Gain of chromosome region 18q21 including the MALT1 gene is associated with the activated B-cell-like gene expression subtype and increased BCL2 gene dosage and protein expression in diffuse large B-cell lymphoma
Judith DierlammEva Maria Murga PenasStefan BentinkSwen WeßendorfHilmar BergerMichael HummelWolfram KlapperDido LenzeAndreas RosenwaldEugenia HaralambievaGerman OttSergio CogliattiPeter MöllerCarsten SchwäenenHarald SteinMarkus LöfflerRainer SpangLorenz TrümperReiner Siebert
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Background The aim of this study was to determine the impact of a gain of the MALT1 gene on gene expression and clinical parameters in diffuse large B-cell lymphoma.Design and Methods We analyzed 116 cases of diffuse large B-cell lymphoma by fluorescence in situ hybridization, array-based comparative genomic hybridization, and transcriptional profiling.Results A gain of 18q21 including MALT1 was detected in 44 cases (38%) and was accompanied by a gain of BCL2 in 43 cases. All cases with a 18q21/MALT1 gain showed BCL2 protein whereas 79% in the group without a 18q21/MALT1 gain did so (pKeywords:
Comparative genomic hybridization
Chromosome 18
Gene dosage
Comparative genomic hybridization
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CD10 is one of the hallmarks of germinal center B‐cells where follicular lymphomas (FL) originate. It has not been clearly established, however, whether CD10 + diffuse B‐cell lymphomas (DLBCL) are genetically similar to FL. We therefore examined 19 CD10 + DLBCL and 40 FL by means of comparative genomic hybridization (CGH) and tissue‐fluorescence in situ hybridization (T‐FISH). Chromosomal imbalance was more frequently detected in CD10 + DLBCLs (19/19) than in FLs (24/40). Significant differences were found in eight frequently imbalanced regions, namely those with gains of chromosomes 7q and 12 and those with losses of chromosomes 1p, 4p, 6q, 15q, 16p and 17. Amplification of the 3q region where BCL6 is located is reported to occur frequently in DLBCL, but it was only found in one of the 19 CD10 + DLBCL cases we examined. The involvement of t(14;18) in CD10 + DLBCL (31%) and in FL (73%) was significantly different ( P =0.0064). The CGH pattern of CD10 + DLBCL with t(14;18) was also different from that of FL with t(14;18). Taken together, our results indicate that CD10 + DLBCL constitutes a unique subtype entity with genetic characteristics significantly different from those of FL and DLBCL.
Comparative genomic hybridization
Follicular lymphoma
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Comparative genomic hybridization
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We applied a combination of comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH), to characterize the genetic aberrations in three osteosarcomas (OS) and one Ewing's sarcoma. CGH identified recurrent chromosomal losses at 10p14-pter and gains at 8q22.3-24.1 in OS. Interphase FISH allowed to confirm 8q gain in two cases. A high amplification level of 11q12-qter was detected in one OS. The Ewing's sarcoma showed gain at 1p32-36.1 as the sole chromosome alteration. These studies demonstrate the value of molecular cytogenetic methods in the characterization of recurrent genomic alterations in bone tumor tissue.
Comparative genomic hybridization
Interphase
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Comparative genomic hybridization
Interphase
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Summary. Chromosomal abnormalities, such as 13q deletions, are emerging as important prognostic factors in multiple myeloma. Fluorescence in situ hybridization (FISH) using specific DNA probes is the technique most widely used for the determination of genomic aberrations in this disease. The utility of comparative genomic hybridization (CGH) for molecular diagnostics in plasma cell malignancies has not been systematically analysed. We investigated tumour samples of patients with multiple myeloma ( n = 43) or plasma cell leukaemia ( n = 3) using CGH and FISH with five DNA probes localized to chromosome bands 1p22, 6q21, 11q22–q23, 13q14 and 17p13. By CGH, the most frequent genomic changes were gains on chromosomes 1q, 9q and 11q, as well as losses on chromosomes 13q, 6q, Xp and Xq. By FISH, trisomy 11q was identified at a similar frequency to the 13q deletion (42%). Compared with FISH data, the sensitivity of CGH was 80·7% and the specificity was 97·5%. Thirty‐two aberrations found by FISH were not identified by CGH, mostly as a result of the proportion of cells carrying the respective aberrations, or because of the limited spatial resolution of CGH. Our data indicate that, for clinical molecular diagnostics in multiple myeloma, FISH with a disease‐specific DNA probe set is superior to CGH analysis.
Comparative genomic hybridization
Trisomy
Hybridization probe
Plasma cell neoplasm
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Comparative genomic hybridization
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Comparative genomic hybridization (CGH) was applied to screen the genetic events in six invasive urinary bladder cancers. These cases were also studied by flow cytometry (FCM) and fluorescence in situ hybridization (FISH). Four samples showed partial gain on chromosome 8, with the common region involved was on 8q23-qter. Full or partial deletion on chromosome 2 and 17p in addition to gain on 20q was found in two cases. Interestingly one diploid tumor with low mitotic index, stage and grade showed more genetic aberrations (8 gains and 7 losses) by CGH than other aneuploid tumors with high mitotic index, stage and grade. The numerical chromosomal aberration detected by FISH for chromosomes 7, 8, 9, 10, 11 and 17 were 50% in T1 cases and 100% in T2-T4 cases. FISH was performed on chromosome 8q and 17p to compare and validate the sensitivity of CGH. The agreement was 100% for 8q24 locus and 50% for p53 locus. This indicates that different molecular genetic techniques showed relatively different aspect of genomic aberrations.
Comparative genomic hybridization
Mitotic index
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Fluorescence in situ hybridization (FISH) has proven useful for the identification of chromosomal material of unknown origin. More recently, comparative genomic hybridization (CGH) has been used to identify deletions and amplifications, particularly in neoplastic samples. Here, we describe the combined use of CGH and FISH to identify the origin of a de novo unbalanced translocation in a newborn with multiple congenital anomalies. GTG banding of metaphases from cultured lymphocytes showed an unbalanced karyotype, with extra material on a chromosome 5: 46, XX, add(5)(q35). Parental karyotypes were both normal. CGH revealed the additional material was from distal 1 1q (11q23→qter). This finding was confirmed by FISH with a whole chromosome paint for chromosome 11. Based on the CGH and FISH analyses, the pro-band’s karyotype was therefore 46, XX, der(5)t(5;11)(q35.2; q23.2).ish der(5)(wcp11+). This case demonstrates the efficient use of CGH and confirmatory FISH for the identification of chromosomal material of unknown origin.
Comparative genomic hybridization
Chromosomal rearrangement
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The amplification of chromosome 9p24.1 encoding PD-L1, PD-L2, and JAK2 has been reported in multiple types of cancer and is associated with poor outcome, upregulation of PD-L1, and activation of the JAK/STAT pathway. We have developed a novel fluorescence in situ hybridization assay which combines 3 probes mapping to 9p24.1 with a commercial chromosome 9 centromere (CEN9) probe for detection of the JAK2/9p24.1 amplification. JAK2 fluorescence in situ hybridization was compared with array-based comparative genomic hybridization in 34 samples of triple negative breast cancer tumor. By array-based comparative genomic hybridization, 15 had 9p24.1 copy-number gain (log2ratio>0.3) and 19 were classified as non-gain (log2ratio≤0.3). Copy-number gain was defined as JAK2/CEN9 ratio ≥1.1 or average JAK2 signals≥3.0. Twelve of 15 samples with copy-number gain by array-based comparative genomic hybridization were also detected by fluorescence in situ hybridization. Eighteen of 19 samples classified as copy-number non-gain by array-based comparative genomic hybridization were concordant by array-based comparative genomic hybridization. The sensitivity and specificity of the fluorescence in situ hybridization assay was 80% and 95%, respectively (P=0.02). The sample with the highest level of amplification by array-based comparative genomic hybridization (log2ratio=3.6) also scored highest by fluorescence in situ hybridization (ratio=8.2). There was a correlation between the expression of JAK2 and amplification status (Mean 633 vs 393, P=0.02), and there was a trend of association with PD-L1 RNA expression (Mean 46 vs 22, P=0.11). No significant association was observed between PD-L1 immunohistochemistry expression and copy-number gain status. In summary, the novel array-based comparative genomic hybridization assay for detection of chromosome 9p24.1 strongly correlates with the detection of copy-number gain by array-based comparative genomic hybridization. In triple negative breast cancer, this biomarker may identify a relevant subset of patients for targeted molecular therapies.
Comparative genomic hybridization
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