Del(6)(q22) and BCL6 Rearrangements in Primary Central Nervous System Lymphoma (PCNSL) Are Indicators of an Aggressive Clinical Course.

Abstract

Purpose: Despite therapeutic advancements, biological markers that predict the natural history of primary central nervous system lymphoma (PCNSL) are lacking and age and performance status are the only consistently identified independent prognostic variables. BCL6 rearrangements and deletion of the tumor suppressor gene R-PTP-κ (PTPRK) at 6q22 are thought to be common genetic abnormalities in PCNSL but their prognostic significance is unknown. The aim of this study is to determine the prevalence and survival impact of del(6)(q22), BCL6, immunoglobulin heavy chain (IGH), and MYC gene rearrangements and prevalence of Epstein-Barr virus (EBV) infection in PCNSL affecting immunocompetent patients. Patients and methods: Seventy-six specimens from 76 HIV-negative, immunocompetent patients with PCNSL newly diagnosed and treated at Mayo Clinic between 1985 and 2006 were studied. Interphase fluorescence in-situ hybridization (FISH) was performed using two-color break apart probes (BAP) for BCL6 and MYC, a two-color dual-fusion probe for IGH-BCL6, and a two-color probe for del(6)(q22) on thin sections of paraffin-embedded tumor samples. Two-color IGH BAP FISH probes were also used to confirm IGH rearrangements in cases showing extra IGH signals without fusion using the IGH-BCL6 probe. In situ hybridization was performed using probes that recognize EBV-encoded RNA (EBER) on paraffin-embedded tumor samples. Survival data were analyzed for patients diagnosed after 1997 (n=53), corresponding to the change to high dose methotrexate as the standard of care. Survival was calculated from the date of tissue diagnosis to date of death or last contact. Survival curves were estimated using the Kaplan-Meier method. The log-rank test was used to compare survival across groups. Two-tailed p-values <0.05 were considered statistically significant. Clinical information for the 1985–2006 and 1997–2006 groups was comparable, including median age (67 years (y) vs 68 y), age range (26–87 y for both groups), percentage of deaths (67 vs 64) and median follow up for survivors (588 d vs 395 d). Results: Thirty-four (45%) cases showed del(6)(q22), 6 of which alsocontained a BCL6 rearrangement. Seventeen (22%) cases had a BCL6 rearrangement. Translocations involving IGH and an unknown partner gene (n=2) and MYC and an unknown partner gene (n=2) were also identified. All cases were EBER negative. Of the 53 patients diagnosed after 1997, 23 lacked del(6)(q22) or BCL6 rearrangement and had a median overall survival (MS) of 731 days (d). The 17 patients with an isolated del(6)(q22) had a MS of 90 d and the 13 patients with a BCL6 rearrangement had a MS of 442 d (p=0.0016). Conclusions: Del(6)(q22) and BCL6 rearrangements are common in PCNSL (45% and 22% of cases, respectively) and are associated with decreased survival, particularly del(6)(q22) seemingly independent of patient age and treatment time trends. IGH translocations were less frequent than in systemic diffuse large B-cell lymphoma (13% vs 51%), suggesting a distinct pathogenesis. MYC translocations and EBV infection are rare in PCNSL affecting immunocompetent patients.

Influence of 6q22‐23 on overall survival in primary central nervous system lymphoma. Analysis of North Central Cancer Treatment Group trials 86 72 52, 93 73 51 and 96 73 51

“…Patient‐specific therapy is difficult to achieve because little is known regarding the molecular pathogenesis of PCNSL. This study confirmed our earlier observation that deletion of the 6q22‐23 region correlated with shorter survival of PCNSL patients, suggesting a biological region of interest (Cady et al , 2008). The study reported here comprised newly diagnosed PCNSL patients enrolled in three successive phase II clinical trials conducted by the NCCTG.…”

“…Based on our earlier observation that deletion of chromosomal region 6q22‐23 correlated with shorter survival of primary central nervous system lymphoma (PCNSL) patients (Cady et al , 2008) the overall goal of this study was to further refine the biomarker potential of 6q22‐23. We now describe the correlation of its deletion with the overall survival (OS) of patients enrolled on three consecutive North Central Cancer Treatment Group (NCCTG) Phase II clinical trials for newly diagnosed PCNSL, 867252 (O’ Neill et al , 1999), 937351 (Laack et al , in press), and 967351 (Laack et al , 2006).…”

“…Formalin‐fixed paraffin embedded blocks (FFPE) from patients enrolled in these three trials were retrieved from the Mayo Clinic Tumor Registry and the Biospecimen Repositories of the 30 participating trial sites (Mayo Foundation Institutional Review Board approval 08‐001933). Interphase FISH was performed on thin sections of the FFPE tumour samples following our previously described method (Cady et al , 2008). Survival data were analysed for all patients, with OS being calculated from the date of tissue diagnosis to date of death or last contact.…”