title: Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma.
abstract: Diffuse large B-cell lymphoma (DLCL) is characterized by a marked degree of morphologic and clinical heterogeneity. We studied 156 patients with de novo DLCL for rearrangements of the BCL2, BCL6, and MYC oncogenes by Southern blot analysis and BCL2 protein expression. We related these data to the primary site of presentation, disease stage, and other clinical risk factors. Structural alterations of BCL2, BCL6, and MYC were detected in 25 of 156, 36 of 116, and 10 of 151 patients, respectively. Three cases showed a combination of BCL2 and BCL6 rearrangements, and two cases had a combination of BCL6 and MYC rearrangements. BCL2 rearrangement was found more often in extensive (39%) and primary nodal (17%) lymphomas than in extranodal cases (4%) (P = .003). BCL2 rearrangement was present in none of 40 patients with stage I disease, but in 22% of patients with stage II to IV (P = .006). The presence of BCL2 rearrangements did not significantly affect overall survival (OS) or disease-free survival (DFS). In contrast, high BCL2 protein expression adversely affected both OS (P = .008) and DFS (P = .01). BCL2 protein expression was poorly correlated with BCL2 rearrangement: only 52% of BCL2-rearranged lymphomas and 37% of BCL2-unrearranged cases had high BCL2 protein expression. Rearrangement of BCL6 was found more often in patients with extranodal (36%) and extensive (39%) presentation versus primary nodal disease (28%). No significant correlation was found with disease stage, lymphadenopathy, or bone marrow involvement. DFS and OS were not influenced by BCL6 rearrangements. MYC rearrangements were found in 16% of primary extranodal lymphomas, versus 2% of primary nodal cases (P = .02). In particular, gastrointestinal (GI) lymphomas (5 of 18 cases, 28%) were affected by MYC rearrangements. The distinct biologic behavior of these extranodal lymphomas was reflected by a high complete remission (CR) rate: 7 of 10 patients with MYC rearrangement attained complete remission and 6 responders remained alive for more than 4 years, resulting in a trend for better DFS (P = .07). These data show the complex nature of molecular events in DLCL, which is a reflection of the morphologic and clinical heterogeneity of these lymphomas. However, thus far, these genetic rearrangements fail as prognostic markers.
authors.affiliation: Departments of Pathology and Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M H
authors.initials: MH
authors.lastname: Kramer
authors.forename: J
authors.initials: J
authors.lastname: Hermans
authors.forename: E
authors.initials: E
authors.lastname: Wijburg
authors.forename: K
authors.initials: K
authors.lastname: Philippo
authors.forename: E
authors.initials: E
authors.lastname: Geelen
authors.forename: J H
authors.initials: JH
authors.lastname: van Krieken
authors.forename: D
authors.initials: D
authors.lastname: de Jong
authors.forename: E
authors.initials: E
authors.lastname: Maartense
authors.forename: E
authors.initials: E
authors.lastname: Schuuring
authors.forename: P M
authors.initials: PM
authors.lastname: Kluin
mesh_terms: D015139:Blotting, Southern; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000401:mortality; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D019254:Genes, bcl-2; D016259:Genes, myc; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D015993:Life Tables; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000401:mortality; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009426:Netherlands; D009857:Oncogenes; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051560:Proto-Oncogene Proteins c-bcl-6; D012074:Remission Induction; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors