title: BCL-6 gene mutations in posttransplantation lymphoproliferative disorders predict response to therapy and clinical outcome.
abstract: Posttransplantation lymphoproliferative disorders (PT-LPDs) represent a heterogeneous group of Epstein-Barr virus-associated lymphoid proliferations that arise in immunosuppressed transplant recipients. Some of these lesions regress after a reduction in immunosuppressive therapy, whereas some progress despite aggressive therapy. Morphological, immunophenotypic, and immunogenotypic criteria have not been useful in predicting clinical outcome. Although structural alterations in oncogenes and/or tumor suppressor genes identified in some PT-LPDs correlate with a poor clinical outcome, the presence of these alterations has not been a consistently useful predictor of lesion regression after reduction of immunosuppression. We examined 57 PT-LPD lesions obtained from 36 solid organ transplant recipients for the presence of mutations in the BCL-6 proto-oncogene using single-strand conformation polymorphism and sequence analysis, followed by correlation with histopathologic classification and clinical outcome, which was known in 33 patients. BCL-6 gene mutations were identified in 44% of the specimens and in 44% of the patients; none were identified in the cases classified as plasmacytic hyperplasia. However, mutations were present in 43% of the polymorphic lesions and 90% of the PT-LPDs diagnosed as non-Hodgkin's lymphoma or multiple myeloma. BCL-6 gene mutations predicted shorter survival and refractoriness to reduced immunosuppression and/or surgical excision. Our results suggest that the BCL-6 gene structure is a reliable indicator for the division of PT-LPDs into the biological categories of hyperplasia and malignant lymphoma, of which only the former can regress on immune reconstitution. The presence of BCL-6 gene mutations may be a useful clinical marker to determine whether reduction in immunosuppression should be attempted or more aggressive therapy should be instituted.
authors.affiliation: Department of Pathology, The New York Hospital-Cornell Medical Center, New York, NY 10021, USA. ecesarm@mail.med.cornell.edu
authors.forename: E
authors.initials: E
authors.lastname: Cesarman
authors.forename: A
authors.initials: A
authors.lastname: Chadburn
authors.forename: Y F
authors.initials: YF
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: Migliazza
authors.forename: R
authors.initials: R
authors.lastname: Dalla-Favera
authors.forename: D M
authors.initials: DM
authors.lastname: Knowles
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006566:Herpesviridae Infections / Q000188:drug therapy / Q000401:mortality / Q000635:transmission; D004854:Herpesvirus 4, Human / Q000472:pathogenicity; D006801:Humans; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015993:Life Tables; D016393:Lymphoma, B-Cell / Q000209:etiology / Q000235:genetics / Q000401:mortality / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000188:drug therapy / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000821:virology; D018807:Polymorphism, Single-Stranded Conformational; D011183:Postoperative Complications / Q000188:drug therapy / Q000209:etiology / Q000401:mortality / Q000821:virology; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051560:Proto-Oncogene Proteins c-bcl-6; D011519:Proto-Oncogenes; D014157:Transcription Factors / Q000235:genetics*; D014180:Transplantation / Q000009:adverse effects*; D016896:Treatment Outcome; D014412:Tumor Virus Infections / Q000188:drug therapy / Q000401:mortality / Q000635:transmission
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors