Chromosome Aberrations In Cancer Research Articles

Tetraploidization Increases the Motility and Invasiveness of Cancer Cells.

Polyploidy and metastasis are associated with a low probability of disease-free survival in cancer patients. Polyploid cells are known to facilitate tumorigenesis. However, few data associate polyploidization with metastasis. Here, by generating and using diploid (2n) and tetraploid (4n) clones from malignant fibrous histiocytoma (MFH) and colon carcinoma (RKO), we demonstrate the migration and invasion advantage of tetraploid cells in vitro using several assays, including the wound healing, the OrisTM two-dimensional cell migration, single-cell migration tracking by video microscopy, the Boyden chamber, and the xCELLigence RTCA real-time cell migration. Motility advantage was observed despite tetraploid cell proliferation weakness. We could also demonstrate preferential metastatic potential in vivo for the tetraploid clone using the tail vein injection in mice and tracking metastatic tumors in the lung. Using the Mitelman Database of Chromosome Aberrations in Cancer, we found an accumulation of polyploid karyotypes in metastatic tumors compared to primary ones. This work reveals the clinical relevance of the polyploid subpopulation and the strategic need to highlight polyploidy in preclinical studies as a therapeutic target for metastasis.

Cancer chromosome breakpoints cluster in gene-rich genomic regions.

Cancer cells are characterized by chromosome abnormalities, of which some, in particular balanced rearrangements, are associated with distinct tumor entities and/or with specific gene rearrangements that represent important steps in the carcinogenic process. However, the vast majority of cytogenetically detectable structural aberrations in cancer cells have not been characterized at the nucleotide level; hence, their importance and functional consequences are unknown. By ascertaining the chromosomal breakpoints in 22 344 different clonal structural chromosome abnormalities identified in the karyotypes of 49 626 cases of neoplastic disorders we here show that the distribution of breakpoints is strongly associated (P < 0.0001) with gene content within the affected chromosomal bands. This association also remains highly significant in separate analyses of recurrent and nonrecurrent chromosome abnormalities as well as of specific subtypes of cancer (P < 0.0001 for all comparisons). In contrast, the impact of band length was negligible. The breakpoint distribution is thus not stochastic—gene‐rich regions are preferentially affected. Several genomic features relating to transcription, replication, and chromatin organization have been found to enhance chromosome breakage frequencies; this indicates that gene‐rich regions may be more break‐prone. The salient finding in the present study is that a substantial fraction of all structural chromosome abnormalities, not only those specifically associated with certain tumor types, may affect genes that are pathogenetically important. If this interpretation is correct, then the prevailing view that the great majority of cancer chromosome aberrations is cytogenetic noise can be seriously questioned.

Molecular Genetics and Cytogenetics in Cancer

This special issue of Genetics Research International focuses on molecular genetics and cytogenetics in cancer. The hunt for informative disease-related genetic biomarkers may become so valuable for the differential diagnosis, prognosis, and disease monitoring of cancer patients that numerous researchers are committed to this challenge. Indeed, a colossal effort of current molecular medicine to progress in the understanding of the hallmarks of cancer is focusing on the field of biomarker discovery through genetic and cytogenetic profiling. Ambitious initiatives such as the Cancer Genome Atlas (http://cancergenome.nih.gov/) or the Cancer Genome Anatomy Project (http://cgap.nci.nih.gov/cgap.html) from the US National Institutes of Health (NIH) are devoted to provide collaborative platforms to better comprehend and fight the malignant signature of cancer. The fast development of high-throughput technologies is bringing to biomedical research more affordable and high-resolution ways to explore whole genomes, chromosomes, genes, proteins, RNA, and metabolites. In consequence, numerous genomic datasets accumulate in international repositories, such as GEO from the US National Center for Biotechnology Information (NCBI), and around 500,000 clonal chromosomal abnormalities belonging to more than 60,000 human neoplasms are described in the latest catalogue of chromosome aberrations in cancer. However, translational application of biomarker discovery still has to face its ultimate challenge: incorporation into routine clinical practice. We are under the pressure to combine the multidisciplinary efforts of basic, clinical, and computational research fields to identify meaningful genetic profiles that can be used as powerful tools for diagnosis, prognosis, and treatment. Every patient who suffers from cancer hopes that our research will deliver alternatives. For scientists, the identification of the specific genetic abnormalities responsible for tumor diversity and heterogeneity is crucial to shed light on the molecular mechanisms of cancer and the identification of druggable targets and functional pathways. For clinicians, the appropriate molecular categorization of patients would allow to enroll them in tailored—more adequate and less toxic—treatments, improving healthcare and optimizing medical costs. Ultimately, any effort to (i) frame the important unsolved problems, (ii) to review what is known about the molecular pathways involved in the pathogenesis of distinct types of cancer, (iii) to catalog recurrent genetic alterations that could serve as biomarkers, (iv) to suggest standardization of routine protocols of diagnosis and molecular detection, and (v) to rank available or potential drugs and their targets, is decisive to help molecular medicine in its challenge against cancer. This is the scope of this special issue where the biographies of some of the most aggressive hematological and solid tumors are discussed. The journal Genetics Research International is serving here as a forum for discussion and review of major genetic risks involved in breast cancer metastasis to the brain as well as in the evolution of myxoid soft-tissue sarcomas and parathyroid tumors. The importance of applying genetic protocols in the risk-based stratification of multiple myeloma is also reviewed here, and new evidences supporting genetic aberrations in a rare variant of T-cell lymphomas known as Sezary syndrome are presented. Finally, myeloid malignancies are revealed as a paradigm to discuss the role of dicentric chromosomes as instigators of genomic instability and suggest a model for their implication in the formation of unbalanced translocations in malignancy. Breaking the barriers of cancer is a difficult task that is continuously challenging the research community. We, the editors of this special issue, are hopeful that the ideas presented here can inspire the critical thinking of the specialized readers and contribute to the common efforts to better understand and fight the multiple faces of cancer. Jose Maria Sayagues Sergio Roa Norma C. gutierrez Ilana Zalcberg Renault

Association between TP53 gene ARG72PRO polymorphism and chromosome aberrations in human cancers

It is well known that the TP53 gene considerably influences on DNA repair processes. Polymorphisms in the TP53 gene, particularly the well-known Arg72Pro in codon 72 of exon 4 (Ex4+119 G>C; rs1042522), can modify the functionality of the p53 protein and activation of DNA repair. Actually, polymorphic variants Arg and Pro were found to have different properties of regulation of TP53-dependent DNA repair target genes, that can effect various levels of chromosome aberrations in cancer patients with these genotypes. Here, we studied frequency of chromatid breaks (CB), chromosome-type aberrations (CTA) and aberrant cells (AC) in cancer patients (n = 102) with various Arg72Pro genotypes. It was shown that the Arg variant of TP53 gene is associated with high frequency of AC and chromatid breaks. That is Arg/Arg carriers have more different chromosome aberrations in comparison to individuals with Arg/Pro and Pro/Pro genotypes (P < 0.05). Conversely, the lowest level of AC and chromatid breaks were detected in cancer patients with the Pro/Pro genotype. A completely unexpected result was that women with Arg/Arg genotype had the most high frequency of CB and AC in comparison to Arg/Pro and Pro/Pro women carriers (P < 0.001). In the group of male patients we did not show any differences in chromosome aberrations between carriers of Arg72Pro genotypes. In conclusion, the TP53 gene Arg72Pro polymorphism appreciably influence on occurrence of chromosome aberrations in cancer.

Definitive molecular cytogenetic characterization of 15 colorectal cancer cell lines

In defining the genetic profiles in cancer, cytogenetically aberrant cell lines derived from primary tumors are important tools for the study of carcinogenesis. Here, we present the results of a comprehensive investigation of 15 established colorectal cancer cell lines using spectral karyotyping (SKY), fluorescence in situ hybridization, and comparative genomic hybridization (CGH). Detailed karyotypic analysis by SKY on five of the lines (P53HCT116, T84, NCI-H508, NCI-H716, and SK-CO-1) is described here for the first time. The five lines with karyotypes in the diploid range and that are characterized by defects in DNA mismatch repair had a mean of 4.8 chromosomal abnormalities per line, whereas the 10 aneuploid lines exhibited complex karyotypes and a mean of 30 chromosomal abnormalities. Of the 150 clonal translocations, only eight were balanced and none were recurrent among the lines. We also reviewed the karyotypes of 345 cases of adenocarcinoma of the large intestine listed in the Mitelman Database of Chromosome Aberrations in Cancer. The types of abnormalities observed in the cell lines reflected those seen in primary tumors: there were no recurrent translocations in either tumors or cell lines; isochromosomes were the most common recurrent abnormalities; and breakpoints occurred most frequently at the centromeric/pericentromeric and telomere regions. Of the genomic imbalances detected by array CGH, 87% correlated with chromosome aberrations observed in the SKY studies. The fact that chromosome abnormalities predominantly result in copy number changes rather than specific chromosome or gene fusions suggests that this may be the major mechanism leading to carcinogenesis in colorectal cancer.

Cytogenetic Aberrations in Soft Tissue Tumors Harvested From Fresh Tissue Submitted for Surgical Pathology: A Single Institutional Experience

Recurrent cytogenetic abnormalities have been reported in many types of soft tissue neoplasms, and the detection of these aberrations imparts diagnostic utility. The aim of this study is to demonstrate that classical karyotyping may be performed with minimal effort as an adjunct to surgical pathology on fresh tissue submitted for histopathological examination. To the authors' knowledge, there are no recently published reviews in the literature in English of cytogenetic abnormalities in soft tissue tumors from a single institution. Conventional metaphase cytogenetics was performed in the authors' cytogenetics laboratory on fresh tissue from mesenchymal tumors from their surgical pathology laboratory over a period of 4 years. Cytogenetics reports, clinical history, and histopathology were reviewed for 48 soft tissue tumors. Recurrent cytogenetic abnormalities were identified using the Mitelman Database of Chromosome Aberrations in Cancer and a review of the literature. The authors reviewed 48 cases of benign and malignant soft tissue tumors, which included 28 distinct morphologies. Cytogenetic abnormalities were observed in 23 (48%) cases, a normal chromosome profile was found in 20 (42%) cases, and 5 (10%) cases had no karyotype reported because of specimen contamination or inadequacy. Of the 23 cases with an aberrant karyotype, 15 (65%) tumors had cytogenetic abnormalities present in 2 or more cases in the literature. Cytogenetic analysis demonstrated abnormal karyotypes in nearly half of this series of mesenchymal neoplasms, the majority of which consisted of recognized aberrations reported in the literature.

A tandem triplication, trp(1)(q21q32), in a patient with follicular lymphoma: a case study and review of the literature

A 1q triplication is a rare karyotypic event in hematologic malignancies, with 26 cases of 1q triplication reported in the literature. Although 1q duplication or triplication is present with a high incidence in Burkitt lymphoma and Fanconi anemia, there have been no detailed reports of an association between non-Burkitt type lymphomas and 1q triplication. Presented here is the case of a 69-year-old man with follicular lymphoma (FL) and 1q triplication, with a review of the pertinent literature. The patient was diagnosed with FL with bone marrow involvement; his bone marrow chromosome study revealed 50,XY,trp(1)(q21q32),+3,+add(3)(q21),+7,+9,add(13)(p11.2)[11]/51∼52,idem,+19,+22[8]/46,XY[3]. Review of the Mitelman Database of Chromosome Aberrations in Cancer revealed 7 previous cases of non-Burkitt type lymphoma (including FL) with 1q triplication. On the basis of these eight cases, we conclude that 1q triplication represents a rare secondary genetic event with prognostic significance in patients with FL or other non-Burkitt types of lymphoma. Further studies are needed to investigate these rare 1q triplication in hematologic malignancies.

Translocations Involving 8q24 in Burkitt Lymphoma and Other Malignant Lymphomas: A Historical Review of Cytogenetics in the Light of Todays Knowledge

Burkitt lymphoma (BL) has a characteristic clinical presentation, morphology, immunophenotype and primary chromosomal aberration, i.e. the translocation t(8;14) (q24;q32) or its variants. However, diagnostic dilemmas may arise in daily practice due to overlap of BL with subsets of other aggressive, mature B cell lymphomas such as a small subset of diffuse large B cell lymphomas (DLBCL). Recently, two gene expression studies have described a distinct molecular profile for BL, but also showed the persistence of some cases intermediate between BL and DLBCL. An alternative approach to define BL is to consider (cyto)genetic data, in particular chromosomal abnormalities other than the t(8;14) or its variants. In this study the “Mitelman Database of Chromosome Aberrations in Cancer”, harboring the majority of all published neoplasia related karyotypes, was explored to define a cytogenetic profile of “true” BL. To that end a core subset of BL was defined bya histologic diagnosis of BL,the presence of a t(8;14), t(2;8) or t(8;22) indicating a MYC/IG breakpoint, andthe absence of a 3q27/BCL6, 18q21/BCL2 or 11q13/CCND1 breakpoint additional to the 8q24/MYC breakpoint.These core BL (N=481) showed a very low complexity of chromosomal changes, with 40% of the cases having the IG-MYC fusion as the sole abnormality; in the remaining cases additional recurrent and partially exclusive abnormalities included gains at chromosomes 1q, 7 and 12, and losses of 6q, 13q32-34 and 17p. No differences were found between pediatric (N=205) and adult patients (N=215). Moreover, no differences were found between such core BL cases published before (N= 280) and after 1994 (N=201) indicating that historical changes in classification systems had no major impact on this profile.The genetic profiles and age distribution of the core subset were significantly different from BL with an 8q24 breakpoint not affecting one of the three IG loci (N=13), lymphomas that were diagnosed as BL but had a translocation involving 18q21/BCL2, 3q27/BCL6 or 11q13/BCL1 additional to a breakpoint at 8q24/MYC (“double hit BL”; N=44), and from other morphological types of lymphomas with an 8q24/MYC breakpoint (N=327; 256/327 cases had an IG-MYC breakpoint). These groups showed an other age distribution and a higher cytogenetic complexity than the core subset of BL. BL without a detectable 8q24/MYC breakpoint (N=108) might have been heterogeneous and deserves further studies. We suggest that, concordant with the WHO classification to be published in 2008, the diagnosis of BL should be restricted to cases with expression of CD10 and BCL6, absence or very weak expression of BCL2 protein, a homogeneously very high proliferation index, and a proven IG-MYC translocation without evidence of a chromosomal translocation typical for other lymphoma entities. Additionally, a high number of non-specific cytogenetic abnormalities should suggest need for a critical review of the diagnosis of BL. Finally, the steady increase in age of lymphomas that mimic BL strongly emphasizes that there is no distinct age at which a pathologist can safely make a diagnosis of BL without any ancillary cytogenetic or molecular studies.

Recurrent Chromosome Abnormalities Define Non-Overlapping, Unique Subgroups of Tumors in Chronic Lymphocytic Leukemia Patients with Known Karyotypic Abnormalities

Background B-cell chronic lymphocytic leukemia (B-CLL) is a well-defined clinical entity with heterogeneous molecular and cytogenetic features. Chromosome aberrations could be associated to specific CLL clinical features and outcomes and their impact on clonal evolution should have been addressed by using temporal analysis. In order to demonstrate the role of temporal analysis in CLL we conducted a comprehensive karyotypic survey of a large number of CLL cases with already known genetic aberrations to fully describe their meaning in terms of biological evolution.Methods A total of 1749 karyotypes were retrieved from the Mitelman Database of Chromosome Aberrations in Cancer. A matrix depicting the 360-band human chromosome ideogram was created. Regions that were either lost or gained in more than 3% of the cases were retained and identified as recurrent imbalances. Early and late imbalances were defined according to the appearance on the complex karyotypes. Descriptive statistics were used to summarize the genetic abnormalities.Results The median chromosome number and the median number of abnormalities per tumor (NAPT) were 46 and 1 respectively. (Figure 1 A and 1B) The most common abnormality seen was trisomy 12 which occurred in 29% (508 cases) followed by 13q14del (10.34%), 13q13del (6.63%) and add14q32 (6.63%). The temporal analysis revealed +12, 13q-, −17, 17p-, −Y and −X to be early imbalances (TO<5), followed predominately by a late loss with TO=5–10.5 (11q-). Hierarchical clustering suggested there are different groups including:trisomy 12,13q-,11q-, and6q-, which at least in this clustering analysis appeared to be mutually exclusive.In summary, we can conclude that overall CLL is a neoplasia that shows remarkable chromosome stability even when only abnormal karyotypes are evaluated. Interestingly, clustering analysis suggests there are non-overlapping, unique subsets of CLL cases where trisomy 12 is the most common and along with 13q-emerged as early events on CLL clonal evolution. [Display omitted] [Display omitted] [Display omitted]

Translocations involving 8q24 in Burkitt lymphoma and other malignant lymphomas: a historical review of cytogenetics in the light of todays knowledge

Burkitt lymphoma (BL) has a characteristic clinical presentation, morphology, immunophenotype and primary chromosomal aberration, that is, the translocation t(8;14)(q24;q32) or its variants. However, diagnostic dilemmas may arise in daily practice due to overlap of BL with subsets of other aggressive, mature B-cell lymphomas such as diffuse large B-cell lymphomas (DLBCL). Recently, two gene expression studies have described a distinct molecular profile for BL, but also showed the persistence of some cases intermediate between BL and DLBCL. An alternative approach to define BL is to consider (cyto)genetic data, in particular chromosomal abnormalities other than the t(8;14) or its variants. In this review the 'Mitelman Database of Chromosome Aberrations in Cancer,' harboring the majority of all published neoplasia-related karyotypes, was explored to define a cytogenetic profile of 'true' BL. This core subset of BL showed a very low complexity of chromosomal abnormalities with 40% of the cases having the IG-MYC fusion as the sole abnormality. In the remaining cases, additional recurrent but partially exclusive abnormalities included gains at chromosomes 1q, 7 and 12, and losses of 6q, 13q32-34 and 17p. Within the core subset, no differences were found between pediatric and adult patients. In addition, the genetic profile of the core subset was significantly different from BL with an 8q24 breakpoint not affecting one of the three immunoglobulin loci, BL with a translocation involving 18q21/BCL2, 3q27/BCL6 or 11q13/BCL1, additionally to a breakpoint at 8q24/MYC, and from other morphological types of lymphomas with an 8q24/MYC breakpoint. These groups showed a higher cytogenetic complexity than the core subset of BL. BL without a detectable 8q24/MYC breakpoint might be heterogeneous and deserves further studies. We suggest that, concordant with the WHO classification to be published in 2008, the diagnosis of BL should be restricted to cases with expression of CD10 and BCL6, absence or very weak expression of BCL2 protein, a homogeneously very high proliferation index and a proven IG-MYC translocation without evidence of a chromosomal translocation typical for other lymphoma entities. In addition, a high number of nonspecific cytogenetic abnormalities should suggest need for a critical review of the diagnosis of BL.

Burkitt Transformation of Mantle Cell Lymphoma.

MYC rearrangements are not included as a genetic change in the blastoid variants of mantle cell lymphoma (Jaffe, et al (2001) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press.). We present two cases both with CCND1/IGH and MYC rearrangements. Case 1. An 82-year-old male with no known history of lymphoma presented with thrombocytopenia, loss of appetite and “abdominal fullness.” Imaging studies showed enlarged retroperitoneal lymph nodes. The peripheral blood smear had 18,000 WBC with approximately 30% circulating atypical lymphocytes. Flow cytometric studies of the bone marrow revealed a surface kappa light chain restricted CD10+ B-cell population. A bone marrow biopsy showed >90% of marrow cellularity comprised of neoplastic lymphocytes. The neoplastic lymphocytes were small to intermediate in size with minimal amounts of dark blue cytoplasm and several cytoplasmic vacuoles (Burkitt like morphology). By immunohistochemical stains, the neoplastic cells were positive for CD20, CD43, CD10, BCL-6, and cyclin D1, weakly and focally positive for BCL-2, and negative for CD23. The Ki-67 proliferation fraction was ∼100%. An immunohistochemical stain for CD5 was predominantly negative with a possible very faint blush on a subset of neoplastic B-cells. The FISH tests on bone marrow interphases were positive for a CCND1/IGH, a variant MYC/IGH, a variant MYC-BA rearrangements and negative for BCL6-BA and BCL2/IGH rearrangements. The variant MYC/IGH pattern was 3xMYC, 3xIGH, 1xFusion signals and MYC-BA pattern was 2x5′MYCcon3′MYC, 1x3′MYC. rearrangements. The karyotype was 44∼45,XY,del(2)(q11.2q21),der(3;17)(p10;q10), der(5)t(3;5)(q12;q15), t(11;14) (q13;q32) [cp6]/46,XY[14]. Since the karyotype had a t(11;14) and two normal 8 chromosomes, a metaphase FISH was analyzed to localize the signals for the MYC/IGH probe. The MYC signal were on both normal 8 chromosomes, a fusion signal was on a F-G sized chromosome. While the IGH signals were on the normal 14, der(14) and der(11). This was consistent with a cryptic MYC/IGH fusion in a three way rearrangement between chromosomes 8, 11 and 14. Case 2. A 69-year-old male having had a kidney transplant in 2001 was on immunosuppressive therapy. He presented with severe leukocytosis, anemia and thrombocytopenia and weight loss of about 12 pounds over several months. A peripheral blood smear showed 74,000 WBC with approximately 30% blasts. Bone marrow biopsies revealed normocellular bone marrow (50% cellularity). Interspersed large neoplastic lymphoid cells were shown by immunohistochemical stains to be positive for CD20, BCL-1, weak positive for BCL-2 and a Ki-67 staining > 90%. Flow cytometry indicated that the neoplastic cells were positive for kappa and CD5 but negative for CD11c and CD23. Interphases FISH on peripheral blood was positive for a CCND1/IGH rearrangement. The karyotype was 42∼44,X,-Y,add(1)(p13), t(2;8)(p12;q24), der(2)t(2;15)(p25;q11.2),+3,del(9)(p22p24),+del(9)(p22p24), − 10, del(11)(q21q23), t(11;14)(q13;q32) , − 13, − 15, − 17,add(17)(p11.2)[cp7]/46,XY[17]. FISH confirmed a MYC rearrangement. Therefore, this case had both CCND1/IGH and MYC/IGK rearrangement. Concomitant occurrence of a CCND1/IGH and a MYC rearrangement is rare in lymphomas. In Mitelman database of chromosome aberrations in cancer 2007, Four cases had both a t(11;14) and a t(8;14) translocation and two cases had both a t(11;14) and a t(2;8) translocation. This study expands the repertoire of abnormalities seen in blastoid transformation of mantle cell lymphoma. Being cognizant of a possible MYC involvement in the transformation of mantle cell lymphoma and its exploration would influence therapy.

Waldenström Macroglobulinaemia: The Impact of Cytogenetic Analysis.

Background Waldenström macroglobulinaemia (WM) is an uncommon indolent B-cell lymphoproliferative characterized by bone marrow infiltration by lymphoplasmacytic cells and an IgM paraproteinemia. This study analyzed the impact of cytogenetics in WM and the pattern of evolution in 73 cases from the Mitelman database and 14 cases evaluated at the Mayo Clinic Arizona (MCA).Patients and Methods The Mitelman database of Chromosome aberrations in cancer (Mitelman et al., 2007) was searched, and 73 WM karyotypes were selected. We also evaluated 14 cases seen at MCA with karyotype analysis at diagnosis. An Excel spreadsheet in which the rows of the first column were labeled to represent each band of a 360-band human chromosome ideogram was created as previously described (Hoglund et al., 2001; Horsman et al., 2003) All karyotypes were scored individually in successive columns for net gain and loss of each chromosome band (loss=0 and gain=1). Recurrent abnormalities were defined as those that were involved in >5% of cases. Histograms of the number of abnormalities per tumor (NAPT) were then plotted, and the modal value extracted as variable called time to occurrence. Statistics correlation between the presence and absence of different abnormalities was analyzed using Spearman correlation matrices. P value of <0.05 was considered as statistical significanResults In total 73 cases of newly diagnosed WM from the Mitelman database were included in the analysis. The median chromosome number was 46 (Range 40 to 49).The most common abnormalities were loss of 6q21 (10%) (Fig 1), +3 (7.1%), loss of X (6%) and −10, −20, −21, +12, +18 and +5 (5.71% respectively). The most common translocation was t(8;14) (4%).The most recurrent breakpoints in our series include: 14q32 (6%), 6q21 (5%), 8q24 (5%), 18q21 (4%) and 19q13 (4%). In the MCA cohort, 14 karyotypes were reviewed and only 3 cases exhibited an abnormal result. Deletion of 6q21, 20q11 and a Robertsonian translocation t(13;14) were reported (3/11, 21%). In the 6q21 case, FISH analysis confirmed the deletion of BLIMP1 on 6q. One case exhibited a 20q deletion in a WM with kidney amyloidosis patient.Discussion In this comprehensive analysis we show a very small complexity of recurrent abnormalities expressed by conventional karyotype analysis in WM. The incidence of 6q21 deletion was 10% by conventional cytogenetics and it is been reported as high as 34% when analysed by FISH (54% when cytoplasmic immunoglobulin M-FISH was used). Interestingly we report the case of a patient with 20q deletion at diagnosis in the MCA cohort. To date, only a limited number of cases with del(20q) as a sole cytogenetic anomaly have been reported in plasma cell dyscrasias, either at diagnosis or later in the disease course. The recurrent immunoglobulin gene translocation is known to be involved in the initial oncogenetic events in plasma cell dyscrasias and, so it is important to identify whether there are any masked translocations involving immunoglobulin genes and 20q in these cases. [Display omitted]

Dissecting Karyotypic Patterns in Non Hyperdiploid Multiple Myeloma: An Overview on the Karyotypic Evolution.

Background Multiple myeloma (MM) is presently an incurable plasma cell (PC) malignancy which involves 16 000 new patients per year in US. In spite of the abundance of cytogenetic information, with more than 600 published karyotypes in Non-hyperdiploid MM (NHMM), very little is known about the mode of karyotypic evolution or of the presence of possible cytogenetic pathways. In our investigation, we have used 647 NHMM karyotypes, to identify the most frequently occurring imbalances. Patients and Methods The Mitelman database of Chromosome aberrations in cancer (Mitelman et al., 2007) was searched, and myelomas with modal chromosome number less than 48 were selected. All karyotypes were described using ISCN nomenclature (ISCN, 1995). Only the main clones were analyzed and incomplete karyotypes were excluded. The following information was obtained from each karyotype: chromosome number, imbalances including whole chromosome gains and losses; specific translocations and breakpoints, including add chromosomes. An Excel spreadsheet in which the rows of the first column were labeled to represent each band of a 360-band human chromosome ideogram was created as previously described (Hoglund et al., 2001; Horsman et al., 2003) All karyotypes were scored individually in successive columns for net gain and loss of each chromosome band. The total number of gains and losses affecting each chromosome band for the total cohort of karyotypes was then calculated using the Excel countif function. Recurrent abnormalities were defined as those that were involved in >5% of cases. Histograms of the number of abnormalities per tumor were then plotted, and the modal value extracted as variable called time to occurrence. Statistics correlation between the presence and absence of different abnormalities was analyzed using Spearman correlation matrices. P value of <0.05 was considered as statistical significant. Results In total 647 cases of newly diagnosed NHMM were included in the analysis. The median chromosome number was 43. Few cases had chromosome numbers under 40. The median NAPT was 12 (1–49) with a normal distribution (Fig 1). The most common abnormalities were monosomies of the chromosomes 13 and 14 (32.44% and 14.88% respectively). Out of 647 cases, more than 300 NHMM cases contained translocations in their karyotypes. The most common translocation was t(11;14), which occurs in 17% of cases followed by t(1;16) in 2.7% of cases and t(4;14) and t(8;14) in 1.5% respectively. The most recurrent breakpoints in our series include: 14q32 (32%), 11q13 (20%), 1q10 (10.5%), 1q12 (8%), 8q24 (6.9%), 1p11 (6.6%) and 1q21 (5.5%). Discussion Although only about 40% of MM has informative karyotypes, karyotyping has the advantage of representing global genetic changes at the cellular level. In this comprehensive survey, loss of chromosome 13 and 14 were the most common abnormalities. The NAPT analysis suggests that most NHMM patients have at least 12 abnormalities at diagnosis. It is possible that accumulation of abnormalities above a threshold results in malignant transformation. In our series the t(11;14) translocation appears to be the most recurrent translocation and exceeds the rate reported in Hyperdiploid-MM (17% vs 3.8%). [Display omitted]

Linking the human cytogenetic map with nucleotide sequence: the CCAP clone set

We present the completed dataset and clone repository of the Cancer Chromosome Aberration Project (CCAP), an initiative developed and funded through the intramural program of the U.S. National Cancer Institute, to provide seamless linkage of human cytogenetic markers with the primary nucleotide sequence of the human genome. Spaced at 1–2 Mb intervals across the human genome, 1,339 bacterial artificial chromosome (BAC) clones have been localized to chromosomal bands through high-resolution fluorescence in situ hybridization (FISH) mapping. Of these clones, 99.8% can be positioned on the primary human genome sequence and 95% are placed at or close to their precise nucleotide starts and stops. This dataset can be studied and manipulated within generally available public Web sites. The clones are available from a commercial repository. The CCAP BAC clone set provides anchors for the interrogation of gene and sequence involvement in oncogenic and developmental disorders when the starting point is the recognition of a structural, numerical, or interstitial chromosomal aberration. This dataset also provides a current view of the quality and coherence of the available genome sequence and insight into the nucleotide and three-dimensional structures that manifest as Giemsa light and dark chromosomal banding patterns.

Chromosome aberrations in solid tumors have a stochastic nature

An important question nowadays is whether chromosome aberrations are random events or arise from an internal deterministic mechanism, which leads to the delicate task of quantifying the degree of randomness. For this purpose, we have defined several Shannon information functions to evaluate disorder inside a tumor and between tumors of the same kind. We have considered 79 different kinds of solid tumors with 30 or more karyotypes retrieved from the Mitelman Database of Chromosome Aberrations in Cancer. The Kaplan–Meier cumulative survival was also obtained for each solid tumor type in order to correlate data with tumor malignance. The results here show that aberration spread is specific for each tumor type, with high degree of diversity for those tumor types with worst survival indices. Those tumor types with preferential variants (e.g. high proportion of a given karyotype) have shown better survival statistics, indicating that aberration recurrence is a good prognosis. Indeed, global spread of both numerical and structural abnormalities demonstrates the stochastic nature of chromosome aberrations by setting a signature of randomness associated to the production of disorder. These results also indicate that tumor malignancy correlates not only with karyotypic diversity taken from different tumor types but also taken from single tumors. Therefore, by quantifying aberration spread, we could confront diverse models and verify which of them points to the most likely outcome. Our results suggest that the generating process of chromosome aberrations is neither deterministic nor totally random, but produces variations that are distributed between these two boundaries.

The interactive online SKY/M‐FISH &amp; CGH Database and the Entrez Cancer Chromosomes search database: Linkage of chromosomal aberrations with the genome sequence

To catalog data on chromosomal aberrations in cancer derived from emerging molecular cytogenetic techniques and to integrate these data with genome maps, we have established two resources, the NCI and NCBI SKY/M-FISH & CGH Database and the Cancer Chromosomes database. The goal of the former is to allow investigators to submit and analyze clinical and research cytogenetic data. It contains a karyotype parser tool, which automatically converts the ISCN short-form karyotype into an internal representation displayed in detailed form and as a colored ideogram with band overlay, and also has a tool to compare CGH profiles from multiple cases. The Cancer Chromosomes database integrates the SKY/M-FISH & CGH Database with the Mitelman Database of Chromosome Aberrations in Cancer and the Recurrent Chromosome Aberrations in Cancer database. These three datasets can now be searched seamlessly by use of the Entrez search and retrieval system for chromosome aberrations, clinical data, and reference citations. Common diagnoses, anatomic sites, chromosome breakpoints, junctions, numerical and structural abnormalities, and bands gained and lost among selected cases can be compared by use of the "similarity" report. Because the model used for CGH data is a subset of the karyotype data, it is now possible to examine the similarities between CGH results and karyotypes directly. All chromosomal bands are directly linked to the Entrez Map Viewer database, providing integration of cytogenetic data with the sequence assembly. These resources, developed as a part of the Cancer Chromosome Aberration Project (CCAP) initiative, aid the search for new cancer-associated genes and foster insights into the causes and consequences of genetic alterations in cancer.

Statistical dissection of cytogenetic patterns in lung cancer reveals multiple modes of karyotypic evolution independent of histological classification

Lung carcinomas are cytogenetically highly complex. In spite of this, patterns of recurrent chromosome aberrations have emerged. Apart from the frequent loss of 3p, losses of 4q, 5q, 8p, 9p, 10q, 13q, and 17p are common and gains often include 1q, 3q, 5p, and 8q. In the present study, we retrieved all aberrant lung carcinoma karyotypes, in total 432 cases, from the Mitelman Database of Chromosome Aberrations in Cancer and identified the most frequent imbalances. Each case was then classified with respect to the presence or absence of these imbalances and the data were statistically analyzed by means of principal component analysis, multidimensional scaling, and hierarchical cluster analysis. The analyses suggest that lung cancer develops through three pathways, initiated by +7, 3p−, and +12, respectively, and that the 3p− pathway is dominated by losses and the +12 pathway by gains. Gain of chromosome 7 was shown to be both important in the 3p− pathway and also forming a group of tumors containing +7 and +20 (with few additional changes). The distribution of the number of imbalances per tumor indicated that the karyotypic evolution might pass through three different phases. Phase I is characterized by tumors with few changes and by well-separated 3p− and +12 pathways. Phase II cases have an increased number of imbalances and exhibit less distinct 3p− and +12 pathways. Phase III tumors are polyploid and highly complex. No marked differences between the karyotypic profiles were found among morphologic subtypes, suggesting that lung cancer morphology is independent of the particular cytogenetic pathway operating in the tumor cells.

Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer.

Cytogenetic aberrations have been reported in 45,000 human neoplasms. Structural balanced rearrangements are associated with distinct tumor subtypes with remarkable specificity and have been essential for identifying genes involved in tumorigenesis. All balanced rearrangements that have been characterized molecularly act by deregulating a gene in one of the breakpoints or by creating a fusion gene. Because most recurrent aberrations and rearranged genes have been found in hematological disorders, whereas numerous genomic imbalances have been identified in solid tumors, it has become generally accepted that there are pathogenetic differences between these neoplasms. We here show that in every tumor type, the numbers of recurrent balanced chromosome abnormalities, fusion genes and genes rearranged as a consequence of balanced aberrations are simply a function of the number of cases with an abnormal karyotype. Hence, there may not be any fundamental tissue-specific differences in the genetic mechanisms by which neoplasia is initiated.

Database resources of the National Center for Biotechnology Information: update

In addition to maintaining the GenBank(R) nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides data analysis and retrieval resources for the data in GenBank and other biological data made available through NCBI’s website. NCBI resources include Entrez, PubMed, PubMed Central, LocusLink, the NCBI Taxonomy Browser, BLAST, BLAST Link (BLink), Electronic PCR, OrfFinder, Spidey, RefSeq, UniGene, HomoloGene, ProtEST, dbMHC, dbSNP, Cancer Chromosome Aberration Project (CCAP), Entrez Genomes and related tools, the Map Viewer, Model Maker, Evidence Viewer, Clusters of Orthologous Groups (COGs) database, Retroviral Genotyping Tools, SARS Coronavirus Resource, SAGEmap, Gene Expression Omnibus (GEO), Online Mendelian Inheritance in Man (OMIM), the Molecular Modeling Database (MMDB), the Conserved Domain Database (CDD) and the Conserved Domain Architecture Retrieval Tool (CDART). Augmenting many of the web applications are custom implementations of the BLAST program optimized to search specialized data sets. All of the resources can be accessed through the NCBI home page at: http://www.ncbi.nlm.nih.gov.

A pooled analysis of karyotypic patterns, breakpoints and imbalances in 783 cytogenetically abnormal multiple myelomas reveals frequently involved chromosome segments as well as significant age- and sex-related differences.

The cytogenetic features (ploidy, complexity, breakpoints, imbalances) were ascertained in 783 abnormal multiple myeloma (MM) cases to identify frequently involved chromosomal regions as well as a possible impact of age/sex. The series included MM patients from the Mitelman Database of Chromosome Aberrations in Cancer and from our own laboratory. Hyperdiploidy was most common, followed by hypodiploidy, pseudodiploidy and tri-/tetraploidy. Most cases were complex, with a median of eight changes per patient. The distribution of modal numbers differed between younger and older patients, but was not related to sex. No sex- or age-related differences regarding the number of anomalies were found. The most frequent genomic breakpoints were 14q32, 11q13, 1q10, 8q24, 1p11, 1q21, 22q11, 1p13, 1q11, 19q13, 1p22, 6q21 and 17p11. Breaks in 1p13, 6q21 and 11q13 were more common in the younger age group. The most frequent imbalances were + 9, - 13, + 15, + 19, + 11 and - Y. Trisomy 11 and monosomy 16 were more common among men, while -X was more frequent among women. Loss of Y as the sole change and + 5 were more common in elderly patients, and - 14 was more frequent in the younger age group. The present findings strongly suggest that some karyotypic features of MM are influenced by endogenous and/or exogenous factors.