title: Definition of MYC genetic heteroclonality in diffuse large B-cell lymphoma with 8q24 rearrangement and its impact on protein expression.
abstract: MYC rearrangement can be detected in a subgroup of diffuse large B-cell lymphoma characterized by unfavorable prognosis. In contrast to Burkitt lymphoma, the correlation between MYC rearrangement and MYC protein expression in diffuse large B-cell lymphoma is less clear, as approximately one-third of rearranged cases show negative or low expression by immunohistochemistry. To better understand whether specific characteristics of the MYC rearrangement may influence its protein expression, we investigated 43 de novo diffuse large B-cell lymphoma positive for 8q24 rearrangement by FISH, using 14 Burkitt lymphoma for comparison. Different cell populations (clones), breakpoints (classical vs non-classical FISH patterns), partner genes (IGH vs non-IGH) and immunostaining were detected and analyzed using computerized image systems. In a subgroup of diffuse large B-cell lymphoma, we observed different clones within the same tumor distinguishing the founder clone with MYC rearrangement alone from other subclones, carrying MYC rearrangement coupled with loss/extra copies of derivatives/normal alleles. This picture, which we defined MYC genetic heteroclonality, was found in 42% of cases and correlated to negative MYC expression (P=0.026). Non-classical FISH breakpoints were detected in 16% of diffuse large B-cell lymphoma without affecting expression (P=0.040). Non-IGH gene was the preferential partner of rearrangement in those diffuse large B-cell lymphoma showing MYC heteroclonality (P=0.016) and/or non-classical FISH breakpoints (P=0.058). MYC heteroclonality was not observed in Burkitt lymphoma and all cases had positive MYC expression. Non-classical FISH MYC breakpoint and non-IGH partner were found in 29 and 20% of Burkitt lymphoma, respectively. In conclusion, MYC genetic heteroclonality is a frequent event in diffuse large B-cell lymphoma and may have a relevant role in modulating MYC expression.
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Locarno, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Valera
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Locarno, Switzerland.
authors.forename: Samantha
authors.initials: S
authors.lastname: Epistolio
authors.affiliation: Laboratory of Pathology, Hospital del Mar, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Lluis
authors.initials: L
authors.lastname: Colomo
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Locarno, Switzerland.
authors.forename: Alice
authors.initials: A
authors.lastname: Riva
authors.affiliation: Hematopathology Section, Laboratory of Pathology, Hospital Clínic, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Balagué
authors.affiliation: Hematopathology Section, Laboratory of Pathology, Hospital Clínic, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dlouhy
authors.affiliation: Institute of Pathology, University Hospital, Basel, Switzerland.
authors.forename: Alexandar
authors.identifier: 0000-0002-1100-3819
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Institute for Surgical Pathology, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Bühler
authors.affiliation: Institute for Surgical Pathology, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Haralambieva
authors.affiliation: Hematopathology Section, Laboratory of Pathology, Hospital Clínic, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Elias
authors.identifier: 0000-0001-9850-9793
authors.initials: E
authors.lastname: Campo
authors.affiliation: Institute for Surgical Pathology, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Soldini
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Locarno, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Mazzucchelli
authors.affiliation: Department of Molecular Pathology, Institute of Pathology, Locarno, Switzerland.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Martin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D050438:Genes, Immunoglobulin Heavy Chain; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000235:genetics*; D013030:Spain; D013557:Switzerland
chemical_list: D014408:Biomarkers, Tumor; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc