Distinct chromosomal imbalances in nonpolypoid and polypoid colorectal adenomas indicate different genetic pathways in the development of colorectal neoplasms

Cytogenetic changes are widely unknown for nonpolypoid (synonymously termed as "flat" or "depressed") colorectal adenomas. A comparison with polypoid adenomas will contribute to the discussion whether different genetic pathways for colorectal tumorigenesis depending on its origin from nonpolypoid or polypoid adenomas exist. Tissue samples of nonpolypoid (n = 22), polypoid (n = 28) adenomas, carcinomas ex-nonpolypoid adenomas (n = 9), carcinomas ex-polypoid adenomas (n = 14), and normal colonic mucosa (n = 9) were investigated by comparative genomic hybridization of whole genomic DNA. Chromosomal imbalances were detected from average comparative genomic hybridization profiles for each entity. Nonpolypoid adenomas show recurrent chromosomal losses on chromosomes 16, 17p, 18, 20, and 22 and gains on chromosomes 2q, 4q, 5, 6, 8q, 12q, and 13q. In polypoid adenomas losses of whole chromosomes 16, 18, and 22 and gains of chromosomes 7q and 13 were detected. The frequency of copy number changes was higher in nonpolypoid compared to polypoid adenomas and early onset of chromosomal changes became apparent in low-grade dysplasias of nonpolypoid adenomas. Gains on chromosomes 2q, 5, 6, 8q, and 12q and losses on chromosomes 17p and 20 occurred exclusively in nonpolypoid adenomas, whereas 16p deletions are significantly more frequent in nonpolypoid than in polypoid adenomas. Carcinomas ex-nonpolypoid adenomas are characterized by more complex aberration patterns compared to nonpolypoid adenomas exhibiting frequent losses on chromosomes 8p, 12q, 14, 15q, 16, 17p, 18, and 22 and gains on 3q, 5, 6, 7, 8q, 12q, and 13, respectively. Normal colonic mucosa showed no chromosomal imbalances. Distinct differences of chromosomal imbalances between nonpolypoid and polypoid colorectal adenomas have been characterized that support the hypothesis that different genetic pathways may exist in the development of colorectal adenomas exhibiting nonpolypoid and polypoid phenotype.     

Comparative genomic hybridization reveals a specific pattern of chromosomal gains and losses during the genesis of colorectal tumors

Comparative genomic hybridization was used to screen the DNA extracted from histologically defined tissue sections from consecutive stages of colorectal carcinogenesis for chromosomal aberrations. No aberrations were detected in normal epithelium (n = 14). Gain of chromosome 7 occurred as a single event in low-grade adenomas (n = 14). In high-grade adenomas (n = 12), an overrepresentation of chromosomes 7 and 20 was present in 30% of the cases analyzed. The transition to colon carcinomas (n = 16) was characterized by the emergence of multiple chromosomal aberrations. Chromosomes 1, 13, and 20 and chromosome arms 7p and 8q were frequently gained, whereas chromosome 4 and chromosome arms 8p and 18q were recurrently underrepresented. The same tissue sections that were used for CGH were analyzed by means of DNA-ploidy measurements and immunohistochemical staining to quantify proliferative activity and p21/WAF-I and TP53 expression. We observed that crude aneuploidy and increased proliferative activity are early events in colorectal carcinogenesis, followed by TP53 overexpression and the acquisition of recurrent chromosomal gains and losses during the progression from high-grade adenomas to invasive carcinomas. Genes Chromosom Cancer (1996). © 1996 Wiley-Liss, Inc.     

Genetic analysis of 53 lymph node-negative breast carcinomas by CGH and relation to clinical, pathological, morphometric, and DNA cytometric prognostic factors

Within the subgroup of lymph node-negative breast cancers, there is a need for accurate prognostic indicators to select high-risk patients. Comparative genomic hybridization (CGH) provides an opportunity to screen the whole genome for chromosomal aberrations which may be associated with poor clinical outcome. The results of CGH analysis of 53 lymph node-negative breast carcinomas are presented and correlated with a set of clinico-pathological and cytometric features with strong prognostic value. The most frequent chromosomal gains were, in descending order of frequency, 8q, 1q, Xq, 5q, 4q, and 3q. Recurring losses were observed at chromosomal arms 19p, 1p, 17p, 22q, 4q, and 8p. There was not a single, unique combination of chromosomal aberrations, but gains of 1q and 8q were frequently observed simultaneously (15/53 cases). DNA aneuploid tumours harboured more gains than DNA diploid tumours, but there was no correlation between the total number of events per tumour detected by CGH and any of the prognostic features. Of the many chromosomal aberrations found, only gains of chromosome 8q were strongly correlated with high values of mean nuclear area. A clearer picture was obtained when comparing only those cases which, according to their cytometric and morphometric features, had either the worst or the best prognosis. Gains occurred mainly in the 'poor prognostic features' group, in particular at 8q, 11q13, 17q, and 20q. It is hypothesized that these gains could be late, progression-related events and may be associated with aggressive clinical behaviour. These four chromosomal regions may therefore be of potential prognostic value. Correlation with real follow-up data will enable us better to identify those patients who have a high risk of recurrence within the subgroup of lymph node-negative breast cancer patients.     

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.     

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.     

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.     

Differentiation of liver cell adenomas from well-differentiated hepatocellular carcinomas by comparative genomic hybridization

Liver cell adenomas (LCAs) are rare tumours which may be difficult to differentiate from low-grade hepatocellular carcinomas (HCCs). This study used comparative genomic hybridization (CGH) to look for cytogenetic aberrations which would serve to distinguish between these tumours. For this purpose, ten LCAs and six well-differentiated HCCs were analysed and the results were compared with those reported previously for 15 well-differentiated HCCs. Aberrations were seen in 2/10 LCAs: a gain of chromosome 7p was observed in one and gains of 17q and 20 in a second case. In 6/6 well-differentiated HCCs, up to 13 aberrations were detectable, with a mean of 7.2 aberrations per case in chromosome sites 1q, 4p, 4q, 5p, 5q, 6p, 6q, 7p, 7q, 8p, 8q, 10q, 11p, 13q, 14q, 16p, 16q, 17p, 17q, 20p, 20q, and 21q. Aberrations focused on gains or losses of six chromosome sites, 1q, 4q, 8p, 8q, 16p, and 17p; in all HCC samples, at least two of these sites were affected. None of these aberrations occurred in any of the LCAs analysed. CGH is therefore helpful in distinguishing between LCA and well-differentiated HCC. Detection of one or more of the six most frequent aberrations in HCC supports the diagnosis of carcinoma and makes LCA unlikely.     

Genetic changes and clonality relationship between primary colorectal cancers and their pulmonary metastases--an analysis by comparative genomic hybridization

About 10% of colorectal carcinoma patients develop pulmonary metastases during their lifetime. We address whether and how the chromosomal abnormalities differ between the primary cancers and their metastatic counterparts, what the clonality relationship (CR) is between them, and whether certain genomic aberrations contribute to this disease progression. Comparative genomic hybridization (CGH) experiments were performed on 18 paired samples of primary and pulmonary metastases obtained from patients who had undergone two consecutive surgeries and from whom clinical data had been collected. The CGH profiles also were used as indexes for determining the CR between the cancers. The overall CGH abnormality profiles were similar for the primary colorectal carcinomas and their pulmonary metastases. Frequent gains were found on chromosome arms 20q, 8q, 13q, and 7q, whereas common losses were found on 18q, 8p, and 18p. The pulmonary metastases, however, contained more CGH abnormalities than did the primary carcinomas (total aberration events per tumor: 12.6 +/- 5.0 vs. 8.3 +/- 5.7, respectively, P = 0.024; gains: 7.6 +/- 3.1 vs. 5.1 +/- 3.5, respectively, P = 0.036; losses: 5.0 +/- 2.8 vs. 3.3 +/- 2.9, respectively, P = 0.076). Comparing CGH profiles between individual primary and metastasis pairs, we found that 10 of the 18 (56%) paired samples examined exhibited a high degree of CR, indicating that they were likely to have originated from the same clone and/or that not many additional chromosomal changes had occurred in the metastases, except for 4q loss, whose incidence was much higher in the metastases than in the primaries (60% vs. 10%; P = 0.030). Also, the primary tumors of the high-CR group carried more genomic aberrations, especially 8p loss, than did the primary tumors in the low-CR group. We found more chromosomal changes associated with the pulmonary metastases of colorectal cancer compared with the corresponding primary tumors. We concluded that primary cancers containing more genomic lesions, especially 8p losses, are more likely to metastasize to the lungs. Loss of 4q is potentially a supplementary factor contributing to the dissemination of this disease.     

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.     

Genetic alterations in epithelial ovarian tumors analyzed by comparative genomic hybridization

The genetic changes involved in the pathogenesis of ovarian carcinoma are not completely understood. To investigate this matter, we studied paraffin-embedded, microdissected tissue of 47 ovarian epithelial tumors (9 adenomas, 11 tumors of low malignant potential [LMP], 14 serous carcinomas, and 13 nonserous carcinomas) using comparative genomic hybridization (CGH). (The primary data used in this study are available at our CGH online tumor database at http://amba.charite.de/cgh.) Chromosomal imbalances were found in 1 serous adenoma and in 7 LMP tumors. In the latter the alterations appeared randomly and showed no overlap with alterations found in invasive carcinomas. Although the mean aberration number of low-grade serous carcinomas was comparable to LMP tumors, the imbalances of the former occurred with high incidence (>50%) and were found at different localizations. High-grade serous carcinomas had more than twice as much chromosomal imbalances as low-grade serous carcinomas and also had pronounced alterations. In serous carcinomas, gains were found on 3q, 6p, 7, 8q, and 20, and losses were found on 4q, 6q, 12q, 13q, and 16q. Comparing serous and nonserous carcinomas, the mean aberration number was comparable, but the number of high incidence changes was lower, and the most frequent imbalances were losses on 13q and gains on 20p. Overlapping alterations occurring in serous and nonserous carcinomas were gains on 3q and 6p, as well as losses on 4q. Chromosomal imbalances associated with poor prognosis of ovarian carcinomas were gains on 6p, 7q, and 13q and losses on 15q, 17p, 18q, and 21q. Our data indicate that serous LMP tumors and invasive carcinomas have different genetic aberrations, indicating that invasive carcinomas do not arise from preexisting serous LMP tumors. On the other hand, there are common genetic abnormalities in serous and nonserous carcinomas, suggesting that they have very early lesions in common but take different paths of further development.     

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.     

Detection of chromosomal aberrations in seminomatous germ cell tumours using comparative genomic hybridization

Comparative genomic hybridization (CGH) was used to evaluate tissue specimens from 16 seminomas in order to elucidate the pathogenesis of germ cell tumours in males. A characteristic pattern of losses and gains within the entire genomes was detected in 94% of the seminomas by comparing the ratio profiles of the tumours with a standard of cytogenetically normal genomic DNA. Losses represented 43% of the total number of alterations often affecting chromosomes and chromosome arms 4, 5, 11, 13q, and 18q. Gains amounted to 57% and were often observed on 1q, 7, 8, 12, 14q, 15q, 21q, and 22q. Aberrations of 12p and 21q appeared most consistently. Results from CGH analysis displayed no relationship to the clinical stages of the malignancy. Some rare aberrations appeared, however, only in clinical stage II and in tumours showing relapse in the contralateral testis following orchiectomy, although the alterations were not present in all of the tumours in question. Losses of 16q13-21 and gains of 9q22.1-22.2 were demonstrated in both groups, while loss of 16p12 and gains of 6p21 and 6q23.3-24 were detected in the latter group as well. In conclusion, a specific pattern of chromosomal alterations was demonstrated in the seminomas by improved detection criteria, which increased specificity and sensitivity. The rare aberrations, which appeared only in tumours in clinical stage II and relapsed tumours, may be linked to tumour progression, invasiveness, and bilateral disease. Genes Chromosomes Cancer 20:412–418, 1997. © 1997 Wiley-Liss, Inc.     

Comparison of chromosomal imbalances in neuroendocrine and non-small-cell lung carcinomas.

Lung carcinomas are represented by non-small-cell lung carcinomas (NSCLC) and neuroendocrine carcinomas (NE) which differ in their clinical presentation and prognosis. We used comparative genomic hybridization (CGH) to characterize and compare the chromosomal pattern of 11 NSCLC and 11 high-grade NE lung carcinomas. Overall, the total number of aberrations was higher in NSCLC than in high-grade NE lung tumors (p < 0.05) and gains predominated over losses in NSCLC (p < 0.0003). Gains common to both lung tumor phenotypes were detected in 1p, 1q, 3q, 5p, 6p, 8q, 12, 17q, 19p, 19q, 20p, 20q, and X, whereas common losses were found in 2q, 3p, 4p, 4q, 5q, 8p, 9p, 10p, 11p, 11q, 13q, and 17p. Major gains on 18q and losses on 2p and 16q were exclusively detected in high-grade NE lung tumors. On the other hand, major gains on 2p and 15q and losses on 21q were found only in NSCLC. Furthermore, gains within 22q11-q12 and 7p12-p15 were associated with NSCLC (p < 0.05). The differences in the pattern and distribution of genetic changes observed in NSCLC as opposed to high-grade NE lung carcinomas suggest the existence of distinct tumorigenic pathways between these two major classes of lung tumors.     

Genome-wide appraisal of thyroid cancer progression

Several lines of evidence suggest that follicular cell-derived thyroid cancers represent a continuum of disease that progresses from the highly curable well-differentiated thyroid cancers to the universally fatal anaplastic cancers. However, the genetic mechanisms underlying thyroid cancer progression remain ill defined. We compared the molecular-cytogenetic profiles derived from comparative genomic hybridization (CGH) analysis of major histological variants of thyroid cancer to define genetic variables associated with progression. Overall, a sequential increase in chromosomal complexity was observed from well-differentiated papillary thyroid cancer to poorly differentiated and anaplastic carcinomas, both in terms of the presence of CGH detectable abnormalities (P = 0.003) and the median number of abnormalities per case (P < 0.001). The presence of multiple abnormalities common to all thyroid cancer variants, including gains of 5p15, 5q11-13, 19p, and 19q and loss of 8p, suggests that these tumors are derived from a common genetic pathway. Gains of 1p34-36, 6p21, 9q34, 17q25, and 20q and losses of 1p11-p31, 2q32-33, 4q11-13, 6q21, and 13q21-31 may represent secondary events in progression, as they were only detected in poorly differentiated and anaplastic carcinomas. Finally, recurrent gains at 3p13-14 and 11q13, and loss of 5q11-31 were unique to anaplastic carcinomas, suggesting they may be markers for anaplastic transformation. Our data suggests that the development of chromosomal instability underlies the progression to more aggressive phenotypes of thyroid cancer and sheds light on the possible genomic aberrations that may be selected for during this process.     

Chromosome arm 20q gains and other genomic alterations in colorectal cancer metastatic to liver, as analyzed by comparative genomic hybridization and fluorescence in situ hybridization.

Comprehensive information about the molecular cytogenetic changes in metastases of colorectal cancer is not yet available. To define such changes in metastases, we measured relative DNA sequence copy numbers by comparative genomic hybridization (CGH). Samples from 27 liver metastases and 6 synchronous primary tumors were analyzed. An average of 9.9 aberrations per tumor was found in the metastases. Gains of chromosome arms 20q (85%), 13q (48%), 7p (44%), and 8q (44%) and losses of chromosome arms 18q (89%), 8p (59%), 1p (56%), and 18p (48%) were detected most frequently. Chromosomes 14 and 15 were lost in 26% and 30% of the metastases, respectively. No consistent differences were observed between primary tumors and synchronous metastases. Fluorescence in situ hybridization (FISH) was used for further characterization of gains of chromosome arm 20q. Touch preparations of 13 tumors that had demonstrated 20q gain with CGH were examined with FISH by use of a set of probes mapping to different parts of 20q. A probe for 20p was used as a reference. FISH showed relative gain of at least one 20q locus in 12 of the tumors. High-level gains were detected in 38% of the tumors, preferentially for probes mapping to band 20q13. Our CGH data indicate that colorectal metastases show chromosomal changes similar to those that have been reported for primary tumors. Chromosomal losses were seen at higher frequency, particularly for chromosomes 14 and 15. By FISH, we identified subregions on chromosome arm 20q that are frequently involved in DNA amplifications in colorectal cancer and that may harbor candidate proto-oncogenes.     

Single nucleotide polymorphism array profiling identifies distinct chromosomal aberration patterns across colorectal adenomas and carcinomas

The progression of benign colorectal adenomas into cancer is associated with the accumulation of chromosomal aberrations. Even though patterns and frequencies of chromosomal aberrations have been well established in colorectal carcinomas, corresponding patterns of aberrations in adenomas are less well documented. The aim of this study was to profile chromosomal aberrations across colorectal adenomas and carcinomas to provide a better insight into key changes during tumor initiation and progression. Single nucleotide polymorphism array analysis was performed on 216 colorectal tumor/normal matched pairs, comprising 60 adenomas and 156 carcinomas. While many chromosomal aberrations were specific to carcinomas, those with the highest frequency in carcinomas (amplification of chromosome 7, 13q, and 20q; deletion of 17p and chromosome 18; LOH of 1p, chromosome 4, 5q, 8p, 17p, chromosome 18, and 20p) were also identified in adenomas. Hierarchical clustering using chromosomal aberrations revealed three distinct subtypes. Interestingly, these subtypes were only partially dependent on tumor staging. A cluster of colorectal cancer patients with frequent chromosomal deletions had the least favorable prognosis, and a number of adenomas (n = 9) were also present in the cluster suggesting that, at least in some tumors, the chromosomal aberration pattern is determined at a very early stage of tumor formation. Finally, analysis of LOH events revealed that copy‐neutral/gain LOH (CN/G‐LOH) is frequent (>10%) in carcinomas at 5q, 11q, 15q, 17p, chromosome 18, 20p, and 22q. Deletion of the corresponding region is sometimes present in adenomas, suggesting that LOH at these loci may play an important role in tumor initiation. © 2015 Wiley Periodicals, Inc.     

Recurrent genetic alterations in 26 colorectal carcinomas and 21 adenomas from Chinese patients

Colorectal cancer (CRC) is one of the most common malignancies worldwide. The incidence of CRC in the Chinese population has increased dramatically during the last two decades; however, nonrandom chromosomal alterations in Chinese patients have not been described. In the present study, comparative genomic hybridization (CGH) was applied to detect recurrent chromosome alterations in 26 primary colorectal carcinomas and 21 colorectal adenomas from Chinese patients. In CRC, several recurrent chromosomal changes were found, including gains of 8q (14/26 cases, 54%), 20q (54%), 3q (50%), 13q (50%), 5p (46%), 7p (42%), 7q (42%), and 12p (38%) and losses of 18q (65%) and 17p (42%). From comparison with previous CGH studies, the frequent gains of 3q and 12p might be distinctive occurrences in Chinese patients. The distribution of frequently found chromosomal alterations in different locations was studied. The gain of 20q was more frequently found in colon cancer (P<0.01) and the gain of 12p was more frequently found in rectal cancer. Chromosomal alterations were found in 19/21 of adenomas; the most frequent chromosomal alteration was the loss of 18q (9/21 cases, 43%). These recurrent alterations provide several starting points for the isolation of candidate oncogenes and tumor suppressor genes.     

Patterns of chromosomal imbalances in parathyroid carcinomas

In this study we have characterized chromosomal imbalances in a panel of 29 parathyroid carcinomas using comparative genomic hybridization (CGH). The most frequently detected imbalances were losses of 1p and 13q that were seen in >40% of the cases. The commonly occurring regions of loss were assigned to 1p21-p22 (41%), 13q14-q31 (41%), 9p21-pter (28%), 6q22-q24 (24%), and 4q24 (21%), whereas gains preferentially involved 19p (45%), Xc-q13 (28%), 9q33-qter (24%), 1q31-q32 (21%) and 16p (21%). The distribution of CGH alterations supports the idea of a progression of genetic events in the development of parathyroid carcinoma, where gains of Xq and 1q would represent relatively early events that are followed by loss of 13q, 9p, and 1p, and by gain of 19p. A sex-dependent distribution was also evident for two of the common alterations with preferential gain of 1q in female cases and of Xq in male cases. When the CGH profiles for the 29 carcinomas were compared with our previously published results for sporadic parathyroid adenomas, highly significant differences were revealed. Loss of 1p, 4q, and 13q as well as gains of 1q, 9q, 16p, 19p and Xq were significantly more common in the carcinomas than in the adenomas. In contrast, loss of the 11q13 region, which is the most common CGH abnormality in sporadic adenomas, was not detected in any of the carcinomas. Taken together, the findings identify several candidate locations for tumor suppressor genes and oncogenes that are potentially involved in parathyroid carcinogenesis.     

Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high-level amplifications

Distinction of adrenocortical carcinoma from benign adrenocortical lesions by standard criteria is often difficult. In order to search for additional diagnostic parameters, a series of 25 adrenocortical tumors, 8 adenomas, 14 primary carcinomas, 1 metastasis, and the 2 adrenocortical carcinoma cell lines SW13 and NCI-H295 were analyzed by the approach of comparative genomic hybridization (CGH). Except for the two smallest adenomas, all tumors showed chromosomal imbalances with a high incidence of chromosomal gains, most frequently involving chromosomes or chromosome arms 5, 7, 8, 9q, 11q, 12q, 14q, 16, 17q, 19, 20, and 22q. The only significant loss of material concerned the distal part of 9p. Furthermore, 21 high-level amplifications were identified in 15 different regions of the genome. The consensus regions of recurrent gains and the focal high-level amplifications allowed identification of a series of chromosomal subregions containing candidate proto-oncogenes of potential pathogenic function in adrenocortical tumors: 1p34.3-pter, 1q22-q25, 3p24-pter, 3q29, 7p11.2-p14, 9q34, 11q12-11q13, 12q13, 12q24.3, 13q34, 14q11.2-q12, 14q32, 16p, 17q24-q25, 19p13.3, 19q13.4, and 22q11.2-q12. A subset of the CGH data was independently confirmed by interphase cytogenetics. Interestingly, the adenomas larger than 4 cm contained gained material of regions also overrepresented in carcinomas. In addition, several chromosomal gains, in particular the high-level amplifications, were exclusive for the malignant status of the tumors. These data indicate that the larger adrenal lesions need to be carefully considered in the diagnosis of adrenocortical tumors, and that genetic aberrations might provide useful markers for a better diagnostic differentiation.