Hodgkin’s lymphoma (HL) is a heterogeneous lymphoid malignancy curable in more than 80% of cases. Its morbility and mortality are mostly contingent upon chemo- and radio-therapy side effects including cardiovascular or pulmonary diseases, infections and second malignancies. Indeed, the high incidence of secondary cancers and leukemias in potentially cured LH patients supports that genomic instability and defective DNA repair system have a crucial role in secondary cancerogenesis/leukemogenesis processes as they let the emergence of genomic aberrations and clonal cell evolution towards a transformed phenotype. The aim of our study was to define the genomic profile associated with HL evolution towards secondary leukemia. To the purpose, formalin-fixed/paraffin-embedded biopsies from 4 LH patients who developed a secondary acute myeloid leukemia (AML) were analyzed by mean of array-based comparative genomic hybridization (aCGH). This method allows the identification of changes in DNA sequence copy number (amplifications or deletions) at high resolution. The microarrays used in our study contain 287 genomic targets involved in most human cancers, including oncogenes, tumor-suppressor genes and DNA sequences localized within chromosomal regions most frequently rearranged. DNAs from lymphonode biopsies of LH patient who developed AML were compared with pooled DNAs from reactive and LH lymphonodes (comparable for histotype and follow-up) from cured patients. CGH profiles of single LH patients were extensively altered. However, they shared a common pattern of structural genomic alterations. Bioinformatic analysis of CGH results performed with dedicated softwares let distinguish statistatically significant (ratio >1,2) amplifications relative to 3 DNA sequences (AFM137XA11, FGFR1, PPABP) and statistatically significant (ratio< 0,83) deletions in 4 (AFM217YD10, FGR(SRC2), GATA3, TOP1, WT1). CGH data relative to the above mentioned sequences were further validated by FISH and immunohistochemistry. In spite of the low number of LH patients our results suggest that the evolution to AML in LH patients may be genetically determined. The role of single genes in leukemic transformation requires further investigation.
GENOMIC SIGNATURE OF LEUKEMIC EVOLUTION IN HODGKIN LYMPHOMA.
REMONDINI, DANIEL;ZINZANI, PIER LUIGI;CAMMELLI, SILVIA;BARBIERI, ENZA;
2005
Abstract
Hodgkin’s lymphoma (HL) is a heterogeneous lymphoid malignancy curable in more than 80% of cases. Its morbility and mortality are mostly contingent upon chemo- and radio-therapy side effects including cardiovascular or pulmonary diseases, infections and second malignancies. Indeed, the high incidence of secondary cancers and leukemias in potentially cured LH patients supports that genomic instability and defective DNA repair system have a crucial role in secondary cancerogenesis/leukemogenesis processes as they let the emergence of genomic aberrations and clonal cell evolution towards a transformed phenotype. The aim of our study was to define the genomic profile associated with HL evolution towards secondary leukemia. To the purpose, formalin-fixed/paraffin-embedded biopsies from 4 LH patients who developed a secondary acute myeloid leukemia (AML) were analyzed by mean of array-based comparative genomic hybridization (aCGH). This method allows the identification of changes in DNA sequence copy number (amplifications or deletions) at high resolution. The microarrays used in our study contain 287 genomic targets involved in most human cancers, including oncogenes, tumor-suppressor genes and DNA sequences localized within chromosomal regions most frequently rearranged. DNAs from lymphonode biopsies of LH patient who developed AML were compared with pooled DNAs from reactive and LH lymphonodes (comparable for histotype and follow-up) from cured patients. CGH profiles of single LH patients were extensively altered. However, they shared a common pattern of structural genomic alterations. Bioinformatic analysis of CGH results performed with dedicated softwares let distinguish statistatically significant (ratio >1,2) amplifications relative to 3 DNA sequences (AFM137XA11, FGFR1, PPABP) and statistatically significant (ratio< 0,83) deletions in 4 (AFM217YD10, FGR(SRC2), GATA3, TOP1, WT1). CGH data relative to the above mentioned sequences were further validated by FISH and immunohistochemistry. In spite of the low number of LH patients our results suggest that the evolution to AML in LH patients may be genetically determined. The role of single genes in leukemic transformation requires further investigation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
