Splenic marginal zone lymphomas are characterized by loss of interstitial regions of chromosome 7q, 7q31.32 and 7q36.2 that include the protection of telomere 1 (POT1) and sonic hedgehog (SHH) genes

To further characterize the genotypic features of splenic (S) and nodal (N) marginal zone lymphomas (MZL) we compared eight SMZL and five NMZL by array-based comparative genomic hybridization (aCGH). Arbitrarily, aberrations were divided into major imbalances, defined as gains or losses involving five or more contiguous genetic loci, and minor imbalances, defined as those involving four or fewer loci. SMZL, but not NMZL, demonstrated major imbalances. These included deletions involving various lengths of 7q (three cases), and 14q23q24 (one case) and gains of 9p13p21 (one case), 13q21q33 (one case) and 16p13.1 (one case). Common minor imbalances in SMZL were: loss of sonic hedgehog gene ( SHH ) at 7q36.2 (four cases), loss of protection of telomere 1 gene ( POT1 ) at 7q31.32 (three cases), and gain of glioma associated oncogene 1 ( GLI1 ) at 12q13.2 (three cases). Common minor alterations in NMZL were: loss of the fas-associated via death domain gene ( FADD ) at 11q13.2 (three cases) and gain of GLI1 (five cases). In conclusion, SMZL, but not NMZL, demonstrates large genomic imbalances and frequent loss of the 7q31.32 and 7q36.2 regions involving POT1 and SHH , respectively. In NMZL, loss of FADD and gain of GLI1 are frequent events.     

Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations

Genomic aberrations in a series of paired biopsy samples from patients who presented initially with follicle center lymphoma (FCL) and subsequently transformed to diffuse large B-cell lymphoma (DLBCL) were measured by array comparative genomic hybridization (CGH). The consequences of these aberrations on gene expression were determined by comparison with expression analysis on these specimens using cDNA microarrays. A heterogeneous pattern of acquired genomic abnormalities was observed upon transformation, some of which were recurrent in small subsets of patients. Some of the genomic aberration acquired upon transformation, such as gain/amplification of 1q21-q24, 2p16 (REL/BCL11A gene loci), 3q27-q29 (including the BCL6 locus), 7q11.2-q22.1, 12pter-q12, 18q21 (including the BCL2 locus) and Xq, and deletion of 6q22-q24, 13q14-q21 and 17p13 (P53 locus) have been previously implicated in the FCL/DLBCL pathogenesis. In addition, novel genomic imbalances not previously reported in association with FCL transformation, such as overrepresentation of 4p12-pter, 5p12-p15, 6p12.3-p21, 9p23, 9q13-q31, 16q, 17q21, and loss of 1p36.3, 4q21-q23, 5q21-q23, 9q31-qter, 11q24-q25, and 15q23, were identified. We observed a differential expression profile of many genes within regions of gain and deletion upon transformation, including novel target genes associated with FCL transformation. However, other genes did not show deregulated expression despite their location within these areas. In summary, the combination of array CGH and expression analysis provides a more comprehensive picture of the transformation of FCL to DLBCL. This process is associated with the acquisition of a variable spectrum of genomic imbalances affecting recurrent chromosomal areas that harbor overexpressed or underexpressed genes targeted upon transformation.     

Cytogenetic abnormalities and clinical correlations in peripheral T-cell lymphoma

Cytogenetic correlations among most types of peripheral T-cell lymphoma (PTCL) have not been very informative to date. This study aimed to identify recurrent chromosomal abnormalities in angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large cell lymphoma (ALK-ALCL) and peripheral T-cell lymphoma, unspecified (PTCL-US), and to evaluate their prognostic value. We reviewed the cytogenetic findings of 90 previously-diagnosed cases of PTCL and correlated the cytogenetic findings with the specific histological subtype. The most common abnormalities for AITL were 5q (55%), 21 (41%) and 3q (36%) gains, concurrent trisomies of 5 and 21 (41%), and loss of 6q (23%). In ALK(-) ALCL, gains of 1q (50%) and 3p (30%), and losses of 16pter (50%), 6q13q21 (30%), 15 (30%), 16qter (30%) and 17p13 (30%) were frequent findings. In PTCL-US, frequent gains involved 7q22q31 (33%), 1q (24%), 3p (20%), 5p (20%), and 8q24qter (22%), and losses of 6q22q24 (26%) and 10p13pter (26%). We did not observe any association between specific chromosomal abnormalities and overall survival (OS). However, cases with complex karyotypes, most frequently observed in ALK(-) ALCL and PTCL-US, had a significantly shorter OS. Although, genetic differences were noted in these subtypes, further studies are needed to determine the key pathogenetic events in PTCL.     

Hepatitis B virus infection is associated with deletion of chromosome 8p in multiple myeloma

Serological analyses within epidemiological cohort and case‐control studies indicate to an association between HBV infection and risk of multiple myeloma (MM). To verify the relationship with an independent approach, we investigated the correlation between HBV positivity and chromosomal aberrations within 680 patients of the National Center for Tumor Diseases Heidelberg for which the serological HBV status (HBsAg and anti‐HBc) and FISH data for five gains (1q21, 9q34, 11q23, 15q22, 19q13), five losses (6q21, 8p21, 13q14, 17p13, 22q11), and three IgH translocations [t(4,14), t(11,14), t(14,16)] were available. Deletion of 8p21 and 13q14 were shown associated with HBV positivity within hepatocellular carcinoma in other investigations. In the present evaluation, the odds ratio for loss of 8p21 was significantly elevated (OR = 2.74, 95% CL = 1.36–5.50, P = 0.0048) and for loss of 13q14 non‐significantly increased (OR = 1.40, 95% CL = 0.74–2.65) in anti‐HBc positive patients. The results provide further support for a role of HBV infection in the pathogenesis of MM.     

New chromosome abnormalities and lack of BCL-6 gene rearrangements in Argentinean diffuse large B-cell lymphomas

OBJECTIVES: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphomas. Cytogenetic studies have revealed a broad spectrum of clonal genetic abnormalities and complex karyotypes. The purpose of this study was to contribute to the understanding of the genomic alterations associated with this group of lymphomas. METHODS: Cytogenetic, fluorescence in situ hybridization (FISH) and molecular analyses were performed in 30 cases with DLBCL: 20 de novo DLBCL (dn-DLBCL) and 10 DLBCL secondary to follicular lymphoma (S-DLBCL). RESULTS: A total of 37 different structural chromosomal rearrangements were found: 27% translocations, 54% deletions, and 19% other alterations. Chromosomes 8, 6, 2, and 9 were the most commonly affected. Interestingly, translocation t(3;14)(q27;q32) and/or BCL-6 gene rearrangements were not observed either by cytogenetic studies or by FISH analysis. Fifteen novel cytogenetic alterations were detected, among them translocations t(2;21)(p11;q22) and t(8;18)(q24;p11.3) appeared as sole structural abnormalities. Translocation t(14;18)(q32;q21) and/or BCL-2-IGH gene rearrangements were the genomic alterations most frequently observed: 50% of S-DLBCL and 30% of dn-DLBCL. Deletions del(4)(q21), del(6)(q27), del(8)(q11), and del(9)(q11) were recurrent. The most common gains involved chromosome regions at 12q13-q24, 7q10-q32, and 17q22-qter; 6q was the most frequently deleted region, followed by losses at 2q35-qter, 7q32-qter, and 9q13-qter. Four novel regions of loss were identified: 5q13-q21, 2q35-qter (both recurrent in our series), 4p11-p12, and 17q11-q12. CONCLUSIONS: These studies emphasize the value of combining conventional cytogenetics with FISH and molecular studies to allow a more accurate definition of the genomic aberrations involved in DLBCL.     

Allelic genotyping reveals a hierarchy of genomic alterations in mantle cell lymphoma associated to cell proliferation

Mantle cell lymphoma (MCL) is a distinct subentity of non-Hodgkin lymphoma, characterized by the chromosomal translocation t(11;14)(q13;q32) leading to an overexpression of cyclin D1 in virtually all cases. However, additional cytogenetic aberrations are apparent in the vast majority of MCL. Applying LOH analysis in 52 MCL patient samples, we confirmed frequent alterations in 9p21 (28.6%) and p53 (28.9%) but also detected allelic losses in 1p21, 9q21, 13q13-14, 13q31-32, 17p13.1, and 17p13.3 in 28–45% of cases and allelic gains in 3q27-28 and 19p13.3 in 14–22% of cases. In addition, losses in the 2p23 and 7q22-35 genomic regions not previously described to be altered in MCL were identified in up to 20% of cases. Applying multivariate analysis, a cluster of genomic aberrations including 1p21, 3q27, 7q22-36, 6p24, 9p21, 9q31, and 16p12 alterations was identified which was closely associated to cell proliferation as determined by Ki67 immunostaining. This proliferation-dependent network of oncogenic alterations complements the previously identified proliferation expression signature described by RNA expression profiling in MCL.     

Characterisation of hairy cell leukaemia by tiling resolution array‐based comparative Genome hybridisation: a series of 13 cases and review of the literature

Little is known about the cytogenetic features and molecular mechanisms behind hairy cell leukaemia (HCL), despite the advances in diagnosis and treatment. Therefore, we used high‐resolution genome‐wide array‐based comparative genomic hybridisation (array‐CGH) and multiplex ligation‐dependent probe amplification (MLPA) to characterise copy number alterations (CNAs) in DNA from 13 cases of HCL. We also summarise CNAs and cytogenetic features in 109 HCL cases comprising our 13 cases and 96 cases from the literature. Genomic array‐CGH revealed imbalances in two out of 13 cases in addition to previously described copy number variants (CNVs) found in healthy individuals. In one case, a 700 kb deletion of 20q11.22 was detected encompassing ten characterised genes, among them the TP53INP2, DNCL2A and ITCH genes. In the second case, trisomy 5, and a deletion of 5p15.2 encompassing a non‐characterised gene AY328033 was found. Altogether only 20/81 (25%) of all cases studied by CGH or gene dose array revealed CNAs. The most common recurrent deletions and breakpoints were 14q22–32 (33%), 6q25 (16%), 2p12 (10%), 22q11 (10%), 17p11–13 (10%), 7q32–36 (9%), 18q11–13 (7%), 1q32–44 (6%), 8p22–23 (6%) and 7q11 (6%). Trisomy 5 occurred in 15%. In addition, several other recurrent breakpoints were identified. Although a number of genomic imbalances were identified in the HCL samples, the genome appeared remarkably stable.     

Prognostic and biologic significance of chromosomal imbalances assessed by comparative genomic hybridization in multiple myeloma

Cytogenetic abnormalities, evaluated either by karyotype or by fluorescence in situ hybridization (FISH), are considered the most important prognostic factor in multiple myeloma (MM). However, there is no information about the prognostic impact of genomic changes detected by comparative genomic hybridization (CGH). We have analyzed the frequency and prognostic impact of genetic changes as detected by CGH and evaluated the relationship between these chromosomal imbalances and IGH translocation, analyzed by FISH, in 74 patients with newly diagnosed MM. Genomic changes were identified in 51 (69%) of the 74 MM patients. The most recurrent abnormalities among the cases with genomic changes were gains on chromosome regions 1q (45%), 5q (24%), 9q (24%), 11q (22%), 15q (22%), 3q (16%), and 7q (14%), while losses mainly involved chromosomes 13 (39%), 16q (18%), 6q (10%), and 8p (10%). Remarkably, the 6 patients with gains on 11q had IGH translocations. Multivariate analysis selected chromosomal losses, 11q gains, age, and type of treatment (conventional chemotherapy vs autologous transplantation) as independent parameters for predicting survival. Genomic losses retained the prognostic value irrespective of treatment approach. According to these results, losses of chromosomal material evaluated by CGH represent a powerful prognostic factor in MM patients.     

Chromosomal imbalances identified by comparative genomic hybridization in sporadic parathyroid adenomas

OBJECTIVE: To identify chromosomal gains and losses in sporadic parathyroid adenomas (PAs). METHODS: Fourteen sporadic PAs were studied by comparative genomic hybridization (CGH). RESULTS: The fourteen studied PAs showed chromosomal imbalances. All cases except one exhibited two or more abnormalities. Chromosomal gains were found in all cases, and three cases (21%) also presented chromosomal losses. Genomic amplification was not observed. Chromosome 9 was involved in ten cases. Recurrent genetic gain was found on 9p22-24 and on 9q34, each in 6 of 14 cases (43%). Other recurrent gains included Xq26 in 6 PAs (43%) and 4q21-28 and 8p22-23, each in 4 of 14 cases (29%). Regions of recurrent genetic loss involved whole chromosome 11 and 20q12-13, each in 2 of 14 cases (14%). CONCLUSIONS: Our findings show chromosomal imbalances in all sporadic PAs studied by CGH, partly confirming previous reports, with the exception that we observed more chromosomal gains than losses. Several regions (9p22-24, 9q34, Xq26, 4q21-28, and 8p22-23) probably deserve further investigation in order to discard the presence of genes involved in parathyroid tumorigenesis.     

Loss of fragile histidine triad and amplification of 1p36.22 and 11p15.5 in primary gastric adenocarcinomas

AIM: To investigate the genomic copy number alterations that may harbor key driver genes in gastric tumorigenesis.METHODS: Using high-resolution array comparative genomic hybridization (CGH), we investigated the genomic alterations of 20 advanced primary gastric adenocarcinomas (seventeen tubular and three mucinous) of Chinese patients from the Jilin province. Ten matching adjacent normal regions from the same patients were also studied.RESULTS: The most frequent imbalances detected in these cancer samples were gains of 3q26.31-q27.2, 5p, 8q, 11p, 18p, 19q and 20q and losses of 3p, 4p, 18q and 21q. The use of high-resolution array CGH increased the resolution and sensitivity of the observed genomic changes and identified focal genetic imbalances, which included 54 gains and 16 losses that were smaller than 1 Mb in size. The most interesting focal imbalances were the intergenic loss/homozygous deletion of the fragile histidine triad gene and the amplicons 11q13, 18q11.2 and 19q12, as well as the novel amplicons 1p36.22 and 11p15.5.CONCLUSION: These regions, especially the focal amplicons, may harbor key driver genes that will serve as biomarkers for either the diagnosis or the prognosis of gastric cancer, and therefore, a large-scale investigation is recommended.     

Analysis of molecular cytogenetic alterations in uterine leiomyosarcoma by array-based comparative genomic hybridization

Objective

The aim of this study was to identify novel genes following genomic DNA copy number changes using a genome-wide array-based comparative genomic hybridization (array-CGH) analysis in uterine leiomyosarcoma (ULMS).

Methods

Genomic DNA copy number changes were analyzed in 15 cases of ULMS from St Mary’s Hospital of the Catholic University of Korea. The paraffin-fixed tissue samples were micro-dissected under microscope, and DNA was extracted. Array-based CGH and genomic polymerase chain reaction were carried out with statistical analyses such as hierarchical clustering and Gene Ontology.

Results

All of 15 cases of ULMS showed specific gains and losses. The percentage of average gains and losses were 8.4 and 16.6?%, respectively. The analysis limit of average gains and losses was 40?%. The regions of high level of gain were 1q23.3, 7p14.2, 7q34, 7q35, 7q36.3, 13q34, and 16p13.3. And the regions of homozygous loss were 2q21.1, 2q22.1, 2p23.2, 12q23.3, 4q21.22, 4q34.3, 11q24.2, 12q23.3, 13q13.1, 13q21.33, and 14q24.3. In ULMS samples, recurrent regions of gain were 1p36.33, 1p36.32, 5q35.3, 7q36.3, and 8q24.3 and recurrent regions of loss were 1p31.1–p31.3, 1p32.1–p32.3, 2p12, 2p13.3, 2p14, 2p16.2–p16.3, 2q12.1–q12.3, 2q21.1–q21.2, 2q22.2–q22.3, 2q34, 2q36.1–q36.3, 5q21.3, 5q23.3, 5q31.1, 6p11.2, 6p12.1, 10q11.23, 10q21.2–q21.3, 10q23.2, 10q23.31, 10q25.1–q25.2, 10q25.3, 10q26.13, 10q26.2–q26.3, 11p11.2, 11p11.12, 11p12, 11p13, 11p15.4, 11q23.1–q23.2, 11q23.3, 13q14.12, 13q14.13–13q14.2, 13q14.2, 13q14.2, 13q14.3, 13q21.33, 13q22.1–q22.3, 14q24.2, 14q24.3, 14q31.1, 14q32.33, 15q11.2–q13, 15q14, 16q22.3, 16q23.1, 16q23.2, 16q24.1, 20p12.1, and 21q22.3. Representative frequently gained BAC clones encoded genes were HDAC9, CRR9, SOX18, PTPRN2, SKI, SOLH, and KIAA1199. The genes encoded by frequently lost BAC clones were LOC150516 and AMY2A. A subset of cellular processes from each gene were clustered by Gene Ontology database.

Conclusions

The present study using array-CGH analyses sought a deeper elucidation of the specific genomic alterations related to ULMS. The high resolution of array-CGH combined with human genome database would give a chance at identifying relevant target genes.     

Distinct comparative genomic hybridisation profiles in gastric mucosa-associated lymphoid tissue lymphomas with and without t(11;18)(q21;q21)

t(11;18)(q21;q21) occurs specifically in mucosa-associated lymphoid tissue (MALT) lymphoma and the translocation generates a functional API2-MALT1 fusion product that activates nuclear factor (NF)kappaB. t(11;18) positive lymphomas usually lack the chromosomal aberrations and microsatellite alterations frequently seen in the translocation-negative MALT lymphomas. To further understand their genetic differences, we investigated gastric MALT lymphomas with and without t(11;18) by comparative genomic hybridisation. In general, both chromosomal gains and losses were far more frequent in t(11;18)-negative (median = 3.4 imbalances) than t(11;18)-positive cases (median = 1.6 imbalances), with gains being more frequent than losses. Recurrent chromosomal gains involving whole or major parts of a chromosome were seen for chromosomes 3, 12, 18 and 22 (23%, 19%, 19% and 27% respectively). Discrete recurrent chromosomal gains were found at 9q34 (11/26 = 42%). Bioinformatic analysis of genes mapping to 9q34 revealed potential targets. Among them, TRAF2 and CARD9 are known interaction partners of BCL10, playing a role in NFkappaB activation. Interphase fluorescent in situ hybridisation confirmed genomic gain of the TRAF2, CARD9 and MALT1 loci in 5/6 and 2/2 cases showing chromosomal gains at 9q34 and 18q21 respectively. The results further highlight the genetic difference between MALT lymphomas with and without t(11;18). Moreover, our findings suggest that genomic gain of genes that modulate NFkappaB activation, such as MALT1, TRAF2 and CARD9, may play a role in the pathogenesis of the translocation-negative MALT lymphoma.     

Comparative Genomic Hybridization Array Analysis and Real-Time PCR Reveals Genomic Copy Number Alteration for Lung Adenocarcinomas

Genomic alterations in lung cancer tissues have been observed in various studies. To analyze the aberrations in the genome of lung cancer patients, we used array comparative genomic hybridization (array CGH) in 15 lung adenocarcinoma (AdC) tissues. Copy number gains and losses in chromosomal regions were detected and corresponding genes were confirmed by real-time polymerase chain reaction (PCR). As for the results, several frequently altered loci, including gain of 16p (46% of samples), were found, and the most common losses were found in 14q32.33 (26% of samples). High-level DNA amplifications (> 0.8 log₂ ratio) were detected at 1p, 5p, 7p, 9p, 11p, 11q, 12q, 14q, 16p, 17q, 19q, 20p, 21q, and 22q. A subset of genes, gained or lost, was checked for over- or underrepresentation by means of real-time PCR. The degree of fold change was highest in ECGF1 (22q13.33), HOXA9 (7p15.2), MAFG (17q25.3), TSC2 (16p13.3), and ICAM1 (19p13.2) genes and the 16p chromosome terminal region (16p13.3pter). Taken together, these results show that array CGH could be used as a powerful tool for identification of genomic alteration for lung cancer, and the above-mentioned genes may represent potential candidate genes in the study of lung cancer pathogenesis and diagnosis.     

Loss of a novel tumor suppressor gene locus at chromosome 8p is associated with leukemic mantle cell lymphoma.

Patients with mantle cell lymphoma (MCL) may present with either nodal or leukemic disease. The molecular determinants underlying this different biologic behavior are not known. This study compared the pattern of genetic abnormalities in patients with nodal and leukemic phases of MCL using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) for specific gene loci. Although both leukemic and nodal MCL showed similar genomic patterns of losses (involving 6q, 11q22-q23, 13q14, and 17p13) and gains (affecting 3q and 8q), genomic loss of chromosome 8p occurred more frequently in patients with leukemic disease (79% versus 11%, P <.001). Subsequent CGH analysis confirmed the genomic loss of 8p21-p23 in 6 of 8 MCL cell lines. Interestingly, MYC gene amplification was restricted to cases with 8p deletion. These data indicate the presence of a novel tumor suppressor gene locus on 8p, whose deletion may be associated with leukemic dissemination and poor prognosis in patients with MCL.     

G-banding and molecular cytogenetic analyses of marginal zone lymphoma

We analysed the acquired chromosomal aberrations of 22 marginal zone lymphoma (MZL) patients by various genome-wide cytogenetic techniques, such as G-banding, multicolour fluorescence in situ hybridisation (M-FISH), cross-species colour banding (RxFISH), and comparative genomic hybridisation (CGH), as well as FISH with locus-specific probes. Patients with an abnormal chromosome 3 (n = 11), the most frequently rearranged chromosome, showed a shorter median survival than patients with a normal chromosome 3 (n = 11, 74 months vs. 219 months, P < 0.03). Four of five patients with nodal MZL had chromosome 3 abnormalities and patients with nodal MZL had a shorter median survival than patients in the other morphological subgroups of MZL (P < 0.003). CGH analysis showed only gains of chromosome material, namely of chromosome regions 3p12-25, 3q12-21, 3q23-28, 12q13-15, 12q22-24, 19p13 and 19q13 in two to four cases each (20-40%). In two MZL, the novel unbalanced translocation der(13)t(3;13)(q24;p11) was detected as the sole karyotypic rearrangement, indicating that gain of 3q24-qter could be an important event in the pathogenesis of these lymphomas. Another two cases showed, in addition to other abnormalities, a t(4;14)(p13;q32). Both these lymphomas had involvement of the IGH gene at 14q32, and one of them also of the RHOH/TTF gene at 4p13, which encodes a new member of the RHO protein subfamily.     

Comparative expressed sequence hybridization studies of hairy cell leukemia show uniform expression profile and imprint of spleen signature

Comparative expressed sequence hybridization (CESH) to chromosomes is a recently introduced technique that identifies chromosomal regions corresponding to a differential gene expression. This technique is analogous to comparative genomic hybridization (CGH) that detects genomic imbalances. We applied CESH for the study of hairy cell leukemia (HCL), a disorder with a largely unknown expression profile. Twelve HCL cases with spleen involvement were investigated by CESH and CGH. While the latter analysis identified only a few nonrecurrent genomic imbalances, CESH showed a consistent expression profile in all HCL cases. In addition, pairing normal spleen with normal lymph node, a "spleen signature" was established by CESH. This signature most likely reflects the expression profile of spleen-specific components, such as the sinusoidal lining cells from the red pulp and the marginal zone B cells from the white pulp. Imprint of the spleen signature was found in the HCL expression profile, suggesting that HCL may originate from a particular B-cell subset present in these splenic components. Besides pairing HCL with normal lymph node and spleen, we identified an "HCL signature" comprising several chromosome regions with altered expression. The most significantly underexpressed regions include 3p24, 3p21, 3q13.3-q22, 4p16, 11q23, 14q22-q24, 15q21-q22, 15q24-q25, and 17q22-q24; and 13q31 and Xq13.3-q21 were the most significantly overexpressed. These regions possibly harbor genes related to the biology and the pathogenesis of HCL. Their identification warrants further molecular investigations.     

Array comparative genomic hybridization reveals similarities between nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte rich large B cell lymphoma (THRLBCL) usually affect middle‐aged men, show tumour cells with a B cell phenotype and a low tumour cell content. Whereas the clinical behaviour of NLPHL is indolent, THRLBCL presents with advanced stage disease and an aggressive behaviour. In the present study, array comparative genomic hybridization was performed in seven typical NLPHL, four THRLBCL‐like NLPHL variants, six THRLBCL and four diffuse large B cell lymphomas (DLBCL) derived from NLPHL. The number of genomic aberrations was higher in THRLBCL compared with typical and THRLBCL‐like variant of NLPHL. Gains of 2p16.1 and losses of 2p11.2 and 9p11.2 were commonly observed in typical and THRLBCL‐like variants of NLPHL as well as THRLBCL. Gains of 2p16.1, affecting the REL locus were confirmed in an independent cohort. Expression of the REL protein was observed at similar frequencies in typical and THRLBCL‐like variant of NLPHL as well as THRLBCL (33–38%). In conclusion, the present study reveals further similarities between NLPHL and THRLBCL on the genomic level, confirming that these entities are part of a pathobiological spectrum with common molecular features, but varying clinical presentations.     

Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas

Anaplastic large cell lymphoma (ALCL) is a T/null-cell neoplasm characterized by chromosomal translocations involving the anaplastic lymphoma kinase (ALK) gene (ALK). Tumours with similar morphology and phenotype but negative for ALK have been also recognized. The secondary chromosomal imbalances of these lymphomas are not well known. We have examined 74 ALCL, 43 ALK-positive and 31 ALK-negative, cases by comparative genomic hybridization (CGH), and locus-specific alterations for TP53 and ATM were examined by fluorescence in situ hybridization and real-time quantitative polymerase chain reaction. Chromosomal imbalances were detected in 25 (58%) ALK-positive and 20 (65%) ALK-negative ALCL. ALK-positive ALCL with NPM-ALK or other ALK variant translocations showed a similar profile of secondary genetic alterations. Gains of 17p and 17q24-qter and losses of 4q13-q21, and 11q14 were associated with ALK-positive cases (P = 0.05), whereas gains of 1q and 6p21 were more frequent in ALK-negative tumours (P = 0.03). Gains of chromosome 7 and 6q and 13q losses were seen in both types of tumours. ALCL-negative tumours had a significantly worse prognosis than ALK-positive. However no specific chromosomal alterations were associated with survival. In conclusion, ALK-positive and negative ALCL have different secondary genomic aberrations, suggesting they correspond to different genetic entities.     

A pooled analysis of karyotypic patterns,breakpoints and imbalances in 783 cytogenetically abnormal multiple myelomas reveals frequently involved chromosome segments as well as significant age- and sex-related differences

The cytogenetic features (ploidy, complexity, breakpoints, imbalances) were ascertained in 783 abnormal multiple myeloma (MM) cases to identify frequently involved chromosomal regions as well as a possible impact of age/sex. The series included MM patients from the Mitelman Database of Chromosome Aberrations in Cancer and from our own laboratory. Hyperdiploidy was most common, followed by hypodiploidy, pseudodiploidy and tri-/tetraploidy. Most cases were complex, with a median of eight changes per patient. The distribution of modal numbers differed between younger and older patients, but was not related to sex. No sex- or age-related differences regarding the number of anomalies were found. The most frequent genomic breakpoints were 14q32, 11q13, 1q10, 8q24, 1p11, 1q21, 22q11, 1p13, 1q11, 19q13, 1p22, 6q21 and 17p11. Breaks in 1p13, 6q21 and 11q13 were more common in the younger age group. The most frequent imbalances were + 9, - 13, + 15, + 19, + 11 and - Y. Trisomy 11 and monosomy 16 were more common among men, while -X was more frequent among women. Loss of Y as the sole change and + 5 were more common in elderly patients, and - 14 was more frequent in the younger age group. The present findings strongly suggest that some karyotypic features of MM are influenced by endogenous and/or exogenous factors.