Analysis of genetic alterations in primary nasopharyngeal carcinoma by comparative genomic hybridization

To identify genetic alterations associated with the development and progression of human nasopharyngeal carcinoma (NPC), 57 tumors were analyzed by comparative genomic hybridization (CGH). In 47 cases, chromosomal imbalances were found. Several recurrent chromosomal abnormalities were identified in the present study. The most frequently detected chromosomal gains involved chromosome arms 12q (24 cases, 51%), 4q (17 cases, 36%), 3q (16 cases, 34%), 1q (15 cases, 32%), and 18q (15 cases, 32%). Common regions of gain involved 12q13--q15, 4q12--q21, and 3q21--q26. High-copy-number increases of chromosomal materials were detected in four chromosomal regions, 3q21--q26.2, 4p12--q21, 8p, and 12q14--q15. The most frequently detected loss of chromosomal materials involved chromosome arms 16q (26 cases, 55%), 14q (21 cases, 45%), 1p (20 cases, 43%), 3p (20 cases, 43%), 16p (19 cases, 40%), 11q (17 cases, 36%), and 19p (16 cases, 34%). The most common regions of loss involved 14q24--qter, 1pter--p36.1, 3p22--p21.3, 11q21--qter, and the distal region of 19p. Genomic alterations detected by CGH were compared and found to be largely consistent with those identified in banding analysis and loss of heterozygosity studies. However, several previously unrecognized recurrent alterations were also identified in the present study, including gain of 4q and 18q, and loss of 16q, 14q, and 19p. In addition, gain of 1q, 8q, 18q, and loss of 9q showed a statistically significant association with advanced clinical stages (P < 0.05). Identification of recurrent sites of chromosomal gain and loss identify regions of the genome that may contain oncogenes or tumor suppressor genes, respectively, which may be involved in the tumorigenesis of NPC. Published 2000 Wiley-Liss, Inc.     

Classical Hodgkin lymphoma is associated with frequent gains of 17q

The etiology of Hodgkin lymphoma (HL) is poorly understood, and studies of the genetics of this disease have been hampered by the scarcity of the Hodgkin and Reed-Sternberg (HRS) cells within tumors. To determine whether recurrent genomic imbalances are a feature of HL, CD30-positive HRS cells were laser-microdissected from 20 classical Hodgkin lymphomas (cHLs) and four HL-derived cells lines and subjected to analyses by comparative genomic hybridization. In primary tumors, the most frequently involved chromosomal gains were 17q (70%), 2p (40%), 12q (40%), 17p (40%), 22q (35%), 9p (30%), 14q (30%), and 16p (30%), with minimal overlapping regions at 17q21, 2p23-13, 12q24, 17p13, 22q13, 9p24-23, 14q32, 16p13.3, and 16p11.2. The most frequent losses involved 13q (35%), 6q (30%), 11q (25%), and 4q (25%), with corresponding minimal overlapping regions at 13q21, 6q22, 11q22, and 4q32. Statistical analysis revealed significantly more gains of 2p and 14q in the older adult cases; loss of 13q was associated with a poor outcome. The results suggest that there is a set of recurrent chromosomal abnormalities associated with cHL and provide further evidence that cHL is genetically distinct from nodular lymphocyte predominance Hodgkin lymphoma (NLPHL). Abnormalities of 17q are infrequent in other lymphomas or NLPHL; this finding, coupled with current knowledge of gene expression in cHL, suggests that genes present on 17q may play an important role in the pathogenesis of cHL.     

DNA Copy Number Losses in Human Neoplasms

This review summarizes reports of recurrent DNA sequence copy number losses in human neoplasms detected by comparative genomic hybridization. Recurrent losses that affect each of the chromosome arms in 73 tumor types are tabulated from 169 reports. The tables are available online at http://www.amjpathol.org and http://www. helsinki.fi/ approximately lglvwww/CMG.html. The genes relevant to the lost regions are discussed for each of the chromosomes. The review is supplemented also by a list of known and putative tumor suppressor genes and DNA repair genes (see Table 1, online). Losses are found in all chromosome arms, but they seem to be relatively rare at 1q, 2p, 3q, 5p, 6p, 7p, 7q, 8q, 12p, and 20q. Losses and their minimal common overlapping areas that were present in a great proportion of the 73 tumor entities reported in Table 2 (see online) are (in descending order of frequency): 9p23-p24 (48%), 13q21 (47%), 6q16 (44%), 6q26-q27 (44%), 8p23 (37%), 18q22-q23 (37%), 17p12-p13 (34%), 1p36.1 (34%), 11q23 (33%), 1p22 (32%), 4q32-qter (31%), 14q22-q23 (25%), 10q23 (25%), 10q25-qter (25%),15q21 (23%), 16q22 (23%), 5q21 (23%), 3p12-p14 (22%), 22q12 (22%), Xp21 (21%), Xq21 (21%), and 10p12 (20%). The frequency of losses at chromosomes 7 and 20 was less than 10% in all tumors. The chromosomal regions in which the most frequent losses are found implicate locations of essential tumor suppressor genes and DNA repair genes that may be involved in the pathogenesis of several tumor types.     

Loss of chromosome 13 is the most frequent genomic imbalance in malignant fibrous histiocytomas. A comparative genomic hybridization analysis of a series of 30 cases.

Regional chromosome localizations of DNA copy number imbalances were studied by comparative genomic hybridization in 30 malignant fibrous histiocytomas: 13 primary tumors (2 myxoid, 9 storiform pleomorphic, and 2 with more undifferentiated phenotype) and 17 local recurrences (2 myxoid, 11 storiform pleomorphic, and 4 with more undifferentiated phenotype). Abnormal comparative genomic hybridization (CGH) profiles were observed in 25 tumors (83%). The most frequent gains (ratio > 1.2) corresponded, by order of frequency, to entire Xp, and bands 1q21, 19q13.1, 19p13, 5p13-p14, 1p31, 17p, 18p, 20q, 1p35, 17q23, and 22q12. High levels of gains (ratio > 1.5) were recurrently detected for Xp (10 cases), and in bands 1q21-q22 (8 cases), 3q27 (4 cases), 5p13-p14 (3 cases), 13q32-q34 (3 cases), 15q22-q26 (3 cases), and 17p11-p12 (3 cases). Losses of 13q12-q14 or 13q21 were observed in a large proportion of tumors (17 cases), suggesting that a gene localized in this region could act as a tumor suppressor gene. Losses of 11q23, 2q32, 11p13, 10p, 1q4, 9p2, 16q12, 4q3, 10q25, 3p23, 2p24, and 12p were also recurrently observed. Taken together, these results provide an overview of chromosome imbalances present in MFH, which could be of use for diagnostic purposes. They point to various chromosome regions which may harbor genes important for malignant fibrous histiocytomas (MFH) oncogenesis and progression.     

Advanced-stage cervical carcinomas are defined by a recurrent pattern of chromosomal aberrations revealing high genetic instability and a consistent gain of chromosome arm 3q

We have analyzed 30 cases of advanced-stage cervical squamous cell carcinoma (stages IIb–IV) by comparative genomic hybridization (CGH). The most consistent chromosomal gain in the aneuploid tumors was mapped to chromosome arm 3q in 77% of the cases. Acquisition of genetic material also occurred frequently on 1q (47%), 5p (30%), 6p (27%), and 20 (23%). Recurrent losses were mapped on 2q (33%), 3p (50%), 4 (33%), 8p (23%), and 13q (27%). High-level copy number increases were mapped to chromosome 8, chromosome arms 3q, 5p, 8q, 12p, 14q, 17q, 19q, 20p, and 20q, and chromosomal bands 3q26-27, 9p23-24, 11q22-23, and 12p13. In the majority of the cases, the presence of high-risk human papilloma virus genomes was detected. High proliferative activity was accompanied by crude aneuploidy. Increased p21/WAF-1 activity, but low or undetectable expression of TP53 were representative for the immunophenotype. This study confirms the importance of a gain of chromosome arm 3q in cervical carcinogenesis and identifies additional, recurrent chromosomal aberrations that are required for progression from stage I tumors to advanced-stage carcinomas. Genes Chromosom. Cancer 19:233–240, 1997. Published 1997 Wiley-Liss, Inc.     

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

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

Genomic profiling of peripheral T-cell lymphoma, unspecified, and anaplastic large T-cell lymphoma delineates novel recurrent chromosomal alterations

To characterize genetic alterations in peripheral T-cell lymphoma, not otherwise specified (PTCL NOS), and anaplastic large T-cell lymphoma (ALCL), 42 PTCL NOS and 37 ALCL [17 anaplastic large cell kinase (ALK)-negative ALCL, 9 ALK-positive ALCL, 11 cutaneous ALCL] were analyzed by comparative genomic hybridization. Among 36 de novo PTCL NOS, recurrent chromosomal losses were found on chromosomes 13q (minimally overlapping region 13q21, 36% of cases), 6q and 9p (6q21 and 9p21-pter, in 31% of cases each), 10q and 12q (10q23-24 and 12q21-q22, in 28% of cases each), and 5q (5q21, 25% of cases). Recurrent gains were found on chromosome 7q22-qter (31% of cases). In 11 PTCL NOS, high-level amplifications were observed, among them 3 cases with amplification of 12p13 that was restricted to cytotoxic PTCL NOS. Whereas cutaneous ALCL and ALK-positive ALCL showed few recurrent chromosomal imbalances, ALK-negative ALCL displayed recurrent chromosomal gains of 1q (1q41-qter, 46%), and losses of 6q (6q21, 31%) and 13q (13q21-q22, 23%). Losses of chromosomes 5q, 10q, and 12q characterized a group of noncytotoxic nodal CD5+ peripheral T-cell lymphomas. The genetics of PTCL NOS and ALK-negative ALCL differ from other T-NHLs characterized genetically so far, among them enteropathy-type T-cell lymphoma, T-cell prolymphocytic leukemia, and adult T-cell lymphoma/leukemia.     

Construction of tree models for pathogenesis of nasopharyngeal carcinoma

Pathogenesis of nasopharyngeal carcinoma (NPC) is a multistep and multipathway process that cannot be fully explained by a fixed linear progression model. We used distance-based and branching-tree methods to construct more general tree-like models for NPC carcinogenesis from 170 comparative genomic hybridization (CGH) samples previously published in five smaller studies. Imbalances were classified into "overlap regions," each containing the most commonly gained or lost band on each chromosome arm as well as adjacent bands that were gained or lost almost as often. The chromosome abnormalities associated with NPC were -3p26-13 (48.9%), -11q22-25 (38.1%), -16q12-24 (38.1%), -14q24-32 (32.4%), -13q21-32 (22.3%), -9p23-21(21.6%), +12p12 (46%), +12q13-15 (43.9%), +1q22-32 (33.1%), +3q13.1-26.2 (30.2%), and +8q22.1-24.2 (27.3%). NPC can be classified into two groups, one marked by +12p12 and +8q22.1-24.2 and the other by -3p26-13, -11q22-25, -14q24-32, and +1q22-32. The tree models predicted -3p26-13 and +12p12 as early events and +8q22.1-24.2 as a late event. The predictions for -3p26-13 and +8q22.1-24.2 were consistent with previous studies. The prediction for +12p12 is being reported for the first time. Many known NPC-related genes on chromosomal regions of these tree models are discussed, some of which may merit additional study. The potential applications of tree models are also discussed.     

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.     

Molecular cytogenetic definition of three distinct chromosome arm 14q deletion intervals in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms characterized by frequent chromosome arm 14q losses. In this study, the 14q changes in a series of 39 histologically and immunohistochemically confirmed GISTs were analyzed in detail by metaphase and/or interphase fluorescence in situ hybridization (FISH) studies using 21 genetically well-characterized, region-specific 14q11-24 YAC clones. By conventional cytogenetic analysis, acquired clonal chromosome aberrations were found in 17 out of 35 tumors. Chromosome 14 was involved in 13 cases; six specimens showed complete chromosome 14 loss, while the remaining seven had structural abnormalities with the breakpoints residing within the intervals 14q11-13 or 14q22-24. Other recurrent chromosome aberrations included frequent deletions of chromosome 1p (11/17), losses of chromosome 22 (7/17), losses or deletions of chromosome arm 13 (6/17) or 15 (4/17), and gains or translocations involving chromosome 17 (4/17). Combining cytogenetic data with double-color FISH analysis, total or partial losses of 14q material were detected in 29 out of 36 tumors (81%). The 14q losses were found in all stages and histological subtypes. Two most frequent common deletion regions flanked by YACs 931B1 and 761D4, and 802E7 and 892C11 at 14q23-24 (25/30 of each; 83%) could be identified. Furthermore, 21 tumors (70%) shared a region of deletion defined by YACs 957H10 and 931E5 at 14q11-12. Our results suggest the presence of at least three distinct critical deletion regions on chromosome 14 in GISTs.     

Clinical implications of chromosomal abnormalities in gastric adenocarcinomas

Gastric carcinoma (GC) is one of the most common malignancies worldwide and has a very poor prognosis. Genetic imbalances in 62 primary gastric adenocarcinomas of various histopathologic types and pathologic stages and six gastric cancer-derived cell lines were analyzed by comparative genomic hybridization, and the relationship of genomic abnormalities to clinical features in primary GC was evaluated at a genome-wide level. Eighty-four percent of the tumors and all six cell lines showed DNA copy number changes. The recurrent chromosomal abnormalities including gains at 15 regions and losses at 8 regions were identified. Statistical analyses revealed that gains at 17q24-qter (53%), 20q13-qter (48%), 1p32-p36 (42%), 22q12-qter (27%), 17p13-pter (24%), 16p13-pter (21%), 6p21-pter (19%), 20p12-pter (19%), 7p21-pter (18%), 3q28-qter (8%), and 13q13-q14 (8%), and losses at 18q12-qter (11%), 3p12 (8%), 3p25-pter (8%), 5q14-q23 (8%), and 9p21-p23 (5%), are associated with unique patient or tumor-related features. GCs of differing histopathologic features were shown to be associated with distinct patterns of genetic alterations, supporting the notion that they evolve through distinct genetic pathways. Metastatic tumors were also associated with specific genetic changes. These regions may harbor candidate genes involved in the pathogenesis of this malignancy.     

Karyotypic characterization of urinary bladder transitional cell carcinomas

Samples from 34 primary transitional cell carcinomas (TCCs) of the bladder were short-term-cultured and processed for cytogenetic analysis after G-banding of the chromosomes. Clonal chromosome abnormalities were detected in 27 tumors and normal karyotypes in 3, and the cultures from 4 tumors failed to grow. Losses of genetic material were more common than gains, indicating that loss of tumor suppressor genes may be of major importance in TCC pathogenesis. There was no clonal heterogeneity within individual tumors, consonant with the view that TCCs are monoclonal in origin. The most striking finding was the involvement of chromosome 9 in 92% of the informative cases, as numerical loss of one chromosome copy in 15 cases, but as structural rearrangement in 8. The changes in chromosome 9 always led to loss of material; from 9p, from 9q, or of the entire chromosome. A total of 16 recurrent, unbalanced structural rearrangements were seen, of which del(1)(p11), add(3)(q21), add(5)(q11), del(6)(q13), add(7)(q11), add(11)(p11), i(13)(q10), del(14)(q24), and i(17)(q10) are described here for the first time. The karyotypic imbalances were dominated by losses of the entire or parts of chromosome arms 1p, 9p, 9q, 11p, 13p, and 17p, loss of an entire copy of chromosomes 9, 14, 16, 18, and the Y chromosome, and gains of chromosome arms 1q and 13q and of chromosomes 7 and 20. The chromosome bands and centomeric breakpoints preferentially involved in structural rearrangements were 1q12, 2q11, 5q11, 8q24, 9p13, 9q13, 9q22, 11p11, and 13p10. Rearrangements of 17p and the formation of an i(5)(p10) were associated with more aggressive tumor phenotypes. There was also a general correlation between the tumors' grade/stage and karyotypic complexity, indicating that progressive accumulation of acquired genetic alterations is the driving force behind multistep bladder TCC carcinogenesis.     

Molecular cytogenetic abnormalities in multiple myeloma and plasma cell leukemia measured using comparative genomic hybridization

Comparative genomic hybridization (CGH) was used to identify recurrent regions of DNA sequence loss and gain in 21 multiple myeloma (MM) and plasma cell leukemia (PCL) primary tumor specimens and cell lines. Multiple regions of non-random sequence loss and gain were observed in 8/8 primary advanced stage tumors and 13/13 cell lines. Identification of sequence copy number changes was facilitated by statistical analyses that reduce subjectivity associated with identification of copy number changes and by requiring that sequence changes are visible using both red- and green-labeled tumor DNA. Loss of sequence on 13q and 14q and gain of sequence on 1q and chromosome 7 occurred in 50–60% of the population. In general, cell lines carry more and larger regions of sequence gain and loss than primary tumors. Regions of sequence copy number change that recur among MM cell lines and primary tumors include, in order of prevalence, enh(1q12qter), dim(13), enh(7), enh(3q22q29), enh(11q13.3qter), dim(14q11.2q31), enh(8q21qter), enh(3p25pter), dim(17p11.2p13), and dim(6q22.1q23). Population distributions of genome-wide changes in primary tumors reveal “hot-spots” of sequence loss from 13q12.1-q21, 13q32-q34, 14q11.2-q13, and 14q23-q31. Genomic changes detected using CGH are consistent with those identified using banding analyses, although recurrent involvement of additional regions of the genome are also evident. A higher prevalence of genomic changes is visible using CGH compared to banding. Identification of recurrent regions of sequence gain and loss provides opportunities to identify regions of the genome that may be involved in the malignant phenotype and/or disease progression. Genes Chromosom. Cancer 19:124–133, 1997. © 1997 Wiley-Liss, Inc.     

Common genetic changes in hereditary and sporadic pituitary adenomas detected by comparative genomic hybridization

Twenty-four pituitary adenomas, both the sporadic type (n = 18) and the type arising in association with either multiple endocrine neoplasia, type 1 (MEN1; n = 2), or Carney complex (CNC, n = 4) were analyzed by comparative genomic hybridization. Twenty-one (88%) tumors displayed chromosomal alterations. The number of chromosomal aberrations in each tumor varied from 2 to greater than 10. Several recurrent chromosomal abnormalities were identified in this study. The most frequently detected losses of chromosomal material involved 1p (14 of 24, 58%), 11p (11 of 24, 46%), 17 (10 of 24, 42%), 16p (9 of 24, 38%), 4 (8 of 24, 33%), 10p (6 of 24, 25%), 12 (6 of 24, 25%), 20 (6 of 24, 25%), 22q (6 of 24, 25%), 13q (5 of 24, 21%), and 9p (4 of 24, 17%). Copy number increases were detected on 4q (7 of 24, 29%), 17 (8 of 24, 33%), 19 (7 of 24, 29%), 1p (6 of 24, 25%), 5 (6 of 24, 25%), 20 (6 of 24, 25%), 6q (5 of 24, 21%), 13q21-qter (5 of 24, 21%), and 16p (5 of 24, 21%). Chromosome 11 loss, which involved 11p in all cases, was the most significant finding and was common to tumors arising sporadically and in association with MEN1 and CNC. In addition, the majority of the tumors (18 of 24, 75% overall and 86% of all tumors with chromosomal abnormalities) showed involvement of chromosome 1. Tumors had either loss (14 of 24, 58%) or gain (6 of 24, 25%) in the 1p32-1pter region. Finally, changes on chromosome 17, either loss or gain, occurred in 71% (17) of all 24 patients. In summary, all the tumors with chromosomal rearrangements (21 of 24, 88%), whether sporadic pituitary adenomas or those associated with MEN1 or CNC, had alteration(s) of 1p32, 11p, or 17.     

Leiomyosarcomas and most malignant fibrous histiocytomas share very similar comparative genomic hybridization imbalances: an analysis of a series of 27 leiomyosarcomas

Twenty-seven tumor samples with a diagnosis of leiomyosarcomas (LMS) were characterized by comparative genomic hybridization. The results were compared with immunohistochemical analysis of the smooth muscle profile of the tumors and expression of the RB1 gene protein. The comparative genomic hybridization profiles suggested that 7 of the 27 tumors might have been misclassified. High levels of DNA amplification were detected in 20 different small regions and recurrently involved bands 1p34, q21, 12q13-15, 17p, and 22q. Most recurrent simple gains were noted at sites such as 1p3, 1q21, 15q12-15, 16p, 17p and 17q, 19, 20q, 22q, and Xp. Significant losses of chromosome 13 were detected in 19 of the 27 tumors with a putative common region of loss in bands 13q14-21. Losses of chromosomes 1q, 2p and 2q, 4q, 9p, 10p and 10q, 11p and 11q23, and 16q were also highly recurrent. A comparative analysis between the most frequent genomic imbalances observed in this study of LMS and the genomic imbalances observed in a large proportion of malignant fibrous histiocytomas (MFH) from a previous study demonstrated that both types of tumors had similar recurrent imbalances. Although MFH were once thought to be a separate member of the soft tissue sarcoma family, our observations support the hypothesis that MFH are a morphologic modulation in the tumoral progression of other sarcomas, particularly LMS.     

Chromosomal alterations in human pancreatic endocrine tumors

Comparative genomic hybridization (CGH) was used to investigate changes in DNA copy numbers in 25 paraffin-embedded samples of pancreatic endocrine tumors from 23 patients. Insulin was the dominant hormone in 12, glucagon in 7, somatostatin in 1, and pancreatic polypeptide in 2 tumors. One to 15 (mean, 8.1) changes in DNA copy numbers were observed in 22 of the 25 tumors. The most recurrent aberration, found in 68% of the tumors, involved gains in chromosome 7 with a minimal overlapping region at 7q11.2. Other frequent gains included chromosomes 19 (60%) and 14 (56%). Chromosome arm 20q was amplified in 48% of the cases with the minimal overlapping region of 20q11.1-13.1. The two most frequent DNA losses were found at 11q21-22 in 32% and at 11p13-15 in 24% of the cases. The amplified chromosomal regions contain several candidate genes that may be involved in islet cell tumorigenesis. The regions with most frequent losses are likely to contain still uncharacterized tumor suppressor genes. Wiley-Liss, Inc.     

Comparative genomic hybridization analysis of sporadic neuroendocrine tumors of the digestive system

Little information is available on the molecular mechanisms underlying neuroendocrine tumorigenesis. To obtain an overview of the genomic imbalances characterizing these tumors, we studied 20 benign or malignant sporadic endocrine gastroenteropancreatic tumors by comparative genomic hybridization. Chromosomal imbalances were found in all tumors. Gains of chromosomal material were more frequent than losses. The most frequent gains were of chromosomes and chromosome arms 5 (55%), 14 (55%), 17q (55%), and 7 (50%). Losses were most frequent from 11q (30%) and 16p (30%). Gains of chromosome 5 did not occur in nonmetastatic tumors, whereas losses of 9p were observed exclusively in intestinal tumors. In addition, we found two high-level amplifications, of 17q11–21 and 19q13. A complementary FISH analysis revealed that the gain in 17q11–21 included amplification of the protooncogene HER2/neu. As in multiple endocrine neoplasia type-1-associated tumors, deletions of chromosome band 11q13 appear to be involved in the development of sporadic digestive tract neuroendocrine tumors, but our results suggest that other chromosomal regions are also involved. Genes Chromosomes Cancer 22:50–56, 1998. © 1998 Wiley-Liss, Inc.     

Cytogenetic patterns in ETV6/RUNX1-positive pediatric B-cell precursor acute lymphoblastic leukemia: A Nordic series of 245 cases and review of the literature

Between 1992 and 2004, 1,140 children (1 to<15 years) were diagnosed with B-cell precursor acute lymphoblastic leukemia (ALL) in the Nordic countries. Of these, 288 (25%) were positive for t(12;21)(p13;q22) [ETV6/RUNX1]. G-banding analyses were successful in 245 (85%); 43 (15%) were karyotypic failures. The modal chromosome numbers, incidence, types, and numbers of additional abnormalities, genomic imbalances, and chromosomal breakpoints in the 245 karyotypically informative cases, as well as in 152 previously reported cytogenetically characterized t(12;21)-positive ALLs in the same age group, were ascertained. The most common modal numbers among the 397 cases were 46 (67%), 47 (16%), 48 (6%), and 45 (5%). High-hyperdiploidy, triploidy, and tetraploidy were each found in approximately 1%; none had less than 40 chromosomes. Secondary chromosomal abnormalities were identified by chromosome banding in 248 (62%) of the 397 ALLs. Of these, 172 (69%) displayed only unbalanced changes, 14 (6%) only balanced aberrations, and 26 (10%) harbored both unbalanced and balanced abnormalities; 36 (15%) were uninformative because of incomplete karyotypes. The numbers of secondary changes varied between 1 and 19, with a median of 2 additional aberrations per cytogenetically abnormal case. The most frequent genomic imbalances were deletions of 6q21-27 (18%), 8p11-23 (6%), 9p13-24 (7%), 11q23-25 (6%), 12p11-13 (27%), 13q14-34 (7%), loss of the X chromosome (8%), and gains of 10 (9%), 16 (6%), and 21 (29%); no frequent partial gains were noted. The chromosome bands most often involved in structural rearrangements were 3p21 (2%), 5q13 (2%), 6q12 (2%), 6q14 (2%), 6q16 (2%), 6q21 (10%), 6q23 (6%), 6q25 (3%), 9p13 (2%), 11q13 (2%), 11q23 (2%), 12p11 (6%), 12p12 (7%), 12p13 (25%), 21q10 (6%), and 21q22 (6%). Considering that the t(12;21) is known to arise in utero and that the postnatal latency period is protracted, additional mutations are most likely necessary for overt ALL. The frequently rearranged chromosome regions may harbor genes of importance for the transformation and/or progression of an initial preleukemic t(12;21)-positive clone.     

Molecular genetic alterations in carcinoma ex-pleomorphic adenoma: a putative progression model?

To determine the genetic changes associated with the development of carcinoma ex-pleomorphic adenoma (Ca Ex-PA), we analyzed 15 microsatellite loci at chromosome arms 8q, 12q, and 17p on DNA from 26 neoplasms (including 8 microdissected benign and malignant components), and 13 pleomorphic adenomas for comparison. Pleomorphic adenomas and the adenoma component of Ca Ex-PAs showed a higher incidence of loss of heterozygosity (LOH) at chromosome arms 8q (52%) and 12q (28%) than at 17p (14%) loci. In the carcinoma component, the combined LOH at chromosome arm 8q, 12q, and 17p regions was 69%, 50%, and 69%, respectively; within these chromosomal regions, 8q11.23-q12 (42%), 12q23-qter (39%), 17p13 (41%), and 17p11 (45%) loci manifested the highest incidence of LOH. Eight carcinomas (30.7%) showed loss at all three chromosomal arms tested. Of the eight microdissected Ca Ex-PAs analyzed, four adenoma and corresponding carcinoma components (50%) had the same LOH at 12q loci and additional LOH at 17p loci only in carcinomas. Chromosome arm 17p alterations correlated significantly with high disease stage and an increased proliferative rate in these tumors. Our results indicate that alterations at regions on chromosome arms 8q and/or 12q may constitute early events associated with pleomorphic adenomas; that LOH at 12q loci may identify a subset of adenoma with potential progression to carcinoma; that acquisition of additional alterations at chromosome arm 17p loci might represent an event preceding malignant transformation and progression; and that 8q, 12q, and 17p regions may harbor tumor suppressor genes involved in the genesis of PA and Ca Ex-PA. Genes Chromosomes Cancer 27:162-168, 2000.