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Klin Padiatr 2012; 224(06): 353-358
DOI: 10.1055/s-0032-1321730
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Human Leukocyte Antigen Distribution in German Caucasians with Advanced Ewing’s Sarcoma

Verteilung humaner Leukozytenantigene bei deutschen Kaukasiern mit fortgeschrittenen Ewing-Sarkomen
U. Thiel
1   Department of Pediatrics and Pediatric Oncology Center, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
,
P. Wolf
2   Institute for Medical Statistics and Epidemiology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
,
A. Wawer
1   Department of Pediatrics and Pediatric Oncology Center, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
,
F. Blaeschke
1   Department of Pediatrics and Pediatric Oncology Center, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
,
T.G. P. Grunewald
1   Department of Pediatrics and Pediatric Oncology Center, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
,
I. T. von Lüttichau
1   Department of Pediatrics and Pediatric Oncology Center, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
,
T. Klingebiel
3   Pediatric Hematology and Oncology, Children’s Hospital III, Johann Wolfgang Goethe University, Frankfurt, Germany
,
P. Bader
3   Pediatric Hematology and Oncology, Children’s Hospital III, Johann Wolfgang Goethe University, Frankfurt, Germany
,
A. Borkhardt
4   Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Germany
,
H.-J. Laws
4   Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Germany
,
R. Handgretinger
5   Department of Hematology and Oncology, University Children’s Hospital, Tübingen, Germany
,
P. Lang
5   Department of Hematology and Oncology, University Children’s Hospital, Tübingen, Germany
,
P. G. Schlegel
6   Department of Pediatric Hematology and Oncology, University Children’s Hospital, Würzburg, Germany
,
M. Eyrich
6   Department of Pediatric Hematology and Oncology, University Children’s Hospital, Würzburg, Germany
,
B. Gruhn
7   Department of Pediatrics, University Hospital of Jena, Germany
,
G. Ehninger
8   Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
,
E. Koscielniak
9   Pediatric 5 (Oncology, Hematology, Immunology), Olga Hospital, Klinikum Stuttgart, Germany
,
C. Klein
10   Department of Pediatric Hematology/Oncology, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, Germany
,
K.-W. Sykora
11   Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany
,
E. Holler
12   Department of Hematology and Oncology, University of Regensburg, Germany
,
C. Mauz-Körholz
13   Clinic and Policlinic for Children and Adolescents, Medical Center Martin-Luther-University of Halle/Wittenberg, Halle/Saale, Germany
,
W. Woessmann
14   Department of Pediatric Hematology and Oncology, University Hospital, Giessen, Germany
,
G.H. S. Richter
1   Department of Pediatrics and Pediatric Oncology Center, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
,
A. H. Schmidt
15   DKMS German Bone Marrow Donor Center, Tübingen, Germany
,
C. Peters
16   Stem Cell Transplantation Unit, St. Anna Children’s Hospital, Vienna, Austria
,
U. Dirksen
17   Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, Germany
,
H. Jürgens
17   Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, Germany
,
M. Bregni
18   Unit of Medical Hematology-Oncology, Ospedale di Circolo, Busto Arsizio, Italy
,
S. Burdach
1   Department of Pediatrics and Pediatric Oncology Center, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
20 July 2012 (online)

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Abstract

Background:

Risk stratification criteria for patients with Ewing’s sarcoma family of tumors (ESFT) are still limited. We hypothesized divergent human leukocyte antigen (HLA) patterns in ESFT patients and compared HLA-A, -B and -DR phenotype frequencies of patients with advanced ESFT with those of healthy controls.

Patients:

HLA types of all German Caucasian patients with advanced ESFT and available HLA-A, -B and -DR data registered in the European Group for Blood and Marrow Transplantation, Paediatric Registry for Stem Cell Transplantation and the MetaEICESS data bases (study group, n=30) were retrospectively compared with HLA types of healthy German stem cell donors (control group, n=8 862 for single HLA frequencies and n=8 839 for allele combinations). Study group patients had been immuno-typed due to eligibility for allogeneic stem cell transplantation for high risk of treatment failure, and thus constituted a selected subgroup of ESFT patients.

Results:

After Bonferroni correction for multiple testing (PC), phenotype frequencies of HLA-A24 remained significantly higher in the study group compared to controls (PC<0.05). Furthermore, several HLA combinations were significantly more frequent in the study group compared to controls (all PC<0.05).

Conclusion:

We report an increased incidence of circumscribed HLA patterns in German Caucasians with advanced ESFT. The possible clinical significance of this observation has to be re-assessed in prospective trials comprising larger ESFT patient numbers of all risk groups.

Zusammenfassung

Hintergrund:

Die Kriterien zur Risikostratifizierung von Patienten mit Ewing-Sarkomen (ESFT) sind immer noch limitiert. Wir postulierten, dass bei Patienten mit ESFT unterschiedliche humane Leukozytenantigen-(HLA)-Verteilungsmuster im Vergleich zu Gesunden vorliegen, und verglichen deshalb HLA-A, -B und -DR-Merkmalsträgerhäufigkeiten.

Patienten:

Die HLA-Typen aller deutsch-kaukasischen Patienten mit fortgeschrittenem ESFT und verfügbaren HLA-A, -B und -DR-Daten, die in den European Group for Blood and Marrow Transplantation, Pädiatrisches Register für Stammzell-Transplantationen und/oder MetaEICESS- Datenbanken registriert waren (Studiengruppe, n=30), wurden retrospektiv mit den HLA-Typen gesunder deutscher Stammzellspender (Kontrollgruppe, n=8 862 bei einzelnen HLA-Frequenzen und n=8 839 bei HLA-Kombinationen) verglichen. Studienpatienten wurden bei Eignung für eine allogene Stammzelltransplantation aufgrund ihres hohen Rückfallrisikos HLA-typisiert. Die Studiengruppe stellt damit eine selektierte Subgruppe aller ESFT-Patienten dar.

Ergebnisse:

Nach Bonferroni-Korrektur für multiples Testen (PC), war ein statistischer Zusammenhang für ein vermehrtes Auftreten von HLA-A24 in der Studiengruppe im Vergleich zur Kontrollgruppe zu beobachten (PC<0,05). Darüber hinaus traten verschiedene HLA-Kombinationen signifikant häufiger in der Studiengruppe im Vergleich zur Kontrollgruppe auf (alle PC<0,05).

Schlussfolgerung:

Wir berichten über ein vermehrtes Vorkommen von umschriebenen HLA-Konstellationen bei deutschen Kaukasiern mit fortgeschrittenem ESFT. Die klinische Signifikanz dieser Beobachtung muss in prospektiven Studien, die größere Patientenzahlen und alle Risikogruppen erfassen, verifiziert werden.

Key words

Ewing’s sarcoma - human leukocyte antigens - risk stratification - biomarkers - immunosurveillance - allogeneic stem cell transplantation

Schlüsselwörter

Ewing-Sarkom - humane Leukozytenantigene - Risikostratifizierung - Biomarker - Immunkontrolle - allogene Stammzelltransplantation

Supplementary Materials

 

  • References

  • 1 Altvater B, Landmeier S, Kailayangiri S et al. gamma delta T cells: Stimulators of specific CD8(+) T cell responses to sarcoma-associated antigens. Klin Padiatr 2010; 222: 224-225
    PubMedSearch in Google Scholar
  • 2 Bateman AC, Howell WM. Human leukocyte antigens and cancer: is it in our genes?. J Pathol 1999; 188: 231-236
    CrossrefPubMedSearch in Google Scholar
  • 3 Berghuis D, de Hooge AS, Santos SJ et al. Reduced human leukocyte antigen expression in advanced-stage Ewing sarcoma: implications for immune recognition. J Pathol 2009; 218: 222-231
    CrossrefPubMedSearch in Google Scholar
  • 4 Berghuis D, Santos SJ, Baelde HJ et al. Pro-inflammatory chemokine-chemokine receptor interactions within the Ewing sarcoma microenvironment determine CD8(+) T-lymphocyte infiltration and affect tumour progression. J Pathol 2011; 223: 347-357
    CrossrefPubMedSearch in Google Scholar
  • 5 Brinkrolf P, Landmeier S, Altvater B et al. A high proportion of bone marrow T cells with regulatory phenotype (CD4+CD25hiFoxP3+) in Ewing sarcoma patients is associated with metastatic disease. Int J Cancer 2009; 125: 879-886
    CrossrefPubMedSearch in Google Scholar
  • 6 Burdach S. Treatment of advanced Ewing tumors by combined radiochemotherapy and engineered cellular transplants. Pediatr Transplant 2004; 8: 67-82
    CrossrefPubMedSearch in Google Scholar
  • 7 Burdach S, Thiel U, Schoniger M et al. Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone Marrow Transplant 2010; 45: 483-489
    CrossrefPubMedSearch in Google Scholar
  • 8 Burdach S, van Kaick B, Laws HJ et al. Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Dusseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria. Ann Oncol 2000; 11: 1451-1462
    CrossrefPubMedSearch in Google Scholar
  • 9 Chan KW, Rosen G, Pollack MS. Distribution of HLA antigens in patients with Ewing’s sarcoma. Tissue Antigens 1980; 16: 314-316
    PubMedSearch in Google Scholar
  • 10 Cotterill SJ, Ahrens S, Paulussen M et al. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol 2000; 18: 3108-3114
    PubMedSearch in Google Scholar
  • 11 Delattre O, Zucman J, Melot T et al. The Ewing family of tumors – a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 1994; 331: 294-299
    CrossrefPubMedSearch in Google Scholar
  • 12 Engelmark M, Beskow A, Magnusson J et al. Affected sib-pair analysis of the contribution of HLA class I and class II loci to development of cervical cancer. Hum Mol Genet 2004; 13: 1951-1958
    CrossrefPubMedSearch in Google Scholar
  • 13 Fujiwara T, Fukushi JI, Yamamoto S et al. Macrophage Infiltration Predicts a Poor Prognosis for the Human Ewing Sarcoma. Am J Pathol. 2011
    PubMedSearch in Google Scholar
  • 14 Gonzalez-Galarza FF, Christmas S, Middleton D et al. Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res 2011; 39: D913-D919
    CrossrefPubMedSearch in Google Scholar
  • 15 Grunewald TG, Ranft A, Esposito I et al. High STEAP1 expression is associated with improved outcome of Ewing’s sarcoma patients. Ann Oncol Feb 8 2012; [Epub ahead of print]
    PubMedSearch in Google Scholar
  • 16 Guerini FR, Agliardi C, Zanzottera M et al. Human leukocyte antigen distribution analysis in North Italian brain Glioma patients: an association with HLA-DRB1*14. J Neurooncol 2006; 77: 213-217
    CrossrefPubMedSearch in Google Scholar
  • 17 Hjalgrim H, Rostgaard K, Johnson PC et al. HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma. Proc Natl Acad Sci USA 2010; 107: 6400-6405
    CrossrefPubMedSearch in Google Scholar
  • 18 Kailayangiri S, Altvater B, Landmeier S et al. STEAP1-specific T cells for immunotherapy of Ewing sarcoma. Klin Padiatr 2010; 222: 225-225
    PubMedSearch in Google Scholar
  • 19 Klingebiel T, Bader P, Hollatz G et al. Immunotherapy in children: report from the Reisensburg-Symposium October 20-22, 2004 and recent advances. Klin Padiatr. 2006 218. 355-365
    PubMedSearch in Google Scholar
  • 20 Koehl U, Esser R, Zimmermann S et al. Ex vivo expansion of highly purified NK cells for immunotherapy after haploidentical stem cell transplantation in children. Klin Padiatr 2005; 217: 345-350
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Lang P, Pfeiffer M, Muller I et al. Haploidentical stem cell transplantation in patients with pediatric solid tumors: preliminary results of a pilot study and analysis of graft versus tumor effects. Klin Padiatr 2006; 218: 321-326
    Thieme ConnectPubMedSearch in Google Scholar
  • 22 Luongo V, Pirozzi G, Caraco C et al. HLA allele frequency and clinical outcome in Italian patients with cutaneous melanoma. Tissue Antigens 2004; 64: 84-87
    CrossrefPubMedSearch in Google Scholar
  • 23 Machulla HK, Muller LP, Schaaf A et al. Association of chronic lymphocytic leukemia with specific alleles of the HLA-DR4:DR53:DQ8 haplotype in German patients. Int J Cancer 2001; 92: 203-207
    CrossrefPubMedSearch in Google Scholar
  • 24 Machulla HK, Steinborn F, Tschigrjai M et al. Meningioma: is there an association with human leukocyte antigens?. Cancer Epidemiol Biomarkers Prev 2003; 12: 1438-1442
    PubMedSearch in Google Scholar
  • 25 Nitta T, Ebato M, Sato K. Association of malignant glioma with the human leukocyte antigen, HLA-A24(9). Neurosurg Rev 1994; 17: 211-215
    CrossrefPubMedSearch in Google Scholar
  • 26 Ozaki T, Schaefer KL, Wai D et al. Population-based genetic alterations in Ewing’s tumors from Japanese and European Caucasian patients. Ann Oncol 2002; 13: 1656-1664
    CrossrefPubMedSearch in Google Scholar
  • 27 Postel-Vinay S, Veron AS, Tirode F et al. Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nat Genet 2012; 44: 323-327
    CrossrefPubMedSearch in Google Scholar
  • 28 Posthuma EF, Falkenburg JH, Apperley JF et al. HLA-DR4 is associated with a diminished risk of the development of chronic myeloid leukemia (CML). Chronic Leukemia Working Party of the European Blood and Marrow Transplant Registry. Leukemia 2000; 14: 859-862
    CrossrefPubMedSearch in Google Scholar
  • 29 Schmidt AH, Baier D, Solloch UV et al. Estimation of high-resolution HLA-A, -B, -C, -DRB1 allele and haplotype frequencies based on 8862 German stem cell donors and implications for strategic donor registry planning. Hum Immunol 2009; 70: 895-902
    CrossrefPubMedSearch in Google Scholar
  • 30 Staege MS, Gorelov V, Bulankin A et al. Stable transgenic expression of IL-2 and HSV1-tk by single and fusion tumor cell lines bearing EWS/FLI-1 chimeric genes. Pediatr Hematol Oncol 2003; 20: 119-140
    CrossrefPubMedSearch in Google Scholar
  • 31 Suttorp M, Claviez A, Bader P et al. Allogeneic stem cell transplantation for pediatric and adolescent patients with CML: results from the prospective trial CML-paed I. Klin Padiatr 2009; 221: 351-357
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Thiel U, Pirson S, Muller-Spahn C et al. Specific recognition and inhibition of Ewing tumour growth by antigen-specific allo-restricted cytotoxic T cells. Br J Cancer 2011; 104: 948-956
    CrossrefPubMedSearch in Google Scholar
  • 33 Thiel U, Wawer A, Wolf P et al. No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients. Ann Oncol 2011; 22: 1614-1621
    CrossrefPubMedSearch in Google Scholar
  • 34 Winkler C, Steingrube DS, Altermann W et al. Hodgkin’s lymphoma RNA-transfected dendritic cells induce cancer/testis antigen-specific immune responses. Cancer Immunol Immunother. 2012
    PubMedSearch in Google Scholar
  • 35 Zucman-Rossi J, Batzer MA, Stoneking M et al. Interethnic polymorphism of EWS intron 6: genome plasticity mediated by Alu retroposition and recombination. Hum Genet 1997; 99: 357-363
    CrossrefPubMedSearch in Google Scholar