Chromosomal aberrations in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma unspecified: A matrix-based CGH approach

Angioimmunoblastic T-cell lymphoma (AILT) is a histopathologically well-defined entity. However, despite a number of cytogenetic studies, the genetic basis of this lymphoma entity is not clear. Moreover, there is an overlap to some cases of peripheral T-cell lymphoma unspecified (PTCL-u) in respect to morphological and genetic features. We used array-based comparative genomic hybridization (CGH) to study genetic imbalances in 39 AILT and 20 PTCL-u. Array-based CGH revealed complex genetic imbalances in both AILT and PTCL-u. Chromosomal imbalances were more frequent in PTCL-u than in AILT and gains exceeded the losses. The most recurrent changes in AILT were gains of 22q, 19, and 11p11-q14 (11q13) and losses of 13q. The most frequent changes in PTCL-u were gains of 17 (17q11-q25), 8 (involving the MYC locus at 8q24), and 22q and losses of 13q and 9 (9p21-q33). Interestingly, gains of 4q (4q28-q31 and 4q34-qtel), 8q24, and 17 were significantly more frequent in PTCL-u than in AILT. The regions 6q (6q16-q22) and 11p11 were predominantly lost in PTCL-u. Moreover, we could identify a recurrent gain of 11q13 in both AILT and PTCL-u, which has previously not been described in AILT. Trisomies 3 and 5, which have been described as typical aberrations in AILT, were identified only in a small number of cases. In conclusion, CGH revealed common genetic events in peripheral T-cell lymphomas as well as peculiar differences between AILT and PTCL-u.     

Recurrent genomic imbalances in B-cell splenic marginal-zone lymphoma revealed by comparative genomic hybridization

The cytogenetics of splenic marginal zone lymphoma (SMZL) is less well characterized than the cytogenetics of other non-Hodgkin B-cell lymphomas. The aim of this study was to address this issue by identifying characteristic copy number imbalances in SMZL, for which purpose we analyzed 20 SMZL cases by comparative genomic hybridization (CGH), adding chromosome banding and fluorescence in situ hybridization (FISH) in some cases. CGH identified copy number imbalances in 70% of the cases. Imbalances were recurrently observed for chromosomes 3 (20%), 6 (20%), 7 (25%), 12 (20%), and 14 (10%). The minimally involved regions of these chromosomes were gains of 3q25 approximately qter and 12q13 approximately q15, and loss of 6q23, 7q31, and 14q22 approximately q24. A compilation of our data with data from 3 previous SMZL CGH studies revealed a significant heterogeneity between the studies. Eleven imbalances were recurrently observed in the compiled data set, as opposed to only 5 in our data set. The most frequently observed imbalances in the 73 SMZL cases of the compiled data set were gains of 3q (27%) and 12q (15%), and loss of 7q (18%). Our data suggest that SMZL constitute a genetically heterogeneous disease where gain of 3q25 and loss of 7q31 are the most likely imbalances to be involved in the pathogenesis of the disease.     

Chromosomal gains at 9q characterize enteropathy-type T-cell lymphoma

Genetic alterations in enteropathy-type T-cell lymphoma (ETL) are unknown so far. In this series, 38 cases of ETL were analyzed by comparative genomic hybridization (CGH). CGH revealed chromosomal imbalances in 87% of cases analyzed, with recurrent gains of genetic material involving chromosomes 9q (in 58% of cases), 7q (24%), 5q (18%), and 1q (16%). Recurrent losses of genetic material occurred on chromosomes 8p and 13q (24% each), and 9p (18%). In this first systematic genetic study on ETL, chromosomal gains on 9q (minimal overlapping region 9q33-q34) were found to be highly characteristic of ETL. Fluorescence in situ hybridization analysis on four cases of ETL, using a probe for 9q34, indicated frequent and multiple gains of chromosomal material at 9q34 (up to nine signals per case). Among 16 patients with ETL who survived initial disease presentation, patients with more than three chromosomal gains or losses (n = 11) followed a worse clinical course than those with three or less imbalances (n = 5). The observation of similar genetic alterations in ETL and in primary gastric (n = 4) and colonic (n = 1) T-cell lymphoma, not otherwise specified, is suggestive of a genetic relationship of gastrointestinal T-cell lymphomas at either localization.     

Splenic marginal zone lymphomas presenting with splenomegaly and typical immunophenotype are characterized by allelic loss in 7q31-32.

Splenic marginal zone lymphoma (SMZL) is a rare non-Hodgkin's lymphoma that recently has been recognized as an entity. The first goal of this study was to identify potential chromosomal aberrations in this entity by cytogenetic analysis and comparative genomic hybridization (CGH). The second goal was to assess the frequency of 7q31-32 allelic imbalances in SMZL with primary involvement of the spleen and the typical immunophenotype (IgM+; IgD(dim); and CD5-, CD10-, and CD23-). We applied CGH and cytogenetics to 13 cases of SMZL with primary splenic involvement. By CGH, we found DNA copy number changes in 11 of 13 cases. Overall chromosomal gains were more frequent than chromosomal losses. Gains were most frequently detected for chromosome X, chromosome 3, and chromosome 18. Losses commonly involved chromosome 7 and chromosome 6.CGH and cytogenetic analysis showed a deletion in chromosome 7q31 in 4 cases. Loss of heterozygosity (LOH) analysis using three microsatellite markers located at 7q31 revealed LOH in 9 cases. Remarkably, 2 of the 4 cases that lacked a 7q31 deletion had an atypical immunophenotype because they were partially CD23 positive. The other 2 cases were not informative. The findings indicate that SMZL with primary splenic presentation and the typical IgM+, IgDdim, CD5-, CD10-, CD23- immunophenotype is characterized by the presence of deletions in chromosome 7q31-32.     

Genetic alterations in intrahepatic cholangiocarcinoma as revealed by degenerate oligonucleotide primed PCR-comparative genomic hybridization

Intrahepatic cholangiocarcinoma (ICC), a malignant neoplasm of the biliary epithelium,is usually fatal because of difficulty in early diagnosis and lack of availability of effective therapy. The genetic mechanisms involved in the development of ICC are not well understood and only a few cytogenetic studies of ICC have been published. Recently, technique of degenerate oligonucleotide primed (DOP)-PCR comparative genomic hybridization (CGH) permits genetic imbalances screening of the entire genome using only small amounts of tumor DNA. In this study chromosomal aberrations in 33 Korean ICC were investigated by DOP-PCR CGH. The common sites of copy number increases were 20q (67%), 17 (61%), 11q11-q13 (42%), 8p12- qter (39%), 18p (39%), 15q22-qter (36%), 16p (36%), 6p21 (30%), 3q25-qter (27%), 1q41-qter (24%), and 5p14-q11.2 (24%). DNA amplification was identified in 16 carcinomas (48%). The frequent sites of amplification were 20q, 17p, 17q23-qter, and 7p. The most frequent sites of copy number decreases were 1p32-pter (21%) and 4q (21%). The recurrent chromosomal aberrations identified in this study provide candidate regions involved in the tumorigenesis and progression of ICC.     

Comparative genomic hybridization analysis of nasopharygeal carcinoma: consistent patterns of genetic aberrations and clinicopathological correlations

To define the patterns of genetic imbalances in nasopharyngeal carcinoma (NPC), we studied 30 primary NPC tumors with comparative genomic hybridization (CGH). The common sites of chromosomal gains were found in descending order of frequency in 12p11.2-p12 (36%), 12q14-q21 (33%), 2q24-q31 (23%), 1q31-qter (20%), 3q13 (20%), 1q13.3 (20%), 5q21 (17%), 6q14-q22 (13%), 7q21 (13%), 8q11.2-q23 (13%) and 18q12-qter (13%). The common sites of chromosomal loss were at 3p14-p21 (20%), 11q23-qter (20%), 16q21-qter (17%) and 14q24-qter (13%). Correlation with clinicopathologic features showed that 3p loss was associated with a significantly higher risk of death related to recurrence as compared with patients without 3p loss (50% vs. 9%, P=.029). The presence of 16q loss was associated with more advanced stage tumors (stages I & II: 6% vs. stages III & IV: 33%, P=.046). We conclude that consistent patterns of genetic imbalances can be observed in NPC. Deletion of 3p and 16q were associated with higher risk of tumor recurrence and advanced stage cancer.     

Low frequency of chromosomal imbalances in anaplastic ependymomas as detected by comparative genomic hybridization

We screened 26 ependymomas in 22 patients (7 WHO grade I, myxopapillary, myE; 6 WHO grade II, E; 13 WHO grade III, anaplastic, aE) using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). 25 out of 26 tumors showed chromosomal imbalances on CGH analysis. The chromosomal region most frequently affected by losses of genomic material clustered on 13q (9/26). 6/7 myE showed a loss on 13q14-q31. Other chromosomes affected by genomic losses were 6q (5/26), 4q (5/26), 10 (5/26), and 2q (4/26). The most consistent chromosomal abnormality in ependymomas so far reported, is monosomy 22 or structural abnormality 22q, identified in approximately one third of Giemsa-banded cases with abnormal karyotypes. Using FISH, loss or monosomy 22q was detected in small subpopulations of tumor cells in 36% of cases. The most frequent gains involved chromosome arms 17 (8/26), 9q (7/26), 20q (7/26), and 22q (6/26). Gains on 1q were found exclusively in pediatric ependymomas (5/10). Using FISH, MYCN proto-oncogene DNA amplifications mapped to 2p23-p24 were found in 2 spinal ependymomas of adults. On average, myE demonstrated 9.14, E 5.33, and aE 1.77 gains and/or losses on different chromosomes per tumor using CGH. Thus, and quite paradoxically, in ependymomas, a high frequency of imbalanced chromosomal regions as revealed by CGH does not indicate a high WHO grade of the tumor but is more frequent in grade I tumors.     

Frequent 7q gains in flow cytometric multiploid/hypertetraploid breast carcinomas: a study of chromosome imbalances by comparative genomic hybridisation

OBJECTIVE: To investigate underlying genetic events associated with complex DNA ploidy breast carcinomas. METHODS: Screening for chromosome imbalances was carried out using comparative genomic hybridisation (CGH) in 14 frozen samples of tumour from a series of 13 breast cancer patients with multiploid (n = 11) and hypertetraploid (n = 2) tumours. They had previously been analysed by DNA flow cytometry and also assessed immunohistochemically for p53 tissue expression. Ploidy status was determined on frozen samples using the Multicycle software program. RESULTS: The total number of copy gains (n = 242) was significantly greater than the number of copy losses (n = 51). The mean (SD) number of gains per sample was 17.3 (5.7), and of losses, 3.6 (4.2) (p = 0.0001). Gains of chromosomal regions at 1q (14/14; 100%), 7q (12/14; 85.7%), and 3q (11/14; 78.6%), as well as 1p, 2q, 5p, 8q, and 13q (10/14; 71.4%) were the most frequent aberrations in this series. Losses were most commonly found on 17p (5/14; 35.7%). Three patients dying of the disease had tumours with high level amplifications at 1q12-qter, 3q22-q25, and 8q22-q23 regions. Six cases had p53 overexpression, of whom four showed 12q gains and two showed 17p losses. CONCLUSIONS: There is a very high incidence of genetic aberrations, mainly related to chromosomal gains, in this subgroup of aneuploid breast cancer patients, associated with a poor clinical outcome. The 7q locus, not previously reported as showing frequent changes in breast cancer, was found to be a potential site for some candidate oncogenes.     

Comparative genomic hybridization analysis of natural killer cell lymphoma/leukemia. Recognition of consistent patterns of genetic alterations.

Putative natural killer (NK) cell lymphoma/leukemia is a rare group of recently characterized hematolymphoid malignancies. They are highly aggressive and frequently present in extranodal sites, including the nasal area and the upper aerodigestive system, and nonnasal areas such as the skin and the gastrointestinal tract. According to clinicopathological features, they can be classified into nasal NK cell lymphoma, nasal-type NK cell lymphoma occurring in nonnasal areas, and NK cell lymphoma/leukemia. Genetic alterations in NK cell lymphoma/leukemia are not well defined. In this study, we have performed comparative genomic hybridization (CGH) on DNA extracted from fresh or frozen tissues of 10 patients with NK cell lymphoma/leukemia. They comprised four nasal NK cell lymphomas, one nasal-type NK cell lymphoma, and five NK cell lymphomas/leukemias. CGH showed frequent deletions at 6q16-q27 (four cases), 13q14-q34 (three cases), 11q22-q25 (two cases), 17p13 (two cases), and loss of the whole chromosome X (two cases). DNA amplification was observed in a majority of the chromosomes. Five cases showed DNA gains at region 1p32-pter. Frequent DNA gains were also found in chromosomes 6p, 11q, 12q, 17q, 19p, 20q, and Xp (three cases each). Interestingly, DNA gains were more frequent in nasal/nasal-type NK cell lymphomas than NK cell lymphoma/leukemia. These genetic alterations correlated well with karyotypic features found in some of the cases. The frequent DNA losses at 6q and 13q suggest that the presence of tumor suppressor genes at these regions is important in NK cell transformation. In addition to establishing novel patterns of genomic imbalances in these rare NK cell malignancies, which may be targets for future molecular analysis, this study also provides important information on genetic alterations in NK cell lymphomas that may be useful in defining their positions in current lymphoma classification schemes, which are increasingly focusing on phenotypic and genotypic correlations.     

Analysis of chromosomal imbalances in sporadic and NF1-associated peripheral nerve sheath tumors by comparative genomic hybridization.

Peripheral nerve sheath tumors arise either sporadically or in association with neurofibromatosis type 1 (von Recklinghausen's neurofibromatosis, NF1) or type 2. In this study, comprehensive screening for relative chromosome copy number changes was performed on 10 benign and 19 malignant peripheral nerve sheath tumors (MPNSTs) by applying comparative genomic hybridization (CGH). In benign tumors, no chromosomal imbalances were found by CGH, whereas in MPNSTs chromosomal gains and losses were frequently detected. No differences regarding the frequency and distribution of chromosomal imbalances were observed between the 13 sporadic and 6 NF1-associated MPNSTs analyzed. In both, the number of gains was significantly higher than the number of losses, suggesting a predominant role of proto-oncogene activation during MPNST progression. Candidate regions with potentially relevant proto-oncogenes included chromosomal bands 17q24-q25, 7p11-p13, 5p15, 8q22-q24, and 12q21-q24; those with putative tumor suppressor genes were 9p21-p24, 13q14-q22, and 1p. High-level amplifications were restricted to sporadic tumors and affected eight different chromosomal subregions. In three of these MPNSTs, identical subregions on chromosomal arms 5p and 12q were coamplified. This study revealed a number of new characteristic chromosomal imbalances and provides a basis for molecular identification of oncogenes and tumor suppressor genes of pathogenetic relevance in both sporadic and NF1-associated MPNSTs. Genes Chromosomes Cancer 25:362-369, 1999.     

Frequent loss of 9p21 (p16(INK4A)) and other genomic imbalances in human malignant fibrous histiocytoma

To search for new recurrent genetic aberrations in malignant fibrous histiocytoma (MFH), a combination of conventional cytogenetic, comparative genomic hybridization (CGH), and Southern blot analyses was applied to a series of 34 tumors. Cytogenetic analysis revealed the presence of multiple structural and numerical aberrations, including marker chromosomes, telomeric associations, double minutes, and ring chromosomes. The most frequent genomic imbalances in this series of neoplasms as detected by CGH were gains of 1q21-q22 (69%), 17q23-qter (41%), and 20q (66%), and losses of 9p21-pter (55%), 10q (48%), 11q23-qter (55%), and 13q10-q31 (55%). Southern blot analyses with p16(INK4A) (CDKN2A; 9p21) and RB1 (13q14) probes provided clear indications for frequent deletions of these tumor suppressor genes, and as such, substantiated the CGH results. Additionally, examination of the TP53 and MDM2 genes showed frequent loss and amplification, respectively. These data indicate that genes involved in the RB1- and TP53-associated cell cycle regulatory pathways may play prominent roles in the development of human MFH.     

Typical genomic imbalances in primary MALT lymphoma of the orbit

Primary orbital non-Hodgkin lymphoma is a mucosa-associated lymphoid tissue (MALT)-type extranodal marginal zone lymphoma. Little information is available on its genome as conventional cytogenetics is limited by scarce biopsy material, while fluorescence in situ hybridization (FISH) explores only selected regions. Comparative genomic hybridization (CGH) performs full genomic analysis and is applicable to different sources of DNA, such as fresh and frozen cells, as well as paraffin-embedded tissues. In this study, CGH was used to analyse primary MALT lymphoma of the orbit. Aneuploidy was identified in six of the ten cases studied. Gains (19) were more frequent than losses (5). The most frequent duplications involved chromosome 3 (common region at 3q24-qter), as expected in marginal zone lymphoma, and chromosome 6 (common region at 6p21.1-21.3), which is typical of an orbital location. Other chromosome gains were found at 1p, 7, 8q, 9q, 12, 13, 17, 18, 19, 22, and X. Losses were located at 1q, 6q, 9q, 11q, and 13q. Two cases showed isolated duplications of chromosome 6p or 9q. Isolated imbalances were found only in tumours affecting the conjunctiva. Complex aneuploidies were observed in lymphoma of the retro-orbital tissue. In summary, CGH in orbital MALT lymphoma provided new insights into typical genomic imbalances and underlying pathogenetic mechanisms.     

Chromosomal imbalances in diffuse large B-cell lymphoma detected by comparative genomic hybridization.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. In contrast to many other hematological malignancies, no chromosomal abnormalities with a diagnostic or prognostic value have been identified in DLBCL. Numerical chromosomal imbalances were characterized by comparative genomic hybridization (CGH) performed on 54 DLBCL tumors from a total of 40 patients. The clonal relatedness was demonstrated in 9 of 11 pairs of matched diagnostic tumors and their relapses as determined by IGH gene rearrangement analysis and/or the CGH profiles. Furthermore, immunohistochemical expression analyses of BCL2 and BCL6/LAZ3 were performed on all cases. Copy number changes were detected in 94% of the diagnostic tumor samples and in all of the relapses. Chromosomal losses in diagnostic tumors were preferentially observed at 8p22-pter (29%), 1p34-pter (26%), 6q23-qter (20%), 17p12-pter (17%) and 22q (17%), 9p23-pter (14%), whereas gains were mainly seen in Xq25-26 (43%), 13q22 (26%), 12cen-q14 (20%), 3q24-25 (11%), 7 (11%), and 18q12-21 (11%). Loss of 22q was significantly more commonly seen in the diagnostic tumor samples with more advanced clinical stage in other words, Stage III-IV compared with Stage I-II, and band 18q21 was significantly more often gained in relapses as compared to diagnostic tumors. None of the recurrent alterations were detected as a single abnormality, suggesting that other genetic lesions below the detection level of CGH may be the initiating event in the tumorigenesis of DLBCL. However, the distribution of CGH alterations support the idea of a progression of genetic events where loss of 8p and 9p and gain of 3q, 13q, and 18q would represent relatively early events because they were distributed in tumors with only two abnormalities.     

Comprehensive characterization of genomic aberrations in gangliogliomas by CGH, array-based CGH and interphase FISH

Gangliogliomas are generally benign neuroepithelial tumors composed of dysplastic neuronal and neoplastic glial elements. We screened 61 gangliogliomas [World Health Organization (WHO) grade I] for genomic alterations by chromosomal and array-based comparative genomic hybridization (CGH). Aberrations were detected in 66% of gangliogliomas (mean ± SEM = 2.5 ± 0.5 alterations/tumor). Frequent gains were on chromosomes 7 (21%), 5 (16%), 8 (13%), 12 (12%); frequent losses on 22q (16%), 9 (10%), 10 (8%). Recurrent partial imbalances comprised the minimal overlapping regions dim(10)(q25) and enh(12)(q13.3–q14.1). Unsupervised cluster analysis of genomic profiles detected two major subgroups (group I: complete gain of 7 and additional gains of 5, 8 or 12; group II: no major recurring imbalances, mainly losses). A comparison with low-grade gliomas (astrocytomas WHO grade II) showed chromosome 5 gain to be significantly more frequent in gangliogliomas. Interphase fluorescence in situ hybridization (FISH) identified the aberrations to be contained in a subpopulation of glial but not in neuronal cells. Two gangliogliomas and their anaplastic recurrences (WHO grade III) were analyzed. Losses of CDKN2A/B and DMBT1 or a gain/amplification of CDK4 found in the anaplastic tumors were already present in the respective gangliogliomas by array CGH and interphase FISH. In summary, genomic profiling in a large series of gangliogliomas could distinguish genetic subgroups even in this low-grade tumor.     

Detection of chromosomal imbalances in growth hormone-secreting pituitary tumors by comparative genomic hybridization.

Although recent molecular investigations have identified a number of genetic alterations that are associated with the development of pituitary adenomas, the exact pathogenesis mechanism of these tumors remains largely unknown. In this study, we used a genome-wide survey to detect specific genetic changes within the genome of pituitary adenomas. A series of 10 growth hormone-secreting adenomas were analyzed for their genetic imbalances on all 22 autosomes by comparative genomic hybridization (CGH). Chromosomal imbalances were detected in 8 GH-secreting adenomas, whereas 2 tumors had no detectable genetic abnormalities. Chromosome gains were more frequent than losses. Overrepresentation of whole or parts of chromosomes were detected in 5/10 (50%) in 19, 3/10 (30%) in each of 5, 9, and 22q, 2/10 (20%) in 17p12-q21, whereas DNA loss were 3/10 (30%) in 13q and 2/10 (20%) in 18. No detectable gain or loss of genetic material was observed in chromosomes 7, 8, 10, 12, 15, and 20. The findings of overrepresentation of chromosomes 5q, 9p, 17q and DNA loss of chromosome 18 were consistent with those detected in nonfunctioning adenomas (Daniely M, Aviram A, Adams EF, et al:J Clin Endocrinol Metab 83:1801-1805, 1998) suggesting that the development of pituitary tumors, at least in somatotroph and nonfunctioning adenomas, may share common pathway. Frequent amplifications in chromosomes 19 and 22q imply that candidate genes residing in these chromosomal regions may be involved in the pathogenesis of GH-secreting adenomas.     

Characterization of genomic alterations in hepatoblastomas. A role for gains on chromosomes 8q and 20 as predictors of poor outcome

As data on the genomic alterations in hepatoblastoma (HB) are limited, 34 HB tumors and three HB cell lines were screened for DNA copy number changes by comparative genomic hybridization. The average number of chromosomal imbalances per tumor was 2.3 +/- 0.5 (mean +/- SEM) with gains sevenfold more frequent than losses. The most frequent gains of chromosomal material in HB tumors were on 2q (44%), 1q (41%), 2p (29%), 20 (24%), 22q (18%), 8q (15%), 8p and 12q (9% each), as well as 7q, 12p, and 17 (6% each) and the only recurrent loss was on 4q in 12% of cases. Highly amplified sequences were identified in four tumors and mapped to 2q24 in two cases, to 8q in two cases (once to 8q11.2-q13 and once to 8q11.2-q21.3) as well as to 10q24-q26 in one case. In one cell line, highly amplified DNA sequences were mapped to 7p and 8q. Comparison to previously published data on this series of HB revealed that the number of chromosomal imbalances was significantly higher in HB tumors with loss of heterozygosity on 11p (P = 0.03), whereas in five of 10 HB biopsies without chromosomal imbalances, beta-catenin gene mutations were found. HB patients were divided into a good (no evidence of disease) and a poor (died of disease) outcome group according to their clinical course after standard therapy. Two alterations were found to be significantly associated with poor outcome: gain on 8q (P = 0.007) and gain on 20 (P = 0.009). In summary, our analysis allowed the identification of gains on chromosomes 1q and 2 as hallmark DNA copy number changes in HB with 2q24 as a critical chromosomal band. Furthermore, this study provided evidence that gains on 8q and 20 play a role as markers of prognostic significance in HB.     

Pattern of chromosomal imbalances in non-B virus related hepatocellular carcinoma detected by comparative genomic hybridization.

Only limited data are available on comparative genomic hybridization (CGH) in hepatocellular carcinoma (HCC). They concern mainly B virus related HCC. Therefore, we used CGH to detect chromosomal imbalances in 16 non-B virus related HCC in alcoholic cirrhosis in 7 cases (HA1 to HA7), in C virus cirrhosis in 7 cases (HC1 to HC7), in non-cirrhotic liver in 2 cases (NC1, NC2), and in 9 non-malignant cirrhotic tissues. The most frequent imbalances in HCC were gains of whole chromosomes or chromosomal regions 7 or 7q (10/16, 62%), 1q (9/16, 56%), 5 or 5q (9/16, 56%), 8q (8/16, 50%), 6p (6/16, 37%), 15q (5/16, 31%), 20 or 20q (5/16, 31%), and losses of 17p (6/16, 37%), and 8p (5/16, 31%). High-level gains were identified in HCC on 1q (2/16), 3q (1/16), 7q (1/16), and 8q (3/16). No chromosomal imbalances were detected in any of the cirrhotic tissues. Most of the gains, losses, and amplifications detected in this CGH study corresponded well to those identified in previous studies, except for gains of whole chromosome 5 or 7 and/or of chromosome arms 5q or 7q and losses on 4q. Our results suggest that other chromosomal regions are involved in hepatocarcinogenesis.     

Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization

Comparative genomic hybridization (CGH) was used to evaluate and map genomic aberrations in 50 hepatocellular carcinomas (HCCs) from patients chronically infected with hepatitis B virus (HBV). CGH clearly detected nonrandom genomic imbalances. Losses were most prevalent on chromosome regions 4q (70%), 8p (65%), 16q (54%), 17p (51%), 13q and 6q (37% each), and 1p (30%). The most frequent gains occurred on 8q (60%), 1q (58%), and 6p and 17q (33% each). In a few cases, sequence amplifications were detected that were mapped to bands 11q12, 12p11, 14q12, and 19q13.1. This study represents the first analysis of primary liver cancers by CGH, and it confirms the presence of previously known chromosomal aberrations in HCC and highlights new quantitative abnormalities and sequence amplifications. These findings should lead to the characterization of new loci involved in liver cancer pathogenesis. Genes Chromosom. Cancer 18:59–65, 1997. © 1997 Wiley-Liss, Inc.