High Resolution Array-Based Analysis in Marginal Zone Lymphomas and Lymphoplasmacytic Lymphomas Identified Disease-Specific Patterns of Chromosome Abnormalities

Abstract

Marginal zone B-cell lymphomas (MZL) represent a sub-group of indolent B-cell lymphomas, normally localized in the “marginal zone” of the secondary lymphoid follicles. Depending on the site of involvement, three distinct sub-types have been identified: extra nodal MZL of MALT type, splenic MZL (SMZL), and nodal MZL (NMZL). MALT lymphoma is the most frequent of the MZL subtypes, representing 70% of MZL and 7% to 8% of non-Hodgkin lymphomas. SMZL and NMZL comprise the remaining 20% and 10% of MZL, respectively, and account for less than 1% of NHL. The relative rarity of these lymphomas and difficulty in distinguishing them from other low-grade B-cell lymphoma subtypes like lymphoplasmacytic lymphomas (LPL), making therapeutic decisions difficult. The aim of this study was to perform a comprehensive high-resolution study to identify distinctive molecular markers in MZL and LPL, which would help to better define these lymphomas at genomic level and distinguish them from other types of low-grade B-cell lymphoma. We analyzed 119 patients, including 22 pulmonary MALT (pMALT), 20 non-pulmonary MALT (npMALT), 34 SMZL, 21 NMZL and 22 LPL (8 Waldenström's Macroglobulinemia and 14 non-WM) cases. Human Agilent 244A platform was used by array-based comparative genomic hybridization (aCGH) analysis. Overall, 93% of patients have an altered genome. LPL had the highest amount of copy number abnormalities (median of 7.5 per patient; average of 11.7; range: 0–44), followed by npMALT (6.5; 7.6; 0–33), NMZL (5; 8.3; 0–31), SMZL (4; 7.1; 0–56) and pMALT (3.5; 4.3; 1–11). When the overall size of the abnormalities was considered, LPL was also the most affected disease with an average size of 245.15Mb included in copy number changes per patient, followed by NMZL (188.6Mb), npMALT (187.2Mb), SMZL (126.4Mb) and pMALT (109Mb). Deletions were more commonly observed than amplifications but the affected area was significantly smaller (average of 55.2Mb and 118.6Mb included in deletions and amplifications per genome, respectively). Partial or total gains of chromosome 3 and 18 were recurrently identified in all the entities, being the most common abnormalities in npMALT (60% and 50%, respectively) and pMALT (27% each). Trisomy 12 was also ubiquitously observed, ranging from 24% of NMZL to 9% of pMALT. Deletions in 6q were commonly identified in LPL (55%), npMALT (35%) and, in a less extent, in SMZL (12%) and NMZL (5%), but not in pMALT. Biallelic and focal monoallelic deletions at 6q23 clearly delineate a minimal deleted region (MDR) that includes TNFAIP3 as being the target gene of the abnormality. Deletions on 7q were found in SMZL and npMALT, thus delineating two MDR. Interstitial 11q deletions were found in LPL, NMZL and SMZL, but not in MALT. Chromosome 13 abnormalities were monosomies in NMZL and interstitial 13q14 deletions in LPL and SMZL, comprising MIRN15A and MIRN16-1 in the MDR. Partial X chromosome gains were common to all the entities but involving different areas: Xq27.3–q28 gains were recurrent events in LPL and NMZL, but not in SMZL and MALT, which were characterized by p arm gains or trisomies. Finally, some recurrent abnormalities were exclusive of specific entities: 1p deletions and 1q gains were only common in NMZL; a focal 2p gain including BCL11A and REL was found in npMALT and partial 8q gains were only identified in LPL. Trisomy 4 was only identified in the subgroup of LPL with WM, but not in the remaining LPL cases or in the remaining diseases. In this study we made a compendium of chromosomal abnormalities present in a group of related diseases, in which the molecular basis remains poorly defined. Using this high-resolution approach we were able to establish recurrent and disease-specific patterns of abnormalities and minimal deleted/amplified regions were redefined. Furthermore, TNFAIP3, a negative regulator of the NF-kB pathway, has been identified as being a commonly affected gene in MALT, LPL and NMZL, highlighting its potential role in pathogenesis.