Helicobacter pylori-related and -non-related gastric cancers do not differ with respect to chromosomal aberrations

Gastric carcinogenesis is strongly associated with Helicobacter pylori infection, but the underlying genetic mechanisms are largely unknown. The aim of this study was to correlate chromosomal aberrations in gastric cancer to H. pylori status and its different strains, as well as to histological type and other clinico-pathological variables. DNA from 46 gastric cancers (male/female 35/11, age 27-85 years) was extracted from formaldehyde-fixed, paraffin-embedded material and tested for chromosomal gains and losses by comparative genomic hybridization (CGH). Chromosomal aberrations with frequencies of 20% or higher were considered to be non-random changes associated with gastric cancer. The mean number of chromosomal events per tumour was 9.7 (range 0-27), with a mean of 3.2 gains (range 0-16) and 6.5 losses (range 0-15). Gains were most frequently found at chromosomes 8q and 13q (24% and 26%, respectively). Losses were predominantly found on chromosome arms 2q, 9p, 12q, 14q, 15q, 16p, 16q, 17p, 17q, 19p, 19q, and 22q (22%, 30%, 43%, 22%, 33%, 50%, 28%, 50%, 39%, 33%, 39%, and 37%, respectively). Common regions of overlap narrowed down to 2q11-14, 8q23, 9p21, 12q24, 13q21-22, 14q24 and 15q11-15. The mean number of gains was higher in tumours with metastases than in localized tumours (4.1 vs. 1.9, p=0.04). Tumours with a loss at 17p showed a higher number of losses than tumours without a 17p loss (9. 5 vs. 4.7 on average, p<0.001). Neither H. pylori status (+, n=25; -, n=21) nor H. pylori strain was correlated to the total number of events or to any specific chromosomal aberration, nor were there differences between intestinal (n=30) and diffuse (n=15) cancers or any other clinico-pathological variable tested. In conclusion, a complex of chromosomal aberrations is involved in gastric cancer, but their pattern does not depend on H. pylori status or strain, nor on the histological type of the tumour. The exact biological meaning of these aberrations in carcinogenesis needs further clarification.     

Comparative genomic hybridisation divides retinoblastomas into a high and a low level chromosomal instability group

BACKGROUND: Retinoblastoma is the most common intraocular malignancy in childhood and is responsible for approximately 1% of all deaths caused by childhood cancer. Aims/methods: Comparative genomic hybridisation was performed on 13 consecutive, histologically confirmed retinoblastomas to analyse patterns of chromosomal changes and correlate these to clinicopathological variables. Six cases were hereditary and seven cases were sporadic. RESULTS: In 11 of the 13 tumours chromosomal abnormalities were detected, most frequently gains. Frequent chromosomal gains concerned 6p (46%), 1q (38%), 2p, 9q (30%), 5p, 7q, 10q, 17q, and 20q (23%). Frequent losses occurred at Xq (46%), 13q14, 16q, and 4q (23%). High level copy number gains were found at 5p15 and 6p11-12. A loss at 13q14 occurred in three cases only. Relatively few events occurred in the hereditary cases (27) compared with the non-hereditary cases (70 events). The number of chromosomal aberrations in these 13 retinoblastomas showed a bimodal distribution. Seven tumours showed less than four chromosomal aberrations, falling into a low level chromosomal instability (CIN) group, and six tumours showed at least eight aberrations, falling into a high level CIN group. In the low level CIN group the mean age was half that seen in the high level CIN group, there were less male patients, and there were more hereditary and bilateral cases. Microsatellite instability was not detected in either of the two groups. CONCLUSION: Despite the complex pattern of genetic changes in retinoblastomas, certain chromosomal regions appear to be affected preferentially. On the basis of the number of genetic events, retinoblastomas can be divided in low and a high level chromosomal instability groups, which have striking differences in clinical presentation.     

Comparative genomic hybridization reveals complex genetic changes in primary breast cancer tumors and their cell lines

DNA copy number changes were characterized by comparative genomic hybridization (CGH) in 18 breast cancer cell lines. In 5 of these, the results were comparable with those from the primary tumors of which the cell lines were established. All of the cell lines showed extensive DNA copy number changes, with a mean of 16.3 +/- 1.1 aberrations per sample (range 7-26). All of the cell lines had a gain at 8q22-qter. Other common gains of DNA sequences occurred at 1q31-32 (89%), 20q12-q13.2 (83%), 8q13 (72%), 3q26.1-qter (67%), 17q21-qter (67%) 5p14 (61%), 6p22 (56%), and 22pter-qter (50%). High-level amplifications were observed in all cell lines; the most frequent minimal common regions were 8q24.1 (89%), 20q12 (61%), 1q41 (39%), and 20p11.2 (28%). Losses were observed less frequently than gains and the minimal common regions of the most frequent losses were Xq11-q12 (56%), Xp11.2-pter (50%), 13q21 (50%), 8p12-pter (44%), 4p13-p14 (39%), 6q15-q22 (39%), and 18q11.2-qter (33%). Although the cell lines showed more DNA copy number changes than the primary tumors, all aberrations, except one found in a primary tumor, were always present in the corresponding cell line. High-level amplifications found both in primary tumors and cell lines were at 1q, 8q, 17q, and 20q. The DNA copy number changes detected in these cell lines can be valuable in investigation of tumor progression in vitro and for a more detailed mapping and isolation of genes implicated in breast cancer.     

Genomic imbalances detected by comparative genomic hybridization are prognostic markers in invasive ductal breast carcinomas

Genomic imbalances detected by comparative genomic hybridization are prognostic markers in invasive ductal breast carcinomas
Aims : The aim of this work is the study of the prognostic significance of the chromosomal aberrations described in a series of invasive ductal breast carcinomas.
Methods and results : We analysed by comparative genomic hybridization a group of 70 formalin-fixed paraffin-embedded invasive ductal breast carcinomas. Aberrations showed a frequency similar to previous studies using frozen tumours. Interestingly, we identified gains involving 6q16-q24 more frequently than in other series. We analysed the association among the chromosomal imbalances, 11 histopathological factors, relapse rate and overall survival of patients. Associations showed 16q losses as a potential marker of good prognosis, as they were more frequent in node-negative ( P =0.025) and in oestrogen-positive tumours ( P  < 0.001). Furthermore, 100% of bcl-2+ tumours presented this aberration compared with 29.3% in bcl-2– ( P =0.014). 1q, 11q, 17q and 20q gains were associated with poor prognosis: 95% of cases with 1q gains were bigger than 20 mm ( P =0.041). Tumours with 1q and 11q gains showed a higher relapse rate ( P =0.063; P =0.066). Within the good prognosis group of lymph node-negative patients, 17q and 20q gains identify a subgroup with increased relapse rate ( P =0.039).
Conclusions : Chromosomal imbalances, together with histopathological factors, may help to predict outcome in breast cancer patients.     

Differences in genetic alterations between primary lobular and ductal breast cancers detected by comparative genomic hybridization

Infiltrating ductal (DC) and lobular carcinoma (LC) of the breast represent the most frequently observed varieties of invasive breast cancer, characterized by differences in their histological and clinical properties. Although comparative genomic hybridization (CGH) of invasive breast carcinomas has revealed a complex and consistent pattern of DNA copy number changes, the data with regard to type specific aberrations are limited. A comprehensive study was therefore performed on 19 LCs and 29 DCs to ascertain type-specific differences of unbalanced DNA copy number changes by CGH. Statistical analysis revealed significantly higher frequencies for underrepresentation of chromosomes 16q (p<0.01), 22 (p<0.05), and 17q (p<0.05), and a lower frequency for overrepresentation of chromosome 8q (p<0.01) in LC. Similar frequencies of non-random chromosomal changes in LC and DC were obtained for gain of 1q (74%/59%) and loss of 19p (53%/52%), parts of 1p (42%/41%) and 11q (21%/24%). Less frequently, gains mainly involving parts of chromosomes 20q, 20p, 3q, and 5p and partial losses of chromosomes 17p and 13 were observed in both groups of tumours. Minimal regions of overlapping amplifications were mapped to 17q23 exclusively in DC (17%) and 11q13-q14 in both DC and LC (21% and 11%, respectively). High occurrences of DNA copy number decreases were detected at the distal part of chromosomes 1p, 19 and 22, but further analysis is required to confirm these imbalances. It is suggested that the observed differences are involved in the development of type-specific properties of DC and LC.     

Chromosomal aberrations associated with invasion in papillary superficial bladder cancer

Non-invasive and invasive papillary transitional cell carcinomas of stages pTa and pT1 represent the first steps of tumour progression in bladder cancer. In order to analyse different chromosomal alterations of pTa and pT1 superficial bladder cancer, 46 tumour specimens were examined by comparative genomic hybridization (CGH). Losses of chromosome 9 material (11/20) and gains of chromosome 17 material (6/20) were frequently found in pTa tumours. Stage pT1 tumours were characterized by gains of chromosome 1q (14/26; including amplification at 1q21–q24 in three cases) and chromosome 17 material (15/26), as well as by losses of 11p (15/26) and 11q (13/26). Other loci frequently showing losses in pT1 tumours were 2q (9/26), 4q (10/26), 5q (9/26), 8p (10/26), 9p (9/26), 9q (12/26), 10q (8/26), 17p (7/26), and 18q (8/26). Amplifications were detected at 8q21/22, 5q21, 7q36, 10p14, 10p12, 10q25, 12q12, and 12q14. The most striking differences between grade 2 pTa and pT1 tumours were gains of 1q (P<0·01) and losses at 2q (P<0·025), 10q (P<0·05), 11p (P<0·01), 11q (P<0·01), and 17p (P<0·05), as well as the total number of aberrations (pTa grade 2: 4·1; pT1 grade 2: 8·6 aberrations per tumour). These data show characteristic chromosomal aberrations associated with invasion in superficial bladder cancer. © 1998 John Wiley & Sons, Ltd.     

Cytogenetic analysis of myxoid liposarcoma and myxofibrosarcoma by array-based comparative genomic hybridisation

AIM: To investigate overall chromosomal alterations using array-based comparative genomic hybridisation (CGH) of myxoid liposarcomas (MLSs) and myxofibrosarcomas (MFSs). Materials and methods: Genomic DNA extracted from fresh-frozen tumour tissues was labelled with fluorochromes and then hybridised on to an array consisting of 1440 bacterial artificial chromosome clones representing regions throughout the entire human genome important in cytogenetics and oncology. RESULTS: DNA copy number aberrations (CNAs) were found in all the 8 MFSs, but no alterations were found in 7 (70%) of 10 MLSs. In MFSs, the most frequent CNAs were gains at 7p21.1-p22.1 and 12q15-q21.1 and a loss at 13q14.3-q34. The second most frequent CNAs were gains at 7q33-q35, 9q22.31-q22.33, 12p13.32-pter, 17q22-q23, Xp11.2 and Xq12 and losses at 10p13-p14, 10q25, 11p11-p14, 11q23.3-q25, 20p11-p12 and 21q22.13-q22.2, which were detected in 38% of the MFSs examined. In MLSs, only a few CNAs were found in two sarcomas with gains at 8p21.2-p23.3, 8q11.22-q12.2 and 8q23.1-q24.3, and in one with gains at 5p13.2-p14.3 and 5q11.2-5q35.2 and a loss at 21q22.2-qter. CONCLUSIONS: MFS has more frequent and diverse CNAs than MLS, which reinforces the hypothesis that MFS is genetically different from MLS. Out-array CGH analysis may also provide several entry points for the identification of candidate genes associated with oncogenesis and progression in MFS.     

Cytogenetic analysis of esophageal squamous cell carcinoma cell lines by comparative genomic hybridization: relationship of cytogenetic aberrations to in vitro cell growth

Cancer is characterized by autonomous growth of cells, and it is widely accepted that cell proliferation is primarily influenced by individual cell genetics. To elucidate the mechanisms of cancer cell proliferation, we studied differences in genetic aberrations for different type of tumors with different proliferation characteristics. We employed comparative genomic hybridization (CGH) to detect genetic aberrations in six cell lines of esophageal squamous cell carcinoma (ESCC). Three cell lines (YES-1, -2, and -3) grow in culture without fetal calf serum (group A), while others require serum to be maintained in vitro (group B). Both groups showed very similar cytogenetic aberrations: over-representations of 11q13 (6/6), 8q23-qter (5/6), Xq25-qter (5/6), 3q26-qter (4/6), 5p (4/6), 7p15-pter (4/6), 8q21.3-q22 (4/6), 17p (4/6), and 20q13 (4/6), and under-representations of 18q21-qter (6/6), 4q28-q33 (4/6), and 9p21 (4/6). Six amplification loci were mapped to chromosomal regions of 6q23 (1 case), 7p12 (2 cases), 9p21 (1 case), 11p11.2-12 (3 cases), 11q13 (2 cases), and 17p12 (2 cases). However, some differences were detected. DNA copy number increases at 7p12-p13, 11q14-q22, and 11q22-qter and under-representations of 4p, 8p, and 11p14-pter. In contrast, gains at 12p and 20p, and losses at 3p and 5q were detected only in group-B cell lines. These observations suggest that cytogenetic differences between the two groups may be linked to differences in cell growth characteristics in vitro, and that the genes in these chromosomal regions may play important roles in cell proliferation.     

Genomic imbalances in Korean hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most prevalent gastrointestinal malignant tumors in Southeast Asia. Thirty-one cirrhotic HCC, 14 noncirrhotic HCC, and 13 metastastic HCC in the Korean population were investigated on microdissected tissues for chromosomal aberrations by degenerate oligonucleotide-primed polymerase chain reaction (PCR) comparative genomic hybridization. A number of prominent sites of genomic imbalances were observed. The gains of 1q, 6p, 7, 8q, 12q, 13q3-q32, 16p, 17q, and 20q and the losses of 1p, 4q, 6q, 8p, 9p, and 13q regions were observed with a similar high frequency in all types. Various chromosomal aberrations were observed preferentially to specific types. Gains of 4p15-pter, 10q24-qter, 18p11-pter, and 19p10-pter and a loss of 11q14-q22 were observed in the cirrhotic HCC, whereas losses of 14q21-q23 and 10q22-q23 were observed in noncirrhotic HCC. In metastatic HCC, gains of 3q25-qter and Xp21-pter and losses of 21q11-qter and Y were observed. The recurrent gains and losses of chromosomal regions identified in this study are consistent with several previous observations and provide possible candidate regions for the involvement of tumorigenesis and progressions of HCC.     

Novel genomic imbalances in B-cell splenic marginal zone lymphomas revealed by comparative genomic hybridization and cytogenetics

Splenic marginal zone lymphoma (SMZL) has recently been recognized in the World Health Organization classification of hematological diseases as distinct type of non-Hodgkin's lymphoma. In contrast to the well-established chromosomal changes associated with other B-cell non-Hodgkin's lymphoma, few genetic alterations have been found associated with SMZL. The aim of our study was to analyze by comparative genomic hybridization (CGH) the chromosomal imbalances in 29 patients with SMZL and to correlate these findings with clinical and biological characteristics and patient outcome. In 21 cases, cytogenetic studies were simultaneously performed. Most of the patients (83%) displayed genomic imbalances. A total of 111 DNA copy number changes were detected with a median of four abnormalities per case (range, 1 to 12). Gains (n = 92) were more frequent than losses (n = 16), while three high-level amplifications (3q26-q29, 5p11-p15, and 17q22-q25) were observed. The most frequent gains involved 3q (31%), 5q (28%), 12q and 20q (24% each), 9q (21%), and 4q (17%). Losses were observed in 7q (14%) and 17p (10%). SMZL patients with genetic losses had a shorter survival than the remaining SMZL patients (P < 0.05). In summary, chromosomal imbalances in regions 3q, 4q, 5q, 7q, 9q, 12q, and 20q have been detected by CGH in SMZL. Patients with SMZL displaying genetic losses by CGH had a short survival.     

Progression from colorectal adenoma to carcinoma is associated with non-random chromosomal gains as detected by comparative genomic hybridisation

AIMS: Chromosomal gains and losses were surveyed by comparative genomic hybridisation (CGH) in a series of colorectal adenomas and carcinomas, in search of high risk genomic changes involved in colorectal carcinogenesis. METHODS: Nine colorectal adenomas and 14 carcinomas were analysed by CGH, and DNA ploidy was assessed with both flow and image cytometry. RESULTS: In the nine adenomas analysed, an average of 6.6 (range 1 to 11) chromosomal aberrations were identified. In the 14 carcinomas an average of 11.9 (range 5 to 17) events were found per tumour. In the adenomas the number of gains and losses was in balance (3.6 v 3.0) while in carcinomas gains occurred more often than losses (8.2 v 3.7). Frequent gains involved 13q, 7p, 8q, and 20q, whereas losses most often occurred at 18q, 4q, and 8p. Gains of 13q, 8q, and 20q, and loss of 18q occurred more often in carcinomas than in adenomas (p = 0.005, p = 0.05, p = 0.05, and p = 0.02, respectively). Aneuploid tumours showed more gains than losses (mean 9.3 v 4.9, p = 0.02), in contrast to diploid tumours where gains and losses were nearly balanced (mean 3.1 v 4.1, p = 0.5). CONCLUSIONS: The most striking difference between chromosomal aberrations in colorectal adenomas and carcinomas, as detected by CGH, is an increased number of chromosomal gains that show a nonrandom distribution. Gains of 13q and also of 20q and 8q seem especially to be involved in the progression of adenomas to carcinomas, possibly owing to low level overexpression of oncogenes at these loci.     

Genetic Aberrations in Hypodiploid Breast Cancer : Frequent Loss of Chromosome 4 and Amplification of Cyclin D1 Oncogene

The evolution of somatic genetic aberrations in breast cancer has remained poorly understood. The most common chromosomal abnormality is hyperdiploidy, which is thought to arise via a transient hypodiploid state. However, hypodiploidy persists in 1 to 2% of breast tumors, which are characterized by a poor prognosis. We studied the genetic aberrations in 15 flow cytometrically hypodiploid breast cancers by comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). Surprisingly, numerous copy number gains were detected in addition to the copy number losses. The number of gains per tumor was 4.3 ± 3.2 and that of losses was 4.5 ± 3.3 (mean ± SD), which is similar to that previously observed in hyperdiploid breast cancers. Gains at chromosomes or chromosomal regions at 11q13, 1q, 19, and 16p and losses of 2q, 4, 6q, 9p, 13, and 18 were most commonly observed. Compared with unselected breast carcinomas, hypodiploid tumors showed certain differences. Loss of chromosome 4 (53%) and gain of 11q13 (60%) were significantly more common in hypodiploid tumors. The gain at 11q13 was found by FISH to harbor amplification of the Cyclin D1 oncogene, which is therefore three to four times more common in hypodiploid than in unselected breast cancers (15 to 20%). Structural chromosomal aberrations (such as Cyclin D1 amplification) were present both in diploid and hypodiploid tumor cell populations, as assessed by FISH and CGH after flow cytometric sorting. Together these results indicate that hypodiploid tumors form a distinct genetic entity of invasive breast cancer, although they probably share a common genetic evolution pathway where structural chromosomal aberrations precede gross DNA ploidy changes.     

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.     

Molecular cytogenetics of primary breast cancer by CGH

Comparative genomic hybridization (CGH) reveals DNA sequence copy number changes that are shared among the different cell subpopulations present in a tumor and may help to delineate the average progression pathways of breast cancer. Previous CGH studies of breast cancer have concentrated on selected subgroups of breast cancer. Here, 55 unselected primary breast carcinomas were analyzed using optimized quality-controlled CGH procedures. Gains of 1q (67%) and 8q (49%) were the most frequent aberrations. Other recurrent gains were found at 33 chromosomal regions, with 16p, 5p12–14, 19q, 11q13–14, 17q12, 17q22–24, 19p, and 20q13 being most often (>18%) involved. Losses found in >18% of the tumors involved 8p, 16q, 13q, 17p, 9p, Xq, 6q, 11q, and 18q. The total number of aberrations per tumor was highest in poorly differentiated (P = 0.01) and in DNA aneuploid (P = 0.05) tumors. The high frequency of 1q gains and presence of +1q as the sole abnormality suggest that it is an early genetic event. In contrast, gains of 8q were most common in genetically and phenotypically advanced breast cancers. The vast majority of breast cancers (80%) have gains of 1q, 8q, or both, and 3 changes (+1q, +8q, or −13q) account for 91% of the tumors. In conclusion, CGH results indicate that certain chromosomal imbalances are very often selected for, sometimes in a preferential order, during the progression of breast cancer. Further studies of such common changes may form the basis for a molecular cytogenetic classification of breast cancer. Genes Chromosomes Cancer 21:177–184, 1998. © 1998 Wiley-Liss, Inc.     

Do DNA copy number changes differentiate uterine from non-uterine leiomyosarcomas and predict metastasis?

DNA copy number changes were investigated in 51 (19 uterine and 32 nonuterine) primary leiomyosarcomas by comparative genomic hybridization. The aim was to evaluate whether true biological differences exist between uterine and nonuterine leiomyosarcoma and whether changes revealed by comparative genomic hybridization have prognostic value. Genomic imbalances were found in 48 (94%) cases. The most frequent DNA copy number changes were losses in 10q (35%), 13q (57%), and 16q (41%), gains in 1q (41%), and gains and high-level amplifications in 17p (39%). Gains were nearly as frequent as losses in both uterine and nonuterine leiomyosarcoma. Correlation-based tree modeling revealed two clusters that segregated significantly a group of uterine (gains at 1q11-q24) and a group of nonuterine (losses at 13q14-q34, 16q11.1-q24, and 10q21-q26) cases. The nonuterine cluster was associated with subcutaneous origin and a trend toward increased metastasis-free survival. Further explorative analyses identified aberrations associated with shorter metastasis-free survival time, including losses at 2q32.1-q37 and gains at 8q24.1-q24.3, whereas the cases with losses at 6cen-p25 showed longer metastasis-free survival time.     

Immunohistochemical and cytogenetic characterization of acantholytic squamous cell carcinoma of the breast

Primary acantholytic squamous cell carcinoma (ASCC) of the breast is a rare and aggressive variant of invasive breast cancer. Here we report two new cases of ASCC and their immunohistochemical and cytogenetic characterization. One case was associated with systemic metastases and death and the other with local failure prior to loss of follow-up. Using comparative genomic hybridization (CGH), both tumors showed a high overall number of chromosomal imbalances with a similar pattern of gains and losses. Genetic aberrations common to both tumors included losses at 3p11-p25, 5q21-q31, 8p, 9, 13p13-q21, 16q12-q21, and 17p and gains at 1q31-qter, 7p, 18q12-qter, 19q, and 20. Immunohistochemically, the tumors were characterized by high proliferative activity, an uncommon cytokeratin expression profile, reduced E-cadherin staining, and overexpression of p53 and epithelial growth factor receptor (EGFR). The results of our analyses suggest that genetic alterations observed in ASCC of the breast include imbalances commonly observed in both mammary adenocarcinoma and squamous cell carcinoma of other locations. Furthermore, the overexpressed EGFR could be a possible therapeutic target for individual cases of this aggressive tumor type.     

Chromosomal imbalances of primary and metastatic lung adenocarcinomas.

Comparative genomic hybridization (CGH) was used to screen 83 lung adenocarcinomas of 60 patients for chromosomal imbalances. The most common alteration was DNA overrepresentation on chromosome 1q, with a peak incidence at 1q22-q23 in 73% of the primary tumours, followed by DNA overrepresentation on chromosomes 8q and 20q, and deletions on chromosomes 3p, 4q, 6q, 9p, 9q, and 13q, in at least 60%. The generation of a difference histogram of metastasizing versus non-metastasizing tumours and a case-by-case histogram for the comparison of 23 paired samples of primary tumours and corresponding metastases suggested that deletions on chromosomes 3p12-p14, 3p22-p24, 4p13-15.1, 4q21-qter, 6q21-qter, 8p, 10q, 14q21, 17p12-p13, 20p12, and 21q, and overrepresentations on chromosomes 1q21-q25, 7q11.2, 9q34, 11q12-q13, 14q11-q13, and 17q25 are associated with the metastatic phenotype. In contrast, losses on chromosome 19 and gains on 3p, 4q, 5p, and 6q were preferentially found in non-metastasizing tumours. The analysis of the paired samples revealed considerable chromosomal instability, but indicated a clonal relationship in each case. The primary tumours often showed additional deletions, suggesting that loss of function mutations are critical in the initial phase of tumour dissemination, whereas the metastases preferentially acquired DNA gains, probably modulating the metastatic phenotype. The primary data from this study (ratio profiles, clinicopathological parameters, histograms) are also available at http://amba.charite.de/cgh.     

Genetic aberrations detected by comparative genomic hybridization predict outcome in patients with endometrioid carcinoma

Endometrial cancer progression is determined by a complex pattern of multiple genetic aberrations, but how these aberrations affect prognosis is unknown. In this study, we undertook a genome-wide screening to detect genetic changes by comparative genomic hybridization (CGH) in 51 tumors from patients with primary endometrioid carcinoma of the uterine corpus. The observed genetic changes were subsequently correlated with the progression of the disease and the clinical outcome in each case. The average number of genetic aberrations (copy number gains and losses) was significantly greater in non-surviving patients than in disease-free patients (12. 6 vs. 2.7, P < 0.0001). According to multivariate analysis, lymph node metastasis (P = 0.015), cervical involvement (P = 0.007) and one or more copy number losses at 9q32-q34, 11q23, or Xq12-q24 (P = 0.023) were significantly predictive of death from the disease. Interestingly, lymph node metastasis was significantly associated with copy number gains at 8q22-q23 and 8q24-qter (P = 0.003 and P = 0.025, respectively). Moreover, cervical involvement was also correlated significantly not only with gains of 8q22-q23 and 8q24-qter but also with loss of 11q23 (P = 0.04, 0.0003, and P = 0. 009, respectively). These results suggest that analysis of genetic changes may help predict clinical outcome and the presence of metastatic disease as well as assist in therapeutic decision making for patients with endometrioid carcinoma.     

Aberrations of chromosomes 5 and 8 as recurrent cytogenetic events in anaplastic carcinoma of the thyroid as detected by fluorescence in situ hybridisation and comparative genomic hybridisation

Comparative genomic hybridisation (CGH) is a technique which identifies gains and losses of DNA sequence copy number in tumours. We used CGH to search for genetic changes in one of the most aggressive malignancies--anaplastic thyroid carcinoma (ATC). For this purpose, we analysed tumour specimens of nine ATCs and DNA of two ATC cell lines. CGH detected aberrations in 10 of 11 samples, with a mean number of gains or losses per carcinoma of 4.8 (range 0-13). Total or partial changes of chromosome 8 (n=6), including gains or losses of 8p (n=6) or 8q (n=5) were those detected most frequently. Chromosome 5p was amplified in five cases. Gains in two of three samples were found for 3q, 7p, 11q and 20q. Gains in a fewer number were seen for 1p (1 case), 1q (1), 7q (2), 9q (2), 11p (2), 12q (1), 14 (1), 15 (1), 17q (2), 18p (2), 18q (1), 20p (1), 21 (2), Xp (2) and Xq (2). Losses were less frequent than gains and observed for 1p (2 cases), 1q (1), 2p (1), 2q (2), 3p (2), 3q (1), 4q (2), 6q (1), 9p (2), 9q (1), 18p (1), 18q (1) and Y (2). Examples of analysis of tumour sections and cell lines performed by fluorescence in situ hybridisation (FISH) confirmed the gains and losses found by CGH and detected additional signals for 8q21 in tumour cells in a sample with no gains or losses normally in CGH. The results suggest that aberrations of 5p, 8p and 8q, which are rarely found in differentiated thyroid carcinoma, may play an important role in the development of ATC. Therefore, these chromosomes could harbour gene loci potentially involved in the aggressiveness of neoplastic tumours, as shown in tumours such as in this study for ATC.     

Chromosomal imbalances in small cell carcinomas of the urinary bladder.

Small cell carcinomas (SCCs) represent a rare histological subtype of urinary bladder cancer. Little is known abut the genetic alterations in these tumours. To identify chromosomal aberrations that are typically present in SCC of the urinary bladder, ten tumours were analysed by comparative genomic hybridization (CGH). CGH allows screening for all relative DNA copy number gains and losses present in a tumour. SCCs of the bladder were characterized by a high number of genomic alterations (mean: 11.3 per tumour). Deletions were most frequent at 10q (7 of 10 tumours deleted), 4q, 5q (5/10 each), and 13q (4/10). These regions may carry tumour suppressor genes with relevance for this particular tumour type. Gains of DNA sequences were most prevalent at 8q (5/10), 5p, 6p, and 20q (4/10 each). High level amplifications were found at 1p22-32, 3q26.3, 8q24, and 12q14-21. These loci may pinpoint the localization of oncogenes with relevance for small cell bladder cancer. The analysis of one tumour having areas of both SCC and transitional cell carcinoma strongly suggests that SCC can develop from TCC through the acquisition of additional genetic alterations.