child Health, London, United Kingdom
| | - Marry Van den Heuvel-Eibrink
- Jeffrey S. Dome, Children's National Health System, Washington, DC; James I. Geller, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Elizabeth A. Mullen, Dana-Farber Cancer Institute, Boston, MA; Norbert Graf, Saarland University, Homburg, Germany; Conrad V. Fernandez, IWK Health Centre, Halifax, Nova Scotia, Canada; Filippo Spreafico, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Marry Van den Heuvel-Eibrink, Princess Màxima Center for Pediatric Oncology, Utrecht, the Netherlands; and Kathy Pritchard-Jones, University College London Institute of Child Health, London, United Kingdom
| | - Kathy Pritchard-Jones
- Jeffrey S. Dome, Children's National Health System, Washington, DC; James I. Geller, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Elizabeth A. Mullen, Dana-Farber Cancer Institute, Boston, MA; Norbert Graf, Saarland University, Homburg, Germany; Conrad V. Fernandez, IWK Health Centre, Halifax, Nova Scotia, Canada; Filippo Spreafico, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Marry Van den Heuvel-Eibrink, Princess Màxima Center for Pediatric Oncology, Utrecht, the Netherlands; and Kathy Pritchard-Jones, University College London Institute of Child Health, London, United Kingdom
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Singh N, Sahu DK, Goel M, Kant R, Gupta DK. Retrospective analysis of FFPE based Wilms' Tumor samples through copy number and somatic mutation related Molecular Inversion Probe Based Array. Gene 2015; 565:295-308. [PMID: 25913740 DOI: 10.1016/j.gene.2015.04.051] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 04/13/2015] [Accepted: 04/20/2015] [Indexed: 01/18/2023]
Abstract
In this report, retrospectively, we analyzed fifteen histo-pathologically characterized FFPE based Wilms' Tumor (WT) samples following an integrative approach of copy number (CN) and loss of heterozygosity (LOH) imbalances. The isolated-DNA was tested on CN and somatic-mutation related Molecular-Inversion-Probe based-Oncoscan Array™ and was analyzed through Nexus-Express OncoScan-3.0 and 7.0 software. We identified gain of 3p13.0-q29, 4p16.3-14.0, 7, 12p13.33-q24.33, and losses of 1p36.11-q44, 11p15.5-q25, 21q 22.2-22.3 and 22q11.21-13.2 in six samples (W1-6) and validated them in nine more samples (W7-9, W12-15, W17-18). Some observed that discrete deletions (1p, 1q, 10p, 10q, 13q, 20p) were specific to our samples. Maximum-LOH was observed in Ch11 as reported in previous studies. However, LOH was also observed in different regions of Ch7 including some cancer genes. The identified LOH-regions (1q21.2-q21.3, 2p24.1-23.3, 2p24.3-24.3, 3p21.3-21.1, 4p16.3, 7p11.2-p11.1, 7q31.2-31.32, 7q34-q35 and Ch 8) in W1-W6 were also validated in W7-9, W12-15 and W18. In addition, previously reported LOH of 1p and 16q region was also observed in our cases. The proven and novel onco (OG)- and tumor-suppressor genes (TSGs) involved in the CNV regions affected the major pathways like Chromatin Modification, RAS, PI3K; RAS in 14/15 cases, NOTCH/TGF-β and Cell Cycle Apoptosis in 10/15 cases, APC in 9/15 cases and Transcriptional Regulation in 7/15 cases, PI3K and genome maintenance in 6/15 cases. This exhaustive profiling of OG and TG may help in prognosis and diagnosis of the disease after validation of all the relevant results, especially the novel ones, obtained in this research in a larger number of samples.
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Affiliation(s)
- Neetu Singh
- Advanced Molecular Science Research Center (Center for Advanced Research), King George's Medical University, Lucknow 226 003, India.
| | - Dinesh K Sahu
- Imperial Life Sciences, 463 Phase City 2nd, Sector 37, Gurgaon, Haryana 122001, India
| | - Madhumati Goel
- Department of Pathology, King George's Medical University, Lucknow 226 003, India
| | - Ravi Kant
- Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India226 003
| | - Devendra K Gupta
- Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi 110029, India
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Szychot E, Apps J, Pritchard-Jones K. Wilms' tumor: biology, diagnosis and treatment. Transl Pediatr 2014; 3:12-24. [PMID: 26835318 PMCID: PMC4728859 DOI: 10.3978/j.issn.2224-4336.2014.01.09] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Accepted: 01/22/2014] [Indexed: 11/14/2022] Open
Abstract
Wilms' tumor is the commonest renal tumor of childhood affecting one in 10,000 children. It is also one of the successes of paediatric oncology with long term survival above 90% for localised disease and 75% for metastatic disease. Successful management of Wilms' tumor necessitates meticulous attention to correct staging of the tumor and a collaborative effort between paediatric oncologists, specialist surgeons, radiologists, pathologists, and radiation oncologists. Although current treatment protocols are based on risk assignment to minimise toxicity for low risk patients and improve outcomes for those with high risk disease, challenges remain in identifying novel molecular, histological and clinical risk factors for stratification of treatment intensity. Knowledge about Wilms' tumor biology and treatment is evolving rapidly and remains a paradigm for multimodal malignancy treatment. Future efforts will focus on the use of biomarkers to improve risk stratification and the introduction of newer molecularly targeted therapies that will minimise toxicity and improve the outcomes for patients with unfavourable histology and recurrent disease. The aim of this article is to summarise advances in our understanding of the biology of Wilms' tumor and to describe the current approaches to clinical management of patients.
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Pritchard-Jones K, Maschietto M, Grundy P. Biological Prognostic Factors in Wilms Tumors. RENAL TUMORS OF CHILDHOOD 2014. [DOI: 10.1007/978-3-662-44003-2_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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28
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Hashemi J, Fotouhi O, Sulaiman L, Kjellman M, Höög A, Zedenius J, Larsson C. Copy number alterations in small intestinal neuroendocrine tumors determined by array comparative genomic hybridization. BMC Cancer 2013; 13:505. [PMID: 24165089 PMCID: PMC3819709 DOI: 10.1186/1471-2407-13-505] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 10/17/2013] [Indexed: 12/23/2022] Open
Abstract
Background Small intestinal neuroendocrine tumors (SI-NETs) are typically slow-growing tumors that have metastasized already at the time of diagnosis. The purpose of the present study was to further refine and define regions of recurrent copy number (CN) alterations (CNA) in SI-NETs. Methods Genome-wide CNAs was determined by applying array CGH (a-CGH) on SI-NETs including 18 primary tumors and 12 metastases. Quantitative PCR analysis (qPCR) was used to confirm CNAs detected by a-CGH as well as to detect CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering was used to detect tumor groups with similar patterns of chromosomal alterations based on recurrent regions of CN loss or gain. The log rank test was used to calculate overall survival. Mann–Whitney U test or Fisher’s exact test were used to evaluate associations between tumor groups and recurrent CNAs or clinical parameters. Results The most frequent abnormality was loss of chromosome 18 observed in 70% of the cases. CN losses were also frequently found of chromosomes 11 (23%), 16 (20%), and 9 (20%), with regions of recurrent CN loss identified in 11q23.1-qter, 16q12.2-qter, 9pter-p13.2 and 9p13.1-11.2. Gains were most frequently detected in chromosomes 14 (43%), 20 (37%), 4 (27%), and 5 (23%) with recurrent regions of CN gain located to 14q11.2, 14q32.2-32.31, 20pter-p11.21, 20q11.1-11.21, 20q12-qter, 4 and 5. qPCR analysis confirmed most CNAs detected by a-CGH as well as revealed CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering of recurrent regions of CNAs revealed two separate tumor groups and 5 chromosomal clusters. Loss of chromosomes 18, 16 and 11 and again of chromosome 20 were found in both tumor groups. Tumor group II was enriched for alterations in chromosome cluster-d, including gain of chromosomes 4, 5, 7, 14 and gain of 20 in chromosome cluster-b. Gain in 20pter-p11.21 was associated with short survival. Statistically significant differences were observed between primary tumors and metastases for loss of 16q and gain of 7. Conclusion Our results revealed recurrent CNAs in several candidate regions with a potential role in SI-NET development. Distinct genetic alterations and pathways are involved in tumorigenesis of SI-NETs.
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Affiliation(s)
- Jamileh Hashemi
- Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital R8:04, Stockholm SE-171 76, Sweden.
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Segers H, van den Heuvel-Eibrink MM, Williams RD, van Tinteren H, Vujanic G, Pieters R, Pritchard-Jones K, Bown N. Gain of 1q is a marker of poor prognosis in Wilms' tumors. Genes Chromosomes Cancer 2013; 52:1065-74. [PMID: 24038759 DOI: 10.1002/gcc.22101] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 07/22/2013] [Indexed: 12/31/2022] Open
Abstract
Wilms' tumor (WT) trials aim to better tailor treatment intensity to the risk of relapse and death. Currently, stage, histology, age (< or > 24 months), and combined loss of heterozygosity at 1p and 16q in chemotherapy-naïve WTs are the only risk factors used for treatment stratification. However, they predict only less than one-third of all relapsing patients, implying that other factors are involved in treatment failure. Previous studies have associated 1q gain with adverse outcome. Therefore, in this study, the role of 1q gain and other common cytogenetic aberrations (CAs) in WTs was investigated and related to follow-up data from patients with WT treated in the United Kingdom; 19% (64/331) had 1q gain. Gain of 1q was significantly associated with 16q loss (P < 0.001) and 1p loss (P < 0.001). In multivariate analysis taking account of age, tumor stage, anaplasia, and common CA (e.g., 1p loss and 16q loss), 1q gain was independently associated with adverse event-free survival [EFS; hazard ratio (HR) = 2.45, P = 0.02] and overall survival (HR = 4.28, P = 0.004). Loss of 14q was independently associated with an adverse EFS (HR = 4.0, P = 0.04). Gain of 1q is a marker of poor prognosis in WTs, independent of high tumor stage and anaplasia which remain the overarching adverse prognostic factors. Confirmation in other studies is necessary before future therapeutic studies can incorporate 1q gain into new risk stratification schema.
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Affiliation(s)
- H Segers
- Department of Pediatric Oncology/Hematology, Erasmus MC, Sophia Children's Hospital, Rotterdam, 3015, GJ, The Netherlands
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Spreafico F, Gamba B, Mariani L, Collini P, D'Angelo P, Pession A, Di Cataldo A, Indolfi P, Nantron M, Terenziani M, Morosi C, Radice P, Perotti D. Loss of heterozygosity analysis at different chromosome regions in Wilms tumor confirms 1p allelic loss as a marker of worse prognosis: a study from the Italian Association of Pediatric Hematology and Oncology. J Urol 2012; 189:260-6. [PMID: 23174227 DOI: 10.1016/j.juro.2012.09.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Indexed: 01/24/2023]
Abstract
PURPOSE The specific aims of the AIEOP-TW-2003 protocol included prospectively investigating a possible association of tumor loss of heterozygosity with outcomes in children treated for Wilms tumor. MATERIALS AND METHODS We analyzed 125 unilateral favorable histology Wilms tumors registered between 2003 and 2008 in the Italian cooperative protocol for microsatellite markers mapped to chromosomes 1p, 7p, 11q, 16q and 22q. RESULTS The 3-year disease-free survival and overall survival probabilities were 0.87 (95% CI 0.81-0.93) and 0.98 (95% CI 0.96-1.0), respectively. Loss of heterozygosity at 1p was significantly associated with a worse disease-free survival (probability 0.67 for patients with and 0.92 for those without 1p loss of heterozygosity, p = 0.0009), as confirmed also by multivariate analysis adjusting for tumor stage and patient age at diagnosis. There was no difference in disease-free survival probability among children with loss of heterozygosity in the other chromosomal regions tested. The worse outlook for children older than 2 years at diagnosis did not seem to be influenced by the loss of heterozygosity patterns considered. CONCLUSIONS Chromosome 1p loss of heterozygosity seems to be a risk factor for nonanaplastic Wilms tumor, possibly regardless of other clinical factors. Our findings were uninformative regarding loss of heterozygosity in the other chromosomal regions tested.
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Affiliation(s)
- Filippo Spreafico
- Pediatric Unit, Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
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31
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Ohshima J, Haruta M, Fujiwara Y, Watanabe N, Arai Y, Ariga T, Okita H, Koshinaga T, Oue T, Hinotsu S, Nakadate H, Horie H, Fukuzawa M, Kaneko Y. Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor. Pediatr Blood Cancer 2012; 59:499-505. [PMID: 22457227 DOI: 10.1002/pbc.24093] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2011] [Accepted: 01/05/2012] [Indexed: 01/27/2023]
Abstract
BACKGROUND Wilms tumor (WT) has a survival rate of 90% following multimodality therapy. Nevertheless, there are some groups of patients with event-free survival rates less than 75%. In addition to clinical prognostic factors, loss of heterozygosity at 1p and/or 16q has been used to determine treatment intensity. However, the incidence of this abnormality is low, and new biomarkers are still needed. PROCEDURE We analyzed methylation status of three tumor suppressor genes; Ras-association domain family 1 protein, isoform A (RASSF1A), DCR2, and CASP8, in 84 WTs using conventional methylation-specific PCR (cMSP), and the results were correlated with outcome. Furthermore, we analyzed the methylation status of RASSF1A by quantitative MSP (qMSP) in 171 WTs, and evaluated clinical and genetic differences between the methylated and unmethylated tumors. RESULTS RASSF1A was the most frequently methylated gene identified by cMSP, and associated with a poor outcome. Patients with a RASSF1A-methylated tumor had shorter overall and event-free survival periods (P = 0.043 and 0.018, respectively), when a cut-off value of 7% by qMSP was used. The methylation was more frequent in tumors of older children than younger children (P < 0.001), and in advanced-stage tumors than early stage tumors (P = 0.001). However, multivariate analysis could not confirm the prognostic significance of RASSF1A methylation, possibly because of a small number of advanced stage tumors examined. RASSF1A methylation was correlated with LOH at 1p and/or 16q (P = 0.017), but not with WT1 abnormality, suggesting the methylation and LOH to involve the same tumorigenic pathway. CONCLUSIONS The methylation status of RASSF1A might be a novel biomarker to predict outcome of WT patients.
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Affiliation(s)
- Junjiro Ohshima
- Research Institute for Clinical Oncology, Saitama Cancer Center, Ina, Saitama, Japan
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Płuciennik E, Nowakowska M, Wujcicka WI, Sitkiewicz A, Kazanowska B, Zielińska E, Bednarek AK. Genetic alterations of WWOX in Wilms' tumor are involved in its carcinogenesis. Oncol Rep 2012; 28:1417-22. [PMID: 22842668 DOI: 10.3892/or.2012.1940] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 05/18/2012] [Indexed: 11/06/2022] Open
Abstract
Loss of heterozygosity (LOH) in 16q appears in ~20-30% cases of Wilms' tumor. Within this region, known as common fragile site FRA16D, the WWOX tumor suppressor gene is located. Abnormalities of WWOX gene expression levels were observed in many tumor types and were associated with worse prognosis. The purpose of this study was to investigate the role of the WWOX tumor suppressor gene in Wilms' tumor samples. We evaluated the correlation between expression of WWOX and genes involved in proliferation (Ki67), apoptosis (BCL2, BAX), signal transduction (ERBB4, ERBB2, EGFR), cell cycle (CCNE1, CCND1), cell adhesion (CDH1) and transcription (TP73) using real-time RT-PCR in 23 tumor samples. We also analyzed the potential causes of WWOX gene expression reduction i.e., promoter methylation status (MethylScreen method) and loss of heterozygosity (LOH) status. We revealed a positive correlation between WWOX expression and BCL2, BCL2/BAX ratio, EGFR, ERBB4 isoform JM-a, TP73 and negative correlation with both cyclins. Loss of heterozygosity of the WWOX gene was observed only at intron 8, however, it had no influence on the reduction of its expression levels. Contrary to LOH, methylation of the region covering the 3' end of the promoter and part of exon 1 was associated with statistically significant reduction of WWOX gene expression levels. In the present study we reveal that in Wilms' tumors the WWOX expression levels are positively associated with the process of apoptosis, signal transduction through the ErbB4 pathway and EGFR and negatively with the regulation of the cell cycle (by cyclin E1 and D1). Moreover, our analysis indicates that in this type of tumor the expression of the WWOX gene can be regulated by an epigenetic mechanism--its promoter methylation.
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Affiliation(s)
- Elżbieta Płuciennik
- Department of Molecular Cancerogenesis, Medical University of Lodz, 90-752 Lodz, Poland.
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Perotti D, Spreafico F, Torri F, Gamba B, D'Adamo P, Pizzamiglio S, Terenziani M, Catania S, Collini P, Nantron M, Pession A, Bianchi M, Indolfi P, D'Angelo P, Fossati-Bellani F, Verderio P, Macciardi F, Radice P. Genomic profiling by whole-genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse. Genes Chromosomes Cancer 2012; 51:644-53. [PMID: 22407497 DOI: 10.1002/gcc.21951] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Revised: 02/01/2012] [Accepted: 02/01/2012] [Indexed: 01/21/2023] Open
Abstract
Despite the excellent survival rate of Wilms tumor (WT) patients, only approximately one-half of children who suffer tumor recurrence reach second durable remission. This underlines the need for novel markers to optimize initial treatment. We investigated 77 tumors using Illumina 370CNV-QUAD genotyping BeadChip arrays and compared their genomic profiles to detect copy number (CN) abnormalities and allelic ratio anomalies associated with the following clinicopathological variables: relapse (yes vs. no), age at diagnosis (≤ 24 months vs. >24 months), and disease stage (low stage, I and II, vs. high stage, III and IV). We found that CN gains at chromosome region 1q21.1-q31.3 were significantly associated with relapse. Additional genetic events, including allelic imbalances at chromosome arms 1p, 1q, 3p, 3q, and 14q were also found to occur at higher frequency in relapsing tumors. Interestingly, allelic imbalances at 1p and 14q also showed a borderline association with higher tumor stages. No genetic events were found to be associated with age at diagnosis. This is the first genome wide analysis with single nucleotide polymorphism (SNP) arrays specifically investigating the role of genetic anomalies in predicting WT relapse on cases prospectively enrolled in the same clinical trial. Our study, besides confirming the role of 1q gains, identified a number of additional candidate genetic markers, warranting further molecular investigations.
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Affiliation(s)
- Daniela Perotti
- Department of Preventive and Predictive Medicine, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
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Spreafico F, Gandola L, D’Angelo P, Terenziani M, Collini P, Bianchi M, Provenzi M, Indolfi P, Pession A, Nantron M, Di Cataldo A, Marchianò A, Catania S, Fossati Bellani F, Piva L. Heterogeneity of Disease Classified as Stage III in Wilms Tumor: A Report From the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP). Int J Radiat Oncol Biol Phys 2012; 82:348-54. [DOI: 10.1016/j.ijrobp.2010.09.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2010] [Revised: 09/09/2010] [Accepted: 09/24/2010] [Indexed: 10/18/2022]
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Abstract
Wilms' tumour (WT) is an embryonal cancer of childhood and is thought to be derived from embryonic kidney precursor cells. The Knudson two hit model was initially thought to occur in WT, but findings emerging from genetic and cytogenetic studies in the past two decades have implicated several genetic events. Recent techniques in genetic analysis have improved our ability to characterise changes in genes involved in WT which include WT1, CTNNB1, IGF2 and WTX. These genetic events have not only provided insight into the pathobiology of this malignancy, but the recognition of these candidate genes may offer potential targets for novel therapies. In this review, we will provide an overview of the pathological, genetic and cytogenetic characteristics of WT.
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Williams RD, Al-Saadi R, Natrajan R, Mackay A, Chagtai T, Little S, Hing SN, Fenwick K, Ashworth A, Grundy P, Anderson JR, Dome JS, Perlman EJ, Jones C, Pritchard-Jones K. Molecular profiling reveals frequent gain of MYCN and anaplasia-specific loss of 4q and 14q in Wilms tumor. Genes Chromosomes Cancer 2011; 50:982-95. [PMID: 21882282 DOI: 10.1002/gcc.20907] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Accepted: 06/22/2011] [Indexed: 11/08/2022] Open
Abstract
Anaplasia in Wilms tumor, a distinctive histology characterized by abnormal mitoses, is associated with poor patient outcome. While anaplastic tumors frequently harbour TP53 mutations, little is otherwise known about their molecular biology. We have used array comparative genomic hybridization (aCGH) and cDNA microarray expression profiling to compare anaplastic and favorable histology Wilms tumors to determine their common and differentiating features. In addition to changes on 17p, consistent with TP53 deletion, recurrent anaplasia-specific genomic loss and under-expression were noted in several other regions, most strikingly 4q and 14q. Further aberrations, including gain of 1q and loss of 16q were common to both histologies. Focal gain of MYCN, initially detected by high resolution aCGH profiling in 6/61 anaplastic samples, was confirmed in a significant proportion of both tumor types by a genomic quantitative PCR survey of over 400 tumors. Overall, these results are consistent with a model where anaplasia, rather than forming an entirely distinct molecular entity, arises from the general continuum of Wilms tumor by the acquisition of additional genomic changes at multiple loci.
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Affiliation(s)
- Richard D Williams
- Molecular Haematology and Cancer Biology Unit, University College London, Institute of Child Health, London, UK
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Gene expression analysis of blastemal component reveals genes associated with relapse mechanism in Wilms tumour. Eur J Cancer 2011; 47:2715-22. [PMID: 21703850 DOI: 10.1016/j.ejca.2011.05.024] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Revised: 04/20/2011] [Accepted: 05/18/2011] [Indexed: 02/05/2023]
Abstract
Wilms tumour (WT) is a paediatric kidney tumour, composed of blastemal, epithelial and stromal cells, with a relapse rate of approximately 15%. Long-term survival for patients with relapse remains approximately 50%. Current clinical and molecular research is directed towards identifying prognostic factors to define the minimal and intensive therapy for successful treatment of children with low and high risk of relapse, respectively. Blastemal component presents a high level of aggressiveness and responsiveness to chemotherapy. To identify molecular prognostic markers that are predictive of chemotherapy sensitivity in tumour relapse, blastemal-enriched samples from stage III and IV WT, from patients with relapse or without relapse, were analysed for 4608 human genes immobilised on a customised cDNA platform. These analyses revealed 69 differentially expressed genes, and the top nine genes were further evaluated by qRT-PCR in the initial WT samples. TSPAN3, NCOA6, CDO1, MPP2 and MCM2 were confirmed to be down-regulated in relapse WT, and TSPAN3 and NCOA6 were also validated in an independent sample group. Protein expression of MCM2 and NCOA6 were observed in 38% (13 out of 34) and 28% (9 out of 32), respectively, of independent stage III and IV WT blastema samples, without association with relapse. However, a significant association between MCM2 positive staining and chemotherapy as first treatment suggests the involvement of MCM2 with drug metabolism in WT blastemal cells.
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Hawthorn L, Cowell JK. Analysis of wilms tumors using SNP mapping array-based comparative genomic hybridization. PLoS One 2011; 6:e18941. [PMID: 21544195 PMCID: PMC3081321 DOI: 10.1371/journal.pone.0018941] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2010] [Accepted: 03/25/2011] [Indexed: 12/18/2022] Open
Abstract
Wilms tumor (WT) has been a model to study kidney embryogenesis and tumorigenesis and, although associated with hereditary, cancer predisposition syndromes, the majority of tumors occur sporadically. To analyze genetic changes in WT we have defined copy number changes and loss of heterozygosity in 56 Wilms tumors using high resolution oligonucleotide arrays at a average resolution of ∼12 Kb. Consistent deletions were seen on chromosomes 1p, 4q, 7p, 9q, 11p, 11q, 14q, 16q, and 21q. High frequency gains were seen for 1q and lower frequency gains were seen on 7q and chromosomes 8, 12 and 18. The high resolution provided by the SNP mapping arrays has defined minimal regions of deletion for many of these LOH events. Analysis of CNAs by tumor stage show relatively stable karyotypes in stage 1 tumors and more complex aCGH profiles in tumors from stages 3–5.
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Affiliation(s)
- Lesleyann Hawthorn
- School of Medicine, MCG Cancer Center, Medical College of Georgia, Augusta, Georgia, United States of America.
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Abstract
Wilms' tumor is the most common malignant renal tumor in children. Survival has improved dramatically over time as a result of prospective randomized clinical trials conducted by the pediatric cooperative cancer groups. Current research is directed toward identifying low-risk patients for whom a reduction in treatment intensity would decrease long-term morbidity. This article reviews the most recent advances in the biology and treatment of children with Wilms' tumor.
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Affiliation(s)
- Leah Nakamura
- Department of Urology, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA
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Mengelbier LH, Karlsson J, Lindgren D, Øra I, Isaksson M, Frigyesi I, Frigyesi A, Bras J, Sandstedt B, Gisselsson D. Deletions of 16q in Wilms tumors localize to blastemal-anaplastic cells and are associated with reduced expression of the IRXB renal tubulogenesis gene cluster. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 177:2609-21. [PMID: 20847289 DOI: 10.2353/ajpath.2010.100130] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Wilms tumor is the most common pediatric renal neoplasm, but few molecular prognostic markers have been identified for this tumor. Somatic deletion in the long arm of chromosome 16 (16q) is known to predict a less favorable outcome in Wilms tumor, but the underlying molecular mechanisms are not known. We show that 16q deletions are typically confined to immature anaplastic-blastic tumor elements, while deletions are absent in maturing tumor components. The smallest region of deletion overlap mapped to a 1.8-Mb segment containing the IRXB gene cluster including IRX3, IRX5, and IRX6, of which IRX3 is a recently identified regulator of tubular maturation during nephrogenesis. Tumors with 16q deletion showed a lower overall mRNA expression of IRXB genes, and 16q-deleted tumor cells failed to express IRX3 while it was expressed in differentiating tubular tumor elements with intact 16q. Consistent with a role for IRX3 in tubular differentiation, gene sets linked to Notch signaling, Rho signaling, and ion channel activity were enriched in tumors with high IRX3 expression, while WTs with low expression were enriched for gene sets linked to cell cycle progression. Low mRNA levels of IRXB genes were associated with diffuse anaplasia, high-stage disease, and death. A disturbed balance between tubular differentiation and self-renewal of anaplastic-blastic elements may thus be one mechanism linking 16q deletion to adverse outcome in Wilms tumor.
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Affiliation(s)
- Linda Holmquist Mengelbier
- Department of Clinical Genetics, University and Regional Laboratories, Lund University, Skåne University Hospital, SE 221 85 Lund, Sweden
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