Chromosome alterations in human hepatocellular carcinomas correlate with aetiology and histological grade--results of an explorative CGH meta-analysis

All available comparative genomic hybridisation (CGH) analyses (n=31, until 12/2003) of human hepatocellular carcinomas (HCCs; n=785) and premalignant dysplastic nodules (DNs; n=30) were compiled and correlated with clinical and histological parameters. The most prominent amplifications of genomic material were present in 1q (57.1%), 8q (46.6%), 6p (22.3%), and 17q (22.2%), while losses were most prevalent in 8p (38%), 16q (35.9%), 4q (34.3%), 17p (32.1%), and 13q (26.2%). Deletions of 4q, 16q, 13q, and 8p positively correlated with hepatitis B virus aetiology, while losses of 8p were more frequently found in hepatitis C virus-negative cases. In poorly differentiated HCCs, 13q and 4q were significantly under-represented. Moreover, gains of 1q were positively correlated with the occurrence of all other high-frequency alterations in HCCs. In DNs, amplifications were most frequently present in 1q and 8q, while deletions occurred in 8p, 17p, 5p, 13q, 14q, and 16q. In conclusion, aetiology and dedifferentiation correlate with specific genomic alterations in human HCCs. Gains of 1q appear to be rather early events that may predispose to further chromosomal abnormalities. Thus, explorative CGH meta-analysis generates novel and testable hypotheses regarding the cause and functional significance of genomic alterations in human HCCs.     

Patterns of chromosomal imbalances in invasive breast cancer

Invasive breast carcinomas are characterized by a complex pattern of chromosomal alterations. We applied comparative genomic hybridization (CGH) to analyze 105 primary breast carcinomas using histograms to indicate the incidence of DNA imbalances of tumor subgroups and difference histograms to compare invasive ductal carcinomas (IDC) with lobular carcinomas (ILC), well and poorly differentiated carcinomas (G1/G3) and estrogen receptor-positive and -negative tumors (ER(+)/ER(-)). Only single imbalances showed a higher incidence in ILC compared with IDC, i.e., gains on chromosomes 4 and 5q13-q23 as well as deletions on chromosomes 6q, 11q14-qter, 12p12-pter, 16q, 17p, 18q, 19, and 22q. Of these, particularly gains of 4 and losses at 16q21-q23, and 18q12-q21 were statistically significant. For most loci, IDC showed more alterations providing a genetic correlate to the fact that ductal carcinoma overall is associated with a worse prognosis than ILC. Of these, many imbalances showing statistical significance were also observed in G3 and ER(-) tumors, i.e., deletions at 2q35-q37, 3p12-p14, 4p15-p16, 5q, 7p15, 8p22-p23, 10q, 11p, 14q21-q31, 15q, and gains at 2p, 3q21-qter, 6p, 8q21-qter, 10p, 18p11-q11, and 20q, suggesting that they contribute to a more aggressive tumor phenotype. By contrast, gains on chromosome 5q13-q23 as well as deletions at 6q, 16q and 22q were more prevalent in G1 and ER(+) tumors. The ratio profiles of all cases as well as histograms are accessible at our CGH online tumor database at http://amba.charite.de/cgh. Our results highlight distinct chromosomal subregions for cancer-associated genes. In addition, these imbalances may serve as markers for a genetic classification of invasive breast cancer.     

Secondary chromosome changes in mantle cell lymphoma: cytogenetic and fluorescence in situ hybridization studies.

To better define the incidence and nature of secondary chromosome anomalies in mantle cell lymphoma (MCL) carrying the t(11:14)/BCL1 rearrangement, cytogenetic and fluorescence in situ hybridization studies (FISH) were performed in 42 patients (39 classical histology, 3 blastoid variant), using 6q21, 9p21/p16, 13q14, 17p13/p53 and chromosome-12-specific probes. Karyotypes from 89 cases published in 5 recent series including patients diagnosed in a homogeneous fashion were reviewed. In our series, FISH confirmed the interpretation of the karyotype in all cases and disclosed cryptic chromosome deletions in a sizeable fraction of cases. One patient (2.4% of total) was found with a cryptic 9p21 deletion by FISH. Two cases (4.8%) had a 6q21 deletion at CCA and at FISH; +12 was found in three cases by CCA plus nine by FISH (28.6%); 13q14 deletion was found in six cases by CCA plus 16 by FISH (52.4%), 17p13 deletion in three cases by CCA plus 8 by FISH (26.2%). In 131 patients (42 present series plus 89 in the literature) secondary chromosome aberrations seen by conventional cytogenetic analysis in more than 5 cases included deletions/translocations (del/t) 6q15-23 [15 cases]; -13 [14 cases]; del/t 1p21-31 [12 cases]; +3q [11 cases]; del/t 17p [9 cases]; 8p translocations and del(Y) [8 cases each]; -20 [7 cases]; 13q14 deletion, del/t 11q22-23, del/t 9q, del(10)(q22q24), -20, -21, -22 and -X [6 cases each]. We arrived at the following conclusions: i) though no secondary anomaly is specific for MCL, there is a distinct profile of recurrent chromosome lesions in MCL with 1p21-31 deletions, 8p translocations, 11q22-23 anomalies having a strong association with CD5+ B-cell lymphomas of low-to-intermediate grade histology; ii) FISH enabled the detection of cryptic chromosome 12, 13q and 17p rearrangements in a sizeable fraction of cases; iii) 9p21/p16 deletions did not occur at a high incidence in this series, possibly because of the low number of cases with blastoid variant.     

Distinct chromosomal bias of gene expression signatures in the progression of hepatocellular carcinoma

To identify the chromosomal aberrations associated with the progression of liver cancer, we applied expression imbalance map analysis to gene expression data from 31 hepatocellular carcinomas and 19 noncancerous tissues. Expression imbalance map analysis, which detects mRNA expression imbalance correlated with chromosomal regions, showed that expression gains of 1q21-23 (74%), 8q13-21 (48%), 12q23-24 (41%), 17q12-21(48%), 17q25 (25%), and 20q11 (22%) and losses of 4q13 (48%), 8p12-21 (32%), 13q14 (32%), and 17p13 (29%) were significantly associated with hepatocellular carcinoma. Most regions with altered expression identified by expression imbalance map were also identified in previous reports using comparative genomic hybridization. We demonstrated chromosomal copy number gain in 1q21-23 and loss in 17p13 by genomic quantitative PCR, suggesting that gene expression profiles reflect chromosomal alterations. Furthermore, expression imbalance map analysis revealed that more poorly differentiated hepatocellular carcinoma contain more chromosomal alterations, which are accumulated in a stepwise manner in the course of hepatocellular carcinoma progression: expression imbalance of 1q, 8p, 8q, and 17p occur as early events in hepatocarcinogenesis, and 12q, 17q25 and 20q occur as later events. In particular, expression gain of 17q12-21 and loss of 4q were seen to accumulate constantly through the dedifferentiation process. Our data suggest that gene expression profiles are subject to chromosomal bias and that expression imbalance map can correlate gene expression to gene loci with high resolution and sensitivity.     

Detection of chromosomal alterations in bladder transitional cell carcinomas from Northern China by comparative genomic hybridization

To identify chromosome alterations in Chinese bladder cancer, forty-six transitional cell carcinomas of the bladder were analyzed by comparative genomic hybridization. Frequent gains of DNA copy number were observed on 1p (13/46), 1q (13/46), 5p (8/46), 6p (9/46), 7p (7/46), 8q (12/46), 11q (8/46), 17q (11/46), 19q (7/46), 20q (8/46) and Yq (8/46), with minimal overlapping regions at 1p32-pter (10/46), 1q21-q24 (12/46), 5p (8/46), 6p22-p23 (7/46), 7p11.2-p14 (7/46), 8q22-q24 (12/46), 11q13-q14 (8/46), 17q22-qter (11/46), 19q11-13.2 (7/46), 20q11-q13.2 (8/46) and Yq11 (8/46). Losses were predominantly found on 2q (16/46), 5q (8/46), 8p (7/46), 9p (8/46), 9q (13/46), 11p (7/46), 13q (7/46), 17p (12/46), 18q (7/46), Xp (18/46) and Xq (19/46), with smallest overlapping regions at 2q32-qter (16/46), 5q12-q31 (8/46), 8p12-pter (7/46), 9p21-pter (10/46), 9q (13/46), 11p (7/46), 13q13-q22 (7/46), 17p (12/46), 18q21-qter (7/46), Xp (18/46) and Xq (19/46). There were significantly higher frequencies of gains of 1q21-q24 and 17q22-qter in moderately differentiated tumors as compared with those in well-differentiated tumors, indicating a possible association of these two abnormalities with the dedifferentiation of tumor cells. Gains of 1p32-pter, 5p, 6p22-p23, 11q13-q14, 17q22-qter and losses of 2q32-qter, 9q, 17p were more frequent in pT1 as compared with those in pTa carcinomas. Gains at 1q21-q24, 7p11.2-p14, 8q22-q24, 19q, 20q11-q13.2 and losses at 5q12-q31, 8p12-pter, 9p21-pter, 11p, 13q13-q22 and 18q21-qter were unique to pT1 and higher stage tumors, suggesting that genes responsible for the invasion and progression of bladder cancer might be located at these chromosomal regions. In multiple tumors from the same patients, consistent alterations such as gains of 8q, 11q13-q14, 12q13-q15, 13q12, 20q and losses of 2q32-qter, 8p, 9, 11p, 11q21-qter, 13q13-qter, X were detected. These abnormalities were possibly earlier events, which might play a critical role during the genesis of the tumors. Further detailed studies to the recurrent aberration regions may lead to the identification of oncogenes and tumor suppressor genes involved in the development and progression of Chinese bladder cancer.     

Chromosomal alterations during lymphatic and liver metastasis formation of colorectal cancer

Comparative genomic hybridization (CGH) was used to screen colorectal carcinomas for chromosomal aberrations that are associated with metastatic phenotype. In total, 63 tumor specimens from 40 patients were investigated, comprising 30 primary tumors, 22 systemic metastases (12 liver, 6 brain, and 4 abdominal wall metastases) and 11 lymph node tumors. Using statistical analysis and histograms to evaluate the chromosomal imbalances, overrepresentations were detected most frequently at 20q11.2-20q13.2, 7q11.1-7q12, 13q11.2-13q14, 16p12, 19p13, 9q34, and 19q13.1-19q13.2. Deletions were prominent at 18q12-18q23, 4q27-4q28, 4p14, 5q21, 1p21-1p22, 21q21, 6q16-6q21, 3p12, 8p22-8p23, 9p21, 11q22, and 14q13-14q21. Hematogenous metastases showed more alterations than lymph node tumors, particularly more deletions at 1p, 3, 4, 5q, 10q, 14, and 21q21 and gains at 1q, 7p, 12qter, 13, 16, and 22q. Comparing liver metastases with their corresponding primary tumors, particularly deletions at 2q, 5q, 8p, 9p, 10q, and 21q21 and gains at 1q, 11, 12qter, 17q12-q21, 19, and 22q were more often observed. The analysis suggested that the different pathways of tumor dissemination are reflected by a nonrandom accumulation of chromosomal alterations with specific changes being responsible for the different characteristics of the metastatic phenotype.     

Genetic alterations in hepatocellular carcinomas: association between loss of chromosome 4q and p53 gene mutations.

The major risk factors for hepatocellular carcinomas (HCC) in high incidence areas include infection with hepatitis B and C viruses (HBV, HCV) and exposure to aflatoxin. Genetic alterations in 24 liver resection specimens from Shanghai and Qidong were studied. Hepatitis B virus was integrated in all patient samples, and a null phenotype for the GSTM1 enzyme was present in 63% of patients. Alteration of p53 was present in 95% (23/24) of cases: mutations of the p53 gene in 12 HCC, p53 overexpression in 13 and loss of heterozygosity (LOH) of chromosome 17p in 17. All seven HCCs with a p53 mutation from Qidong and three of five from Shanghai had the aflatoxin-associated point mutation with a G to T transversion at codon 249, position 3. No HCC had microsatellite instability. LOH of chromosome 4q, 1p, 16q and 13q was present in 50%, 46%, 42% and 38%, respectively, and 4q was preferentially lost in HCCs containing a p53 mutation: LOH of 4q was present in 75% (9/12) of HCC with, but only 25% (3/12) of HCC without, a p53 gene mutation (P = 0.01). These data indicate a possible interaction between p53 gene mutation and 4q loss in the pathogenesis of HCC.     

Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer

Many cytogenetic alterations are known to occur in urinary bladder cancer, but the significance of most of them is poorly understood. To define these chromosomal regions where clinically relevant genes may be located, a series of 54 pT1 urinary bladder carcinomas with clinical follow-up information (median, 52 months; range, 5-167 months) were examined by comparative genomic hybridization. The most frequent alterations included DNA sequence copy number gains at 1q22-24 (33%), 20q11.2-ter (33%), 8q22 and 17q21 (28% each), and 6p22 (15%) as well as deletions at Y (37%), 9p (31%), 9q22-33 and 11p14-ter (28% each), 11q23 (26%), 8p (24%), 13q31 (19%), 2q35-ter (17%), and 2q22-33 (11%). Whereas the histological grade was unrelated to prognosis (P = 0.9752), the risk of tumor progression was significantly associated with the number of deletions per tumor (P = 0.0014). Individual cytogenetic alterations that were linked to subsequent tumor progression included gains of 3p22-24 (P = 0.0112) and 5p (P = 0.0003) as well as losses of 4p11-15 (P = 0.0052), 5q15-23 (P = 0.0410), 6q22-23 (P = 0.0090), 10q24-26 (P = 0.0232), and 18q12-23 (P = 0.0005). Genes with a role for bladder cancer progression may be located at these regions.     

A comparison of DNA copy number changes detected by comparative genomic hybridization in malignancies of the liver, biliary tract and pancreas

Tumors arising from the liver, biliary tract and pancreas, which originate in the foregut and are in close anatomical proximity to each other, sometimes show similar histological features. No studies have focused on genetic similarities and differences between tumors of these organs. To elucidate the similarities and differences in DNA copy number alterations between tumors of these organs, we applied comparative genomic hybridization (CGH) to cancers of the liver (31 cases), biliary tract (42 cases) and pancreas (27 cases). Some alterations were common to tumors of all three organs, and some were preferential in certain types of tumor. Gains of 1q and 8q and losses of 8p and 17p were common to all tumors. In contrast, 13q14 and 16q losses were detected exclusively in hepatocellular carcinomas (HCCs; p < 0.01). The incidence of 17q21 gain and 5q loss was higher in biliary tract cancers than in the other two types (p < 0.05). Pancreatic cancers exhibited higher incidence of 5q14-q23 gain and 19p loss than tumors of other organs (p < 0.01). Gains of 7p, 7q, 12p and 20q and losses of 3p, 6q, 9p and 18q were frequent in both biliary tract and pancreatic cancers but rare in HCCs (p < 0.05). The present results suggest that although genes located at 1q, 8p, 8q and 17p are frequently involved in HCC, biliary tract and pancreatic cancer, at least some of the genes implicated in carcinogenesis are different between these three types. It is also suggested that CGH analysis is useful as a potential adjunct for the diagnosis and management of these tumors of organs that are anatomically close to one another.     

Genetic Changes and Histopathological Grades in Human Hepatocellular Carcinomas

Loss of heterozygosity (LOH) on chromosomes 1p, 4q, 5q, 8p, 13q, 16q, 17p, and 22q, and mutation of the p53 gene were simultaneously analyzed in 63 hepatocellular carcinomas (HCCs) with distinct histopathological grades, 80% of the tumors being from patients who had been exposed to hepatitis B virus (HBV) or hepatitis C virus (HCV). The frequencies of LOH on 8 chromosomes were 0–25% in 10 well differentiated HCCs, LOH being observed on 4q, 5q and 17p, 21–53% in 26 moderately differentiated HCCs, LOH on 8p and 17p being high, and 29–75% in 27 poorly differentiated HCCs, LOH on 17p, 4q and 8p heing the most frequent. p53 gene mutation was detected in moderately and poorly differentiated HCCs at 15% and 52%, respectively, but not at all in well differentiated HCCs. Of the mutations detected, 42% were transition mutation and only 5% were CpG transition, in contrast to the high frequencies of these types of mutations in colon tumors (78% and 54%, respectively). LOH on every chromosome and p53 mutation were more frequent in more advanced tumors, and accumulation of genetic changes increased with increase of the histopathological grade. Frequency of genetic changes in HCCs from HBV-positive patients was comparable to that from HCV-positive patients. The present results suggest that accumulation of genetic changes in multiple tumor suppressor genes, especially LOH on 17p, 4q and 8p, and mutation in p53 gene, are involved in the progression of liver cancer, and LOH on 17p and 4q precedes other genetic changes. Differences in the direction of p53 mutation between HCC and colon carcinoma suggest that liver carcinogens are distinct from colon carcinogens. Furthermore, mechanisms affecting the frequency of LOH in HCCs in HBV-infected patients may be similar to those in HCV-infected patients.     

Cytogenetic analysis in mantle cell lymphoma: a review of 214 cases

Cytogenetic (CG) analysis was performed in 78 consecutive cases of mantle cell lymphoma (MCL) at the British Columbia Cancer Agency (BCCA). A clone containing a t(11;14) translocation was identified in 53 cases. Data from 47 cases with sufficient CG details were reviewed along with 167 cases of t(11; 14)-associated lymphoproliferative diseases (LPD) from the literature. Common aneuploidies included -Y, -13, -9, -18, +3 and +12. Common structural changes included: +3q, +12q, del(6q), del(1p), del(13q), del(10q), del(11q), del(9p) and del(17p). The commonest breakpoints clusters were 1p21-22, 1p31-32, 1q21, 6q11-q15, 6q23-25, 8q24, 9p21-24, 11q13-23, 13q12-14, and 17p12-13. When analyzed separately as lymph node-based disease (LN group) and peripheral blood disease (PB group), deletions and chromosomal losses were more common in the LN group, while gains of chromosome segments 3q and 12q were similar. The LN group was cytogenetically more complex. CG analysis is useful for confirming the diagnosis of MCL. Almost all cases will have t(11; 14), but poor quality and number of metaphases may render a difficult analysis. CG evolution in MCL follows a complex but defined pattern. Regions affected by recurrent changes are similar to other B cell lymphomas. The LN and PB groups of t(11;14)-associated LPD may have subtle differences in clonal evolution.     

Loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in Taiwan.

Elucidation of the basic genetic changes of human hepatocellular carcinoma is important for the understanding and treatment of this cancer. We used microsatellite polymorphism markers to study 30 cases of hepatocellular carcinoma (34 tumours) on all human chromosomes. DNA from 34 pairs of hepatocellular carcinomas and corresponding non-tumour parts was prepared. Loss of heterozygosity (LOH) and microsatellite instability on 23 chromosomes were investigated by 231 sets of microsatellite markers. More than 20% LOH was shown for loci on 16q (47.1%), 13q (32.4%), 17p (32.4%), 5q (26.5%), 11p (23.5%) and 9p (20.6%). The commonly affected regions were mapped to 16q12.1, 16q12.2, 16q24, 13q12.1-32, 17p13, 5q32, 5q34, 5q3, 11p15, 11q23-24 and 9p21. Hepatitis B virus carriers had a significantly higher frequency of LOH on chromosomes 5q, 11p and 16q. Furthermore, larger tumour size tended to have higher frequency of LOH at D16S409 locus (16q12.1). Microsatellte instability was only found in 12 of 231 markers and the frequency is very low. These data suggest that the chromosomes 16q, 13q, 17p, 5q, 11p and 9p might participate in hepatocarcinogenesis. However, microsatellite instability might play little role in the development of this cancer in Taiwan.     

High resolution allelotype of microdissected primary nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is a common cancer in South China but is rare in other parts of the world. To better understand the molecular basis of this cancer, we performed high-resolution allelotyping on 27 microdissected primary tumors using 382 microsatellite markers. We have detected high frequencies of allelic imbalance on 3p (96.3%), 9p (85.2%), 9q (88.9%), 11q (74.1%), 12q (70.4%), 13q (55.6%), 14q (85.2%), and 16q (55.6%). Nonrandom allelic changes of 12q and 16q were revealed for the first time. In addition, loss of heterozygosity on chromosomal arms 1p (37.0%), 5q (44.4%), and 12p (44.4%) were also common in NPC. Multiple minimally deleted regions, 7-40 cM, were identified at 3p14-24.2, 11q21-23, 13q12-14, 13q31-32, 14q24-32, and 16q22-23. Frequent deletions of these minimally deleted regions implied the presence of tumor suppressor genes that may be involved in the development of NPC. Consistent loss of heterozygosity on 3p, 9p, and 14q in almost all tumors suggested that such changes are critical events in NPC tumorigenesis.     

Genome-wide allelotype analysis of sporadic primary nasopharyngeal carcinoma from southern China

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in Southern China, especially in the Guangdong area. To demonstrate a comprehensive profile of loss of heterozygosity (LOH) in NPC, we applied a large panel of 382 microsatellite polymorphism markers covering all the 22 autosomes in 98 cases of sporadic primary NPC. Of the 335 informative markers, 83 loci showed high level of LOH (presence in equal to or more than 30% cases) and most of the high frequent loci were clustered to chromosome 1p36 and 1p34, 3p14-p21, 3p24-p26, 3q25-q26 and 3q27, 4q31 and 4q35, 5q15-21 and 5q32-q33, 8p22-p23, 9p21-p23 and 9q33-q34, 11p12-p14, 13q14-q13 and 13q31-q32, 14q13-q11, 14q24-q23 and 14q32. High frequency of LOH was found in chromosomes 3, 5, 9 and 11 (>/=50%), while medium frequency of LOH was found in chromosomes 1, 4, 6, 14, 17 and 19 (40-49%). Several new regions showing high frequency of LOH were found in chromosome 1p36, 3q25-q26, 3q27, 5q15-q21, 8p22-p23 and 11p12-14. The relationship between LOH and TNM stage of NPC was evaluated. Regions 6p23 (D6S289), 8p23.1 (D8S549) and 9q34.2 (D9S1826) showed higher frequency of LOH in later stages (III and IV) than in earlier stages (I and II) (P<0.05). Thus, our study provides a global view on allelic loss in the development of NPC and should shed light on the way for localization of putative tumor suppressor genes associated with the pathogenesis of NPC.     

Distinct chromosomal abnormality pattern in primary liver cancer of non-B, non-C patients

To discriminate among the chromosomal abnormalities associated with the etiology of hepatocellular carcinoma (HCC), we performed a comparative genomic hybridization (CGH) analysis on 34 HCCs resected on non-cirrhotic livers from patients serologically negative for both hepatitis B (HBV) and C (HCV) viruses. The results were compared to those of a previous analysis of 50 HCCs selected on the basis of their positivity for HBV infection. The majority of the abnormalities found in the HBV positive cases (losses of chromosome arms 1p, 8p, 6q, 13q and 14q and gains of 1q, 8q, 6p and 17q) were similarly detected in the virus negative specimens. In contrast, a significant decrease (40% on average) was observed for losses at 4q, 16q and 17p in non-viral HCC samples, suggesting that these abnormalities are tightly associated with HBV infection. Thus, in addition to a common pathway towards malignancy, a subset of alterations may preferentially contribute to virus-induced carcinogenesis. In a parallel CGH study of 10 fibrolamellar carcinomas, a rare subtype of HCC, we found in six out of the seven informative cases, gains of chromosome arm 1q. This region, which is also preferentially amplified in non fibrolamellar tumors (58%), may contain an essential proto-oncogene commonly implicated in liver carcinogenesis.     

Frequent Loss of Heterozygosity on Chromosomes 16 and 4 in Human Hepatocellular Carcinoma

By restriction fragment length polymorphism analysis, we examined loss of heterozygosity at 34 loci on 23 chromosomes in 35 surgically resected human hepatocellular carcinomas. Allele losses at the HP locus on chromosome 16q22 and at the MT2P1 locus on chromosome 4p11-q21 were detected in 57% (8/14) and 50% (8/16) of cases, respectively. Loss of heterozygosity on chromosomes 16q and 4 occurred simultaneously in 4 of 7 informative cases for both loci, and seemed to be important in the development of human hepatocellular carcinoma irrespective of the presence of hepatitis B virus infection. In contrast, the incidence of allele loss was low at the other loci, e.g., chromosome 1p, 3p, 11p, 13q or 17p, where one allele is frequently lost in other cancers.     

Frequent loss of heterozygosity on chromosomes 16 and 4 in human hepatocellular carcinoma

By restriction fragment length polymorphism analysis, we examined loss of heterozygosity at 34 loci on 23 chromosomes in 35 surgically resected human hepatocellular carcinomas. Allele losses at the HP locus on chromosome 16q22 and at the MT2P1 locus on chromosome 4p11-q21 were detected in 57% (8/14) and 50% (8/16) of cases, respectively. Loss of heterozygosity on chromosomes 16q and 4 occurred simultaneously in 4 of 7 informative cases for both loci, and seemed to be important in the development of human hepatocellular carcinoma irrespective of the presence of hepatitis B virus infection. In contrast, the incidence of allele loss was low at the other loci, e.g., chromosome 1p, 3p, 11p, 13q or 17p, where one allele is frequently lost in other cancers.     

Cytogenetic profile of 109 lipomas

Cytogenetic analysis of short-term cultures was carried out on 109 lipomas from 92 patients. Clonal chromosomal abnormalities were present in 50% of the tumors analyzed. Based on the results, three main cytogenetic groups were identified and included: (a) tumors with normal karyotypes, (b) tumors with abnormalities involving region q13-15 on chromosome 12, and (c) tumors with other clonal aberrations. Within each of these groups, cytogenetic subgroups could be identified, each characterized by a specific anomaly. Tumors with abnormalities of 12q included specific subgroups with t/ins(1;12)(p32-33;q13-15), t(2;12)(p21-22;q13-14), t(3;12)(q28;q14), t(12;21)(q13;q21), complex, and nonrecurrent aberrations. The group containing heterogeneous clonal aberrations included subgroups with del(13)(q12q22), der(6)(p21-23), der(11)(q13), and nonspecific aberrations. Chromosome bands 1p36, 1p32-33, 2p21-22, 3q27-28, 6p21-23, 11q13, 12q13-15, 13q12, 13q22, 17p13, 17q21, and 21q21-22 were preferentially involved in structural rearrangements in lipomas. The identification of these sites of nonrandom rearrangements may serve to identify genes (at or near the junctions of chromosomal aberrations) involved in normal cellular growth control. Statistical analysis of the data revealed a correlation among karyotypic abnormalities and clinical data, such as age and sex of the patient, and tumor depth, site, and size.     

Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM

Mantle cell lymphoma (MCL) is characterized by 11q13 chromosomal translocation and CCND1 overexpression, but additional genomic changes are also important for lymphomagenesis. To identify the genomic aberrations of MCL at higher resolutions, we analysed 29 patient samples and seven cell lines using array-based comparative genomic hybridization (array CGH) consisting of 2348 artificial chromosome clones, which cover the whole genome at a 1.3 mega base resolution. The incidence of identified genomic aberrations was generally higher than that determined with chromosomal CGH. The most frequent imbalances detected by array CGH were gains of chromosomes 3q26 (48%), 7p21 (34%), 6p25 (24%), 8q24 (24%), 10p12 (21%) and 17q23 (17%), and losses of chromosomes 2p11 (83%), 11q22 (59%), 13q21 (55%), 1p21-p22 (52%), 13q34 (52%), 9q22 (45%), 17p13 (45%), 9p21 (41%), 9p24 (41%), 6q23-q24 (38%), 1p36 (31%), 8p23 (34%), 10p14 (31%), 19p13 (28%), 5q21 (21%), 22q12 (21%), 1q42 (17%) and 2q13 (17%). Our analyses also detected several novel recurrent regions of loss located at 1p36, 1q42.2-q43, 2p11.2, 2q13, 17p13.3 and 19p13.2-p13.3, as well as recurrent regions of homozygous loss such as 2p11 (Ig(kappa)), 2q13 and 9p21.3-p24.1 (INK4a/ARF). Of the latter, we investigated the 2q13 loss, which led to identification of homozygous deletions of the proapoptotic gene BIM. The high-resolution array CGH technology allowed for the precise identification of genomic aberrations and identification of BIM as a novel candidate tumor suppressor gene in MCL.     

原发性肺鳞状细胞癌染色体不平衡及其与吸烟的关系

背景与目的:染色体不平衡在肺癌发生中具有重要作用,并可能受不同致癌物的影响。本研究旨在探讨原发性肺鳞状细胞癌(squamous cell carcinoma,SCC)染色体不平衡特征及吸烟对其的影响。方法:采用比较基因组杂交(comparative genomic hybridization,CGH)技术对39例原发性肺SCC的染色体扩增和缺失进行检测,并分析吸烟与肺SCC染色体不平衡之间的关系。结果:肺SCC染色体扩增常见于3q(74.4%,29/39),5p(66.7%,26/39),1q(43.6%,17/39),8q(41%,16/39),12p(42.6%,18/39),2p(38.5%,15/39)、18p(33.3%,13/39)等;最小扩增区位于3q26.2鄄29、5p14.3鄄15.3、1q41鄄44、8q23和12p13;38.5%和15.4%的病例发生3q和5p高拷贝扩增。染色体缺失主要见于3p(56.4%,22/39),5q(53.8%,21/39),13q(51.3%,20/39),8p(46.1%,18/39),4p(43.6%,17/39)、4q(43.6%,17/39)、1p(41%,16/39)、2q(38.5%,15/39),9q(35.9%,14/39)、13p(35.9%,14/39)、16p(35.9%,14/39),6p(33%,13/39)、6q(30.7%,12/39)等;最小缺失区位于3p14.2鄄21.2(51.3%,20/39)、5q15鄄22(51.3%,20/39)、13q14.2鄄21.2(48.7%,19/39)、8p21.1鄄22(44%,17/39)、2q32(36%,14/39)和16p12鄄13.1(33%,13/39)。与非吸烟患者相比,吸烟患者3q和8q扩增率显著增加(P<0.05);两者共同的染色体