Comparative genomic hybridization analysis of genetic aberrations associated with development of esophageal squamous cell carcinoma in Henan, China

AIM： To characterize cytogenetic alterations in esophageal squamous cell carcinoma （ESCC） and its metastasis. METHODS： A total of 37 cases of primary ESCC and 15 pairs of primary ESCC tumors and their matched metastatic lymph nodes cases were enrolled from Linzhou, the high incidence area for ESCC in Henan, northern China. The comparative genomic hybridization （CGH） was applied to determine the chromosomal aberrations on the DNA extracted from the frozen ESCC and metastatic lymph node samples from these patients. RESULTS： CGH showed chromosomal aberrations in all the cases. In 37 cases of primary ESCC, chromosomal profile of DNA copy number was characterized by frequently detected gains at 8q （29/37, 78%）, 3q （24/37, 65%）, 5p （19/37, 51%）; and frequently detected losses at 3p （21/37, 57%）, 8p and 9q （14/37, 38%）. In 15 pairs of primary ESCC tumors and their matched metastatic lymph node cases, the majority of the chromosomal aberrations in both primary tumor and metastatic lymph node lesions were consistent with the primary ESCC cases, but new candidate regions of interest were also detected. The most significant finding is the gains of chromosome 6p with a minimum high-level amplification region at 6p12-6q12 in 7 metastatic lymph nodes but only in 2 corresponding primary tumors （P = 0.05） and 20p with a minimum high-level amplification region at 20p12 in 11 metastatic lymph nodes but only in 5 corresponding primary tumors （P 〈 0.05）. Another interesting finding is the loss of chromosome 10p and 10q in 8 and 7 metastatic lymph nodes but only in 2 corresponding primary tumors （P 〈 0.05）. CONCLUSION： Using the CGH technique to detect chromosomal aberrations in both the primary tumor and its metastatic lymph nodes of ESCC, gains of 8q, 3q and 5p and loss of 3p, 8p, 9q and 13q were specifically implicated in ESCC in Linzhou population. Gains of 6p and 20p and loss of 10pq may contribute to the lymph node metastasis of ESCC. These findings suggest that the gains and     

Comparative genomic hybridization study of de novo myeloid neoplasia

Comparative genomic hybridization (CGH) was used to detect chromosomal imbalances in 20 patients with a diagnosis of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). The results obtained were compared with G-banding analysis. This last methodology showed 50% of cases with clonal abnormalities whereas CGH detected 70% of cases with copy number changes. Gains were more frequent than losses and constituted 66% of total changes detected. The most common gains included chromosomes 21 and chromosome region 18p for AML and chromosome 17 and region 1p33p35 for MDS. Losses represent 34% of changes and the regions involved were 5q31q32, 7q22, 7p12 and 13q21q22. CGH revealed additional chromosome imbalances in 12 of 20 cases (60%) which were not detected by traditional cytogenetic studies, demonstrating complex karyotype in 50% (6/12). Combination of CGH and G-banding provides an efficient method to identify critical regions present in the malignant clone, which is of great value in the prognosis and outcome of myeloid neoplasias.     

Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation

BACKGROUND: Chromosomal instability is observed in a wide spectrum of human cancer syndromes. However, to date, little is known of the characteristic genetic changes in sporadic neuroendocrine tumours of the gastroenteropancreatic system. AIMS AND METHOD: We have studied copy number aberrations (CNAs) in 26 sporadic neuroendocrine tumours of the enteropancreatic system (12 foregut and 14 midgut tumours) by comparative genomic hybridisation (CGH), allowing simultaneous evaluation of the entire tumour genome. RESULTS: Nearly all tumours (25/26; that is, 96%) showed chromosomal imbalances, including full chromosomal aneuploidies, losses and gains of chromosome arms, interstitial deletions, and amplifications. Whereas gains of chromosomes 4, 5, and 19 were found in both foregut and midgut tumours, gains of chromosomes 20q (58%), 19 (50%), as well as 17p (50%), and partial losses of chromosomes 1p (42%), 2q (42%), 3p, 4q, and 6q (25% each) were frequently observed only in foregut tumours. In contrast, midgut tumours displayed less CNAs. Gains were detected for chromosomes 17q and 19p (57%). Most frequent losses affected chromosomes 18 (43%) and 9p (21%). CONCLUSIONS: The results of our CGH analyses revealed new distinct candidate regions in the human genome associated with sporadic neuroendocrine tumours. Some of the genetic alterations were shared by foregut and midgut tumours while others discriminated between the two groups. Thus our results allude to the involvement of identical as well as discriminative genetic loci in tumorigenesis and progression of neuroendocrine neoplasms of the foregut and midgut. Based on these findings potential new candidate genes will be discussed.     

Chromosome 8p deletion is associated with metastasis of human hepatocellular carcinoma when high and low metastatic models are compared

Recently, we found that chromosome 8p deletion might be associated with hepatocellular carcinoma (HCC) metastasis by analyzing the differences in chromosomal alterations between primary tumors and their matched metastatic lesions of HCC with comparative genomic hybridization (CGH) (Qin et al. 1999). To further confirm this interesting finding, the genomic changes of two models bearing human HCC with different metastatic potentials (LCI-D20 and LCI-D35), and the new human HCC cell line with high metastatic potential (MHCC97) were analyzed by CGH. Gains on 1q, 6q, 7p, and 8q, and losses on 13p, 14p, 19p, 21, and 22 were detected in both LCI-D20 and LCI-D35 models. However, high copy number amplification of a minimum region at 1q12-q22 and 12q, and deletions on 1p32-pter, 3p21-pter, 8p, 9p, 10q, 14q, and 15p were detected only in the LCI-D20 model. Gains on 1p21-p32, 2p13-p21, 6p12-pter, 9p, 15q, and 16q11-q21, and losses on 2p23-pter, 4q24-qter, 7q31-qter, 12q, 17p, and 18 were detected only in the LCI-D35 model. The chromosomal aberration patterns in the MHCC97 cell line were similar to its parent LCI-D20 model, except that gains on 19q and losses on 4, 5, 10q, and 13q were found only in the cell line. These results provide some indirect clues to the metastasis-related chromosomal aberrations of HCC and further support the finding that 8p deletion is associated with HCC metastasis. 1q12–22 and 12q might harbor a novel oncogene(s) that contributes to the development and progression of HCC. Amplification on 8q and deletions on 4q and 17p may be not necessary for HCC metastasis. Received: 24 November 2000 / Accepted: 11 January 2001     

Genomic changes in salivary gland pleomorphic adenomas detected by comparative genomic hybridization

The aim of this study was to investigate whether so far unknown chromosomal alterations in pleomorphic adenoma (PA) exist. To this end, tissue samples from 18 patients with parotid gland PA were studied by comparative genomic hybridization (CGH) using Phi-29-DNA-polymerase for DNA amplification. The most common aberrations were losses of chromosomal material of 19p (6/18), 9q, 16p, and 19q (in 3 out of 18 patients each). Additional losses were observed on 4p, 5q, and 17q (2 / 18 each). Gains involved chromosomes 2p, 4p, 6p, 17q, and 21q (2 / 18 each). Losses of 19p have been associated with inactivation of tumor-suppressor genes in carcinomas previously. As a result, pleomorphic adenomas show a considerable diversity of chromosomal gains and losses detected by CGH. The 19p arm, and particularly its 19p13 region, need be further studied to elucidate the potential impact of associated lost tumor suppressor genes on PA development.     

Chromosomal and genetic imbalances in synovial sarcoma detected by conventional and microarray comparative genomic hybridization

Purpose: To analyze the relationship between chromosomal instabilities and clinicopathological factors in synovial sarcoma (SS). Methods: Twenty-two fresh-frozen SS were analyzed by metaphase comparative genomic hybridization (CGH). Additional microarray CGH was performed in 13 cases. Results: Fourteen patients with SYT–SSX1 rearrangements and nine patients with biphasic tumor subtypes had better prognosis than the eight patients with SYT–SSX2 rearrangements and 13 patients with monophasic subtypes, respectively. Gains (average 3.0) were more frequent than losses (average 1.0). Frequent gains were identified on chromosomal regions 2, 6q, 7, 8q, 12, 17q, 18q, and 21q, whereas frequent losses were over-lapped on chromosomes 1p31–p35, 3p, 6q, 16, and 17p. High-level gains were observed on chromosomes 1q21–q31, 7, 8, 12, 17q, 18q, and 21q. Thirteen monophasic and nine biphasic tumors had an average of 5.1 and 2.8 aberrations, respectively. Patients with tumors harboring numerous aberrations (≥3) had a worse clinical course. Microarray CGH more specifically detected genetic imbalances including gains in MDM2, MSH2, KCNK12, DCC, CDK2, ERBB3, SAS, and CDK4 and losses in HRAS, RASSF1, and CCND1. Gain of SAS was an important prognostic factor of SS. Conclusion: We have identified several factors influencing the prognosis of SS patients by metaphase and microarray CGH.     

Comparative genomic hybridization analysis of adrenocortical tumors

Comparative genomic hybridization (CGH) is a molecular cytogenetic technique that allows the entire genome of a tumor to be surveyed for gains and losses of DNA copy sequences. A limited number of studies reporting the use of this technique in adult adrenocortical tumors have yielded conflicting results. In this study we performed CGH analysis on 13 malignant, 18 benign, and 1 tumor of indeterminate malignant potential with the aim of identifying genetic loci consistently implicated in the development and progression of adrenocortical tumors. Tissue samples from 32 patients with histologically proven adrenocortical tumors were available for CGH analysis. CGH changes were seen in all cancers, 11 of 18 (61%) adenomas, and the 1 tumor of indeterminate malignant potential. Of the adrenal cancers, the most common gains were seen on chromosomes 5 (46%), 12 (38%), 19 (31%), and 4 (31%). Losses were most frequently seen at 1p (62%), 17p (54%), 22 (38%), 2q (31%), and 11q (31%). Of the benign adenomas, the most common change was gain of 4q (22%). Mann-Whitney analysis showed a highly significant difference between the cancer group (mean changes, 7.6) and the adenoma group (mean changes, 1.1) for the number of observed CGH changes (P < 0.01). Logistic regression analysis showed that the number of CGH changes was highly predictive of tumor type (P < 0.01). This study has identified several chromosomal loci implicated in adrenocortical tumorigenesis. Activation of a protooncogene(s) on chromosome 4 may be an early event, with progression from adenoma to carcinoma involving activation of oncogenes on chromosomes 5 and 12 and inactivation of tumor suppressor genes on chromosome arms 1p and 17p.     

Nonrandom DNA copy number changes related to lymph node metastases in squamous cell carcinoma of the lung

Lung cancer is one of the most common malignancies and cancer-related death worldwide. Lymph node metastasis is the main cause of treatment failure. Although many studies were performed to evaluate genetic events associated with development and progression of lung cancer, molecular mechanism still remains poorly defined. In the present study, using comparative genomic hybridization (CGH) technique, we described the pattern of DNA copy number changes in a cohort of 42 primary squamous cell carcinomas (SCC) of the lung. A direct comparison of nonmetastatic (TxN0M0) and metastatic (TxN1-2M0) tumors was performed to define chromosomal imbalances related to lymph node metastases. Some genetic alterations were observed more frequently in metastatic than in non-metastatic tumors, including losses at 11q, 16p, 16q, 19p and gains at 4q, 7q, 12p, 13q, 18p. The gain at 7q with the smallest common altered region 7q31.2-q32, was found to be directly associated with lymph node involvement (p=0.0407). We suggest that the established chromosomal region harbors two putative tumor suppressor genes WNT2 and c-Met. An overexpresion of these genes seems to be involved in inducing the invasive growth and metastatic potential of SCC of the lung.     

Chromosomal imbalances identified by comparative genomic hybridization in sporadic parathyroid adenomas

OBJECTIVE: To identify chromosomal gains and losses in sporadic parathyroid adenomas (PAs). METHODS: Fourteen sporadic PAs were studied by comparative genomic hybridization (CGH). RESULTS: The fourteen studied PAs showed chromosomal imbalances. All cases except one exhibited two or more abnormalities. Chromosomal gains were found in all cases, and three cases (21%) also presented chromosomal losses. Genomic amplification was not observed. Chromosome 9 was involved in ten cases. Recurrent genetic gain was found on 9p22-24 and on 9q34, each in 6 of 14 cases (43%). Other recurrent gains included Xq26 in 6 PAs (43%) and 4q21-28 and 8p22-23, each in 4 of 14 cases (29%). Regions of recurrent genetic loss involved whole chromosome 11 and 20q12-13, each in 2 of 14 cases (14%). CONCLUSIONS: Our findings show chromosomal imbalances in all sporadic PAs studied by CGH, partly confirming previous reports, with the exception that we observed more chromosomal gains than losses. Several regions (9p22-24, 9q34, Xq26, 4q21-28, and 8p22-23) probably deserve further investigation in order to discard the presence of genes involved in parathyroid tumorigenesis.     

Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course

Sixty-four patients with adult T-cell leukemia/lymphoma (ATL; 18 patients with indolent subtype and 46 with aggressive subtype) associated with human T-lymphotropic virus type 1 (HTLV-1) were analyzed using comparative genomic hybridization (CGH). The most frequent observations were gains at chromosomes 14q, 7q, and 3p and losses at chromosomes 6q and 13q. Chromosome imbalances, losses, and gains were more frequently observed in aggressive ATL than in indolent ATL, with significant differences between the 2 ATL subtypes at gains of 1q and 4q. An increased number of chromosomal imbalances was associated with a significantly shorter survival in all patients. A high number of chromosomal losses was associated with a poor prognosis in indolent ATL, whereas the presence of 7q+ was marginally associated with a good prognosis in aggressive ATL. Paired samples (ie, samples obtained at different sites from 4 patients) and sequential samples from 13 patients (from 6 during both chronic disease and acute crisis and from 7 during both acute onset and relapse) were examined by CGH and Southern blotting for HTLV-1. All but 2 paired samples showed differences on CGH assessment. Two chronic/crisis samples showed distinct results regarding both CGH and HTLV-1 integration sites, indicating clonal changes in ATL at crisis. In 11 patients, the finding of identical HTLV-1 sites and clonally related CGH results suggested a common origin of sequential samples. In contrast to chronic/crisis samples, CGH results with all acute/relapse sample pairs showed the presence of clonally related but not evolutional subclones at relapse, thereby suggesting marked chromosomal instability. In summary, clonal diversity is common during progression of ATL, and CGH alterations are associated with clinical course. (Blood. 2001;97:3875-3881)     

Comparative genomic hybridization analysis of adrenocortical tumors of childhood

Although several genes have been investigated in adrenal tumorigenesis, the genetic background of adrenocortical tumors (ACT) remains poorly characterized. In southern Brazil, the annual incidence of ACT is unusually high, ranging from 3.4-4.2/million children, compared with a worldwide incidence of 0.3/million children younger than 15 yr. Environmental factors have been implicated because the distribution of these tumors follows a regional, rather than a familial, pattern. However, decreased penetrance of a particular gene defect cannot be excluded. Because linkage or other traditional genetic analyses would not be appropriate to investigate the defect(s) associated with ACT in this population, we used comparative genomic hybridization (CGH) to screen for DNA sequence copy number changes in 9 nonfamilial ACT (6 carcinomas and 3 adenomas) from unrelated patients from this region. Six female (aged 10 months to 6 3/4 yr) and 3 male (1 1/12 to 3 1/4 yr) patients were studied. Three carcinomas were at stage I, 1 was at stage II, and another was at stage III. Two carcinomas had evidence of invasion of the vena cava, and 3 were more than 3 cm in size. All patients underwent surgical excision of their tumors; chemotherapy was administered to cancer patients. Currently, all patients are alive and in remission, with the exception of 1 patient with stage III cancer. High mol wt DNA was extracted from tumor tissue obtained at surgery and frozen at -70 C. This DNA was labeled and used for CGH according to standard procedures. Digital image analysis was performed to detect chromosomal gains or losses. CGH evaluation revealed extensive genetic aberrations in both adenomas and carcinomas; there were no significant differences relative to age, gender, size, or stage of the tumor (P > 0.1). Chromosomes and chromosomal regions 1q, 5p, 5q, 6p, 6q, 8p, 8q, 9q, 10p, 11q, 12q, 13q, 14q, 15q, 16, 18q, 19, and 20q demonstrated gains, whereas 2q, 3, 4, 9p, 11, 13q, 18, 20p, and Xq showed losses. The most striking finding was consistent copy number gain of chromosomal region 9q34 in 8 of the 9 tumors. We conclude that both benign and malignant ACT from southern Brazil show multiple genetic aberrations, including a consistent gain of chromosomal region 9q34. This genomic area may harbor genetic defects that predispose to ACT formation and are shared by the patients who were investigated in this study or are accumulated epigenetically under the influence of a common factor, such as an environmental mutagen.     

Chromosomal imbalances in post-chernobyl thyroid tumors.

Tissue samples from 60 post-Chernobyl childhood thyroid tumors have been investigated. We used comparative genomic hybridization (CGH) to detect chromosomal gains and losses within the tumor DNA. This is the first CGH study on childhood thyroid tumors. The post-Chernobyl tumors showed chromosomal imbalances in 30% of tumors. The most frequent DNA copy number changes in post-Chernobyl tumors involved chromosomes 2, 7q11.2-21, 13q21-22, 21 (DNA gains), and chromosomes 16p/q, 20q, 22q (DNA losses). Some of these specific alterations detected in post-Chernobyl thyroid tumors (deletions on chromosomes 16p/q and 22q) have previously been reported in thyroid tumors as associated with an aggressive biologic behavior and may therefore also account for the more aggressive phenotype of papillary thyroid carcinoma (PTC) found in post- Chernobyl tumors. Eighteen percent of post-Chernobyl PTC that exhibit RET rearrangements also showed chromosomal imbalances indicating that either additional genetic events are involved in this subset of tumors, or that intratumoral genetic heterogeneity exists in these tumors, suggesting a oligoclonal pattern to tumor development.     

Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas

Anaplastic large cell lymphoma (ALCL) is a T/null-cell neoplasm characterized by chromosomal translocations involving the anaplastic lymphoma kinase (ALK) gene (ALK). Tumours with similar morphology and phenotype but negative for ALK have been also recognized. The secondary chromosomal imbalances of these lymphomas are not well known. We have examined 74 ALCL, 43 ALK-positive and 31 ALK-negative, cases by comparative genomic hybridization (CGH), and locus-specific alterations for TP53 and ATM were examined by fluorescence in situ hybridization and real-time quantitative polymerase chain reaction. Chromosomal imbalances were detected in 25 (58%) ALK-positive and 20 (65%) ALK-negative ALCL. ALK-positive ALCL with NPM-ALK or other ALK variant translocations showed a similar profile of secondary genetic alterations. Gains of 17p and 17q24-qter and losses of 4q13-q21, and 11q14 were associated with ALK-positive cases (P = 0.05), whereas gains of 1q and 6p21 were more frequent in ALK-negative tumours (P = 0.03). Gains of chromosome 7 and 6q and 13q losses were seen in both types of tumours. ALCL-negative tumours had a significantly worse prognosis than ALK-positive. However no specific chromosomal alterations were associated with survival. In conclusion, ALK-positive and negative ALCL have different secondary genomic aberrations, suggesting they correspond to different genetic entities.     

Comparative genomic hybridization in chronic B-cell leukemias shows a high incidence of chromosomal gains and losses

In chronic B-cell leukemias, fluorescence in situ hybridization has greatly improved the ability to detect certain chromosomal aberrations, as cells in all phases of the cell cycle are analyzed. To obtain a comprehensive view of chromosomal gains and losses, we applied the recently developed technique of comparative genomic hybridization (CGH) to 28 patients with chronic B-cell leukemias. CGH results were compared with those obtained by chromosome banding analysis and interphase cytogenetics. In 19 of the 28 cases, chromosomal imbalances were detected, including amplified DNA sequences in three instances. The most common aberrations included gains of chromosomal material on 8q and 12 as well as losses of 6q, 11q, 13q, and 17p. In 13 cases, CGH revealed chromosomal gains and losses not detected by banding analysis. In 8 of these 13 cases, discrepancies were further investigated using other methods, and in all instances, the CGH findings were confirmed. A limitation of detecting small deleted regions by CGH was found in one example of 18p. In conclusion, our data show that the results of banding analysis in chronic B-cell leukemias often do not reflect the chromosomal changes in the predominant cell clone. This may be one explanation for the as yet poor correlation between cytogenetic findings and clinical course in this group of neoplasms.     

Gains on 9p are common genomic aberrations in idiopathic myelofibrosis: a comparative genomic hybridization study

Ideopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder resulting in bone marrow fibrosis as a consequence of growth factor release from clonal haematopoiesis. Conventional cytogenetic analysis identifies abnormalities in approximately a third of cases at diagnosis, although rarely uncovers unique, primary genetic events. We have used comparative genomic hybridization (CGH) to study 25 IMF cases and have compared the results with conventional cytogenetics. Metaphase cells were available for analysis in 13 cases, of which seven showed an abnormal karyotype. CGH chromosomal profiles showed imbalances in 21 of 25 cases. The most frequent aberrations were gains of 9p (12 cases), 2q (seven cases), 3p (seven cases), chromosome 4 (seven cases), 12q (seven cases), 13q (eight cases). The main losses were at 17q and occurred in six cases. The results for CGH and cytogenetics were matched for one case only. Investigation of IMF by CGH suggests that genomic aberrations are much more common than has been previously indicated by conventional cytogenetic analysis and occur in the majority of cases. Gains of 9p were the most frequent finding, occurring in 50% of patients and suggests that genes on 9p may play a crucial role in the pathogenesis of IMF.     

Prognostic and biologic significance of chromosomal imbalances assessed by comparative genomic hybridization in multiple myeloma

Cytogenetic abnormalities, evaluated either by karyotype or by fluorescence in situ hybridization (FISH), are considered the most important prognostic factor in multiple myeloma (MM). However, there is no information about the prognostic impact of genomic changes detected by comparative genomic hybridization (CGH). We have analyzed the frequency and prognostic impact of genetic changes as detected by CGH and evaluated the relationship between these chromosomal imbalances and IGH translocation, analyzed by FISH, in 74 patients with newly diagnosed MM. Genomic changes were identified in 51 (69%) of the 74 MM patients. The most recurrent abnormalities among the cases with genomic changes were gains on chromosome regions 1q (45%), 5q (24%), 9q (24%), 11q (22%), 15q (22%), 3q (16%), and 7q (14%), while losses mainly involved chromosomes 13 (39%), 16q (18%), 6q (10%), and 8p (10%). Remarkably, the 6 patients with gains on 11q had IGH translocations. Multivariate analysis selected chromosomal losses, 11q gains, age, and type of treatment (conventional chemotherapy vs autologous transplantation) as independent parameters for predicting survival. Genomic losses retained the prognostic value irrespective of treatment approach. According to these results, losses of chromosomal material evaluated by CGH represent a powerful prognostic factor in MM patients.     

Chromosomal aberrations by comparative genomic hybridization in hürthle cell thyroid carcinomas are associated with tumor recurrence

Hürthle cell thyroid neoplasms are classified as variants of follicular neoplasms, but they have distinct clinicopathological features. Chromosomal aberrations by comparative genomic hybridization (CGH) are common in Hürthle cell neoplasms. However, there is currently only limited information concerning the relationship between the chromosomal aberrations by CGH and tumor behavior. We, therefore, investigated chromosomal aberrations in primary Hürthle cell neoplasms (13 carcinomas and 15 adenomas) using CGH and correlated the aberrations identified with tumor node metastasis (TNM) stage, tumor differentiation, capsular invasion, and tumor recurrence. Chromosomal aberrations were found in 62% (8 of 13) of carcinomas and 60% (9 of 15) of adenomas. Overall, common chromosomal gains were found on 5p (29%), 5q (36%), 7 (29%), 12p (14%), 12q (21%), 17p (29%), 17q (32%), 19p (32%), 19q (25%), 20p (21%), 20q (29%), and 22q (18%). Common chromosomal losses were found on 2q (18%) and 9q (18%). Thirty-eight percent (5 of 13) of carcinomas were TNM stage III, 31% (4 of 13) were moderately to poorly differentiated, and 46% (6 of 13) were intermediately to widely invasive. Recurrence occurred in 38% (5 of 13). Carcinomas that subsequently recurred had a greater number of chromosomal gains (9.0 vs. 1.3; <0.005) and had more frequent chromosomal gains on 12q, 19q, and 20p (<0.001), 5p, 7, 19p, and 20q (<0.005), and 12p (<0.01) than those that did not recur. Five of the eight (63%) patients with aberrations developed recurrence, whereas none of the five patients without aberrations developed recurrence. In conclusion, chromosomal gains by CGH on 5p, 7, 12p, 12q, 19p, 19q, 20p, and 20q in Hürthle cell carcinomas are associated with tumor recurrence. Such chromosomal aberrations may be predictive for recurrent disease in patients with Hürthle cell thyroid carcinoma.     

Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants.

Mantle cell lymphomas (MCLs) are characterized by 11q13 chromosomal translocations and cyclin D1 overexpression. The secondary genetic and molecular events involved in the progression of these tumors are not well known. In this study, we have analyzed 45 MCLs (32 typical and 13 blastoid variants) by comparative genomic hybridization (CGH). To identify the possible genes included in the abnormal chromosome regions, selected cases were analyzed for P53, P16(INK4a), RB, C-MYC, N-MYC, BCL2, BCL6, CDK4, and BMI-1 gene alterations. The most frequent imbalances detected by CGH were gains of chromosomes 3q (49%), 7p (27%), 8q (22%), 12q (20%), 18q (18%), and 9q34 (16%) and losses of chromosomes 13 (44%), 6q (27%), 1p (24%), 11q14-q23 (22%), 10p14-p15 (18%), 17p (16%), and 9p (16%). High-level DNA amplifications were identified in 11 different regions of the genome, predominantly in 3q27-q29 (13%), 18q23 (9%), and Xq28 (7%). The CGH analysis allowed the identification of regional consensus areas in most of the frequently involved chromosomes. Chromosome gains (P =. 02) and losses (P =.01) and DNA amplifications (P =.015) were significantly higher in blastoid variants. The significant differences between blastoid and typical tumors were gains of 3q, 7p, and 12q, and losses of 17p. CGH losses of 17p correlated with P53 gene deletions and mutations. Similarly, gains of 12q and high-level DNA amplifications of 10p12-p13 were associated with CDK4 and BMI-1 gene amplifications, respectively. One of 2 cases with 8q24 amplification showed C-MYC amplification by Southern blot. Alterations in 2p, 3q, 13, and 18q were not associated with N-MYC, BCL6, RB, or BCL2 alterations, respectively, suggesting that other genes may be the targets of these genetic abnormalities in MCLs. Increased number of gains (0 v 1-4 v >4 gains per case) (P =.002), gains of 3q (P =.02), gains of 12q (P =.03), and losses of 9p (P =. 003) were significantly associated with a shorter survival of the patients. These results indicate that an increased number of chromosome imbalances are associated with blastoid variants of MCLs and may have prognostic significance.     

Genome-wide DNA profiling of marginal zone lymphomas identifies subtype-specific lesions with an impact on the clinical outcome

Marginal zone B-cell lymphomas (MZLs) have been divided into 3 distinct subtypes (extranodal MZLs of mucosa-associated lymphoid tissue [MALT] type, nodal MZLs, and splenic MZLs). Nevertheless, the relationship between the subtypes is still unclear. We performed a comprehensive analysis of genomic DNA copy number changes in a very large series of MZL cases with the aim of addressing this question. Samples from 218 MZL patients (25 nodal, 57 MALT, 134 splenic, and 2 not better specified MZLs) were analyzed with the Affymetrix Human Mapping 250K SNP arrays, and the data combined with matched gene expression in 33 of 218 cases. MALT lymphoma presented significantly more frequently gains at 3p, 6p, 18p, and del(6q23) (TNFAIP3/A20), whereas splenic MZLs was associated with del(7q31), del(8p). Nodal MZLs did not show statistically significant differences compared with MALT lymphoma while lacking the splenic MZLs-related 7q losses. Gains of 3q and 18q were common to all 3 subtypes. del(8p) was often present together with del(17p) (TP53). Although del(17p) did not determine a worse outcome and del(8p) was only of borderline significance, the presence of both deletions had a highly significant negative impact on the outcome of splenic MZLs.