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Clonal Evolution (clonal + evolution)
Selected AbstractsComments on editorial entitled "ISCN (2005) Is Not Acceptable for Describing Clonal Evolution in Cancer"GENES, CHROMOSOMES AND CANCER, Issue 5 2007FHGSA, FRCPA, Lynda J Campbell MB No abstract is available for this article. [source] Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy,CANCER, Issue 11 2010Dushyant Verma MD Abstract BACKGROUND: Clonal evolution is frequently detected in patients developing resistance to imatinib. The outcome of patients with clonal evolution treated with second generation tyrosine kinase inhibitors is not known. METHODS: The authors analyzed the outcome of 177 CML patients after second tyrosine kinase inhibitor therapy. RESULTS: Ninety-five patients were in chronic phase, 30 had clonal evolution, 28 were in accelerated phase (AP), and 24 were in AP plus clonal evolution. Major cytogenetic response rates were 58%, 54%, 28%, and 13%; 2-year overall survival (OS) rates were 86%, 73%, 68%, and 33%; and 2-year event-free survival (EFS) rates were 69%, 67%, 31%, and 8%, respectively. The hematologic and cytogenetic response rates, OS, and EFS were no different between patients in chronic phase with clonal evolution and patients with chronic phase and no clonal evolution. However, clonal evolution had a significant adverse impact when associated with other features of AP. On multivariate analysis, clonal evolution had no independently significant effect on achieving major cytogenetic response on the second generation tyrosine kinase inhibitors. The factors predicting increasing major cytogenetic response to second generation tyrosine kinase inhibitors were prior achievement of major cytogenetic response with imatinib, higher hemoglobin levels, no splenomegaly, lower percentage of Philadelphia chromosome-positive metaphases, and no prior chemotherapy. CONCLUSIONS: Clonal evolution constitutes a heterogeneous entity with variable outcome with second generation tyrosine kinase inhibitors, with trisomy 8, chromosome 17, and complex abnormalities having the worst outcome, regardless of the number of metaphases involved. The molecular events behind these abnormalities and potential therapeutic approaches directed at them need to be defined. Cancer 2010. © 2010 American Cancer Society. [source] Biallelic deletion 13q14.3 in patients with chronic lymphocytic leukemia: cytogenetic, FISH and clinical studiesEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2008Christian Chena Abstract Background and objective:, Monoallelic deletion of 13q14.3 (13q14x1) is the most common abnormality in chronic lymphocytic leukemia (CLL). As a sole alteration, it predicts a favorable outcome. Biallelic 13q14.3 (13q14x2) deletion or concomitant 13q14x1/13q14x2 has been scarcely evaluated in the literature. We present the clinical, cytogenetic and fluorescence in situ hybridization (FISH) analysis of six CLL patients with normal karyotypes and 13q14x2 and their comparison to cases with 13q14x1 as a single abnormality. Patients and methods:, A total of 103 CLL patients were studied. Cytogenetic and FISH analysis were performed on stimulated peripheral blood lymphocytes. Specific fluorescence DNA probes for CLL were used. Results:, Six out of 103 (5.8%) patients showed normal karyotypes and 13q14x2. It was observed as a single alteration in one patient and combined with 13q14x1 in five cases. Biallelic clones were larger than monoallelic ones in 3/5 patients (60%). The comparison of clinical and hematological data between 13q14x1 and 13q14x2 groups showed progression of the disease in all 13q14x2 patients respect to 12/32 (37.5%) cases with 13q14x1 (P = 0.008), significant differences in the distribution by Rai stage (P = 0.042) and a tendency of a higher lactate dehydrogenase level in 13q14x2 patients (P = 0.054). Treatment free survival for 13q14x2 group was 28.5 months, shorter than those observed in patients with 13q14x1 alone (49 months). Conclusions:, Our data would suggest that 13q14x2 could represent a more aggressive FISH anomaly than 13q14x1 alone, probably as a consequence of clonal evolution and/or due to the complete inactivation of this critical region by mean of more complex mechanisms. [source] Cytogenetic, FISH, and molecular studies in a case of B-cell chronic lymphocytic leukemia with karyotypic evolutionEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5-6 2002Christian Chena Abstract:, We report the clinical, cytogenetic, fluorescence in situ hybridization (FISH) and molecular findings in a 54-yr-old male patient diagnosed with B-cell chronic lymphocytic leukemia (B-CLL), who showed progression to a diffuse large B-cell lymphoma (Richter's syndrome). Genetic studies were performed at diagnosis and during the Richter's transformation (RT). A clonal karyotype with two dicentric chromosomes, psu dic(12,21)(q24;q10) and dic(17,18)(p11.2;p11.2), was found. Both rearrangements were confirmed by FISH. Molecular cytogenetics analysis using p53 probe showed monoallelic loss of this tumor suppressor gene in 43.8% and 77.3% of cells for the first and the second studies, respectively). In both studies, deletions of D13S319 (18% and 12% of cells) and D13S25 loci (13% and 12% of cells) at 13q14 were found. Polymerase chain reaction analysis showed the MBR/JH rearrangement of the bcl-2 gene. FISH studies using LSI bcl-2/IgH probe allowed quantifying the clonal cell population with this rearrangement (4% and 6.6% of cells at diagnosis and RT, respectively). To our knowledge, this is the first case with a psu dic(12,21) described in B-CLL. The low percentage of cells with the 13q14 deletion and bcl-2/IgH rearrangement suggests that they were secondary events that resulted from clonal evolution. Our patient had a short survival (9 months) and a clear lack of response to several therapeutic agents, confirming the association of p53 gene deletion and karyotypic evolution with disease progression. [source] Prognostic significance of secondary cytogenetic alterations in follicular lymphomasGENES, CHROMOSOMES AND CANCER, Issue 12 2008Nathalie A. Johnson Follicular lymphoma (FL) is an indolent lymphoma with a long median survival. Transformation to a more aggressive histology (TLy) is a major cause of mortality. The critical events leading to TLy are unknown. We assessed the prognostic significance of secondary cytogenetic alterations on overall survival (OS) and transformation from 210 diagnostic FL biopsies. We analyzed serial and transformed karyotypes for recurrent alterations that predict transformation. Over 10 years, 31% of cases developed TLy. The only alteration in diagnostic karyotypes that correlated with an inferior OS was an additional X chromosome in males only (P = 0.005) suggesting that other mechanisms including epigenetic factors and over-expression of genes on the X chromosome may play a role in FL pathogenesis. In transformed karyotypes, 8q24 (MYC) translocations were common (14/37) and resulted in a median survival of 3 months posttransformation (P = 0.01). In serially obtained biopsies (28 pts), 43% of the later biopsies lacked the cytogenetic alterations found in the original FL karyotype, suggesting that karyotypic progression of FL is not strictly linear in all cases. Consequently, studying clonal evolution in FL using serial biopsies may not represent the full complexity of genetic alterations leading to transformation. © 2008 Wiley-Liss, Inc. [source] Mutational inactivation of TGFBR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor , resistant cellsGENES, CHROMOSOMES AND CANCER, Issue 2 2008Swati Biswas The mutational inactivation of transforming growth factor , receptor type II (TGFBR2) occurs in ,30% of colon cancers and promotes the formation of colon cancer by inhibiting the tumor suppressor activity of the TGFB signaling pathway. TGFBR2 mutations occur in >90% of microsatellite unstable (MSI) colon cancers and affect a polyadenine tract in exon 3 of TGFBR2, called BAT-RII, which is vulnerable to mutation in the setting of DNA mismatch repair (MMR) system deficiency. In light of the vulnerable nature of the BAT-RII tract in the setting of MMR inactivation and the favorable effects of TGFBR2 inactivation in colon cancer, analysis of TGFBR2 inactivation provides an opportunity to assess the roles of genomic instability vs. clonal selection in cells acquiring TGFBR2 BAT-RII tract mutations in MSI colon cancer formation. The contribution of genomic instability and/or clonal evolution to the mutational inactivation of TGBFR2 in MSI colon cancers has not been studied in a systematic way that would allow a determination of the relative contribution of these two mechanisms in the formation of MSI colon cancer. It has not been demonstrated whether the BAT-RII tract mutations are strictly a consequence of the BAT-RII region being hypermutable in the setting of MMR deficiency or if the mutations are rather a consequence of clonal selection pressure against the TGFB receptor. Through the use of defined cell line systems, we show that both genomic instability and clonal selection of TGFB resistant cells contribute to the high frequency of TGFBR2 mutations in MSI colon cancer. © 2007 Wiley-Liss, Inc. [source] Increasing genomic instability during premalignant neoplastic progression revealed through high resolution array-CGHGENES, CHROMOSOMES AND CANCER, Issue 6 2007Lisa A. Lai Chromosomal instability is regarded as an underlying mechanism of neoplastic progression, integral to the clonal selection and evolution that leads to cancer. We evaluated chromosomal instability in premalignant Barrett's esophagus tissue using high resolution Affymetrix mapping 100K SNP arrays as patients progressed through three molecular stages of disease,CDKN2ALOH only, CDKN2ALOH/TP53LOH, and CDKN2ALOH/TP53LOH with aneuploidy. Within individuals over time, we observed increases in both numbers and sizes of regions of LOH or copy number change. In the earliest CDKN2ALOH only samples, we detected few regions with both copy change and LOH, whereas copy loss and LOH were highly correlated in more advanced samples. These data indicate that genomic instability increases in severity and changes character during neoplastic progression. In addition, distinct patterns of clonal evolution could be discerned within a segment of Barrett's esophagus. Overall, this study illustrates that pre-malignant disease can be associated with extensive instability and clonal dynamics that evolve from an initial stage characterized by small recombination-based alterations to one with larger copy change events likely associated with mitotic instability. © 2007 Wiley-Liss, Inc. [source] Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumorsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Christopher M. Heaphy Abstract Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our results are in agreement with the concepts of "field cancerization" and "cancer field effect," concepts that were previously introduced to describe areas within tissues consisting of histologically normal, yet genetically aberrant, cells that represent fertile grounds for tumorigenesis. The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast-sparing surgery. © 2006 Wiley-Liss, Inc. [source] Origin of multifocal carcinomas of the bladder and upper urinary tract: Molecular analysis and clinical implicationsINTERNATIONAL JOURNAL OF UROLOGY, Issue 8 2005TOMONORI HABUCHI Abstract The simultaneous or metachronous development of multifocal tumors with identical or variable histological features in the urothelial tract in a single patient is a well-known characteristic of urothelial cancer. To explain this phenomenon, two distinct concepts have been proposed: the ,field defect' hypothesis according to which urothelial cells in patients are primed to undergo transformation by previous carcinogenic insults and the ,single progenitor cell' hypothesis, which asserts that the multifocal development is caused by the seeding or intraepithelial spread of transformed cells. Results of recent molecular genetic studies support the ,single progenitor cell' hypothesis, and indicate that the genetic and phenotypic diversity observed in multifocal urothelial tumors is a consequence of clonal evolution from a single transformed cell. An understanding of the mechanism of the heterotopic recurrence of urothelial cancer may provide new prospects for early molecular detection and prevention of heterotopic recurrence of urothelial cancer. [source] Molecular aspects of diagnostic nucleolar and nuclear envelope changes in prostate cancerJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2004Andrew H. Fischer Abstract Prostate cancer is still diagnosed by pathologists based on subjective assessment of altered cell and tissue structure. The cellular-level structural changes diagnostic of some forms of cancer are known to be induced by cancer genes, but the relation between specific cellular-level structural features and cancer genes has not been explored in the prostate. Two important cell structural changes in prostate cancer,nucleolar enlargement and nuclear envelope (NE) irregularity,are discussed from the perspective that they should also relate to the function of the genes active in prostate cancer. Enlargement of the nucleolus is the key diagnostic feature of high-grade prostatic intraepithelial neoplasia (PIN), an early stage that appears to be the precursor to the majority of invasive prostate cancers. Nucleolar enlargement classically is associated with increased ribosome production, and production of new ribosomes appears essential for cell-cycle progression. Several cancer genes implicated in PIN are known (in other cell types) to augment ribosome production, including c-Myc, p27, retinoblastoma, p53, and growth factors that impact on ERK signaling. However, critical review of the available information suggests that increased ribosome production per se may be insufficient to explain nucleolar enlargement in PIN, and other newer functions of nucleoli may therefore need to be invoked. NE irregularity develops later in the clonal evolution of some prostate cancers, and it has adverse prognostic significance. Nuclear irregularity has recently been shown to develop dynamically during interphase following oncogene expression, without a requirement for post-mitotic NE reassembly. NE irregularity characteristic of some aggressive prostate cancers could reflect cytoskeletal forces exerted on the NE during active cell locomotion. NE irregularity could also promote chromosomal instability because it leads to chromosomal asymmetry in metaphase. Finally, NE irregularity could impact replication competence, transcriptional programming and nuclear pore function. © 2003 Wiley-Liss, Inc. [source] Current and emerging concepts in tumour metastasis,THE JOURNAL OF PATHOLOGY, Issue 1 2010Caroline Coghlin Abstract Disseminated cancer accounts for most deaths due to malignancy. Despite this, research has focused predominantly on tumour development and progression at the primary site. Recently, attention has shifted towards the field of tumour metastasis. Several new and exciting concepts that have emerged in the past few years may shed light on this complex area. The established canonical theory of tumour metastasis, as a process emerging from a stepwise accumulation of genetic events fuelled by clonal evolution, has been challenged. New evidence suggests that malignant cells can disseminate at a much earlier stage than previously recognized in tumourigenesis. These findings have direct relevance to clinical practice and shed new light on tumour biology. Gene-profiling studies support this theory, suggesting that metastatic ability may be an innate property shared by the bulk of cells present early in a developing tumour mass. There is a growing recognition of the importance of host factors outside the primary site in the development of metastatic disease. The role of the ,pre-metastatic niche' is being defined and with this comes a new understanding of the function of bone marrow-derived progenitor cells in directing the dissemination of malignant cells to distant sites. Current research has highlighted the crucial roles played by non-neoplastic host cells within the tumour microenvironment in regulating metastasis. These new concepts have wide-ranging implications for our overall understanding of tumour metastasis and for the development of cancer therapeutics. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Insights into the cell of origin in breast cancer and breast cancer stem cellsASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 2 2010Geoffrey J LINDEMAN Abstract The precise cell types that give rise to tumors and mechanisms that underpin tumor heterogeneity are poorly understood. There is increasing evidence to suggest that diverse solid tumors are hierarchically organized and may be sustained by a distinct subpopulation of cancer stem cells (CSCs). The CSC hypothesis provides an attractive cellular mechanism that can account for the therapeutic refractoriness and dormant behavior exhibited by many tumor types. Breast cancer was the first solid malignancy from which CSCs were identified and isolated. Direct evidence for the CSC hypothesis has also recently emerged from mouse models of mammary tumorigenesis, although alternative models to explain heterogeneity also seem to apply. Our group has found that the luminal epithelial progenitor marker CD61/,3 integrin identified a CSC population in mammary tumors from MMTV- wnt-1 mice. However, no CSCs could be identified in the more homogeneous MMTV- neu/erbB2 model, suggesting an alternate (clonal evolution or stochastic) model of tumorigenesis. It seems likely that both paradigms of tumor propagation exist in human cancer. From a clinical perspective, the CSC concept has significant implications. Quiescent CSCs are thought to be more resistant to chemotherapy and targeted therapy. Enrichment of putative CSCs has been noted in studies of chemotherapy-treated patients, lending support to the CSC hypothesis and their potential role in chemoresistance. Although many unresolved questions on CSCs remain, ongoing efforts to identify and characterize CSCs continue to be an important area of investigation, with the potential to identify novel tumor targeting strategies. [source] Monitoring minimal residual disease in acute myeloid leukaemia with NPM1 mutations by quantitative PCR: clonal evolution is a limiting factorBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2009Christina Papadaki Summary Nucleophosmin (NPM1) mutations in exon 12 represent the most frequent molecular aberrations in adult patients with acute myeloid leukaemia (AML). Molecular detection of NPM1 mutation A could be a useful marker for routine monitoring of minimal residual disease (MRD). We established a calibrator-normalized relative quantification real-time polymerase chain reaction (PCR) assay for NPM1 mutation A. ABL1 was used as a reference housekeeping gene and the NPM1 mutation A-containing OCI/AML3 cell line as a calibrator. Relative quantification was performed by calculating the NPM1 mutation A/ABL1 ratio which was normalized to the NPM1 mutation A/ABL1 ratio of OCI/AML3 calibrator cDNA. The assay showed a sensitivity of 10,5. The clinical usefulness was evaluated by monitoring MRD in 51 AML patients with NPM1 mutation A. In 27 patients analysed at diagnosis and after induction treatment, NPM1 mutation A ratios showed a median log10 reduction of 2·48, which correlated with response to therapy. Among the 51 patients, 21 relapsed and two lost the mutation. We established a sensitive, specific and reproducible assay for routine quantification and monitoring of NPM1 mutation A levels. However, clonal evolution was observed in 9·5% limiting the usefulness of the NPM1 mutation A mutation as a molecular marker in these patients. [source] IgV gene intraclonal diversification and clonal evolution in B-cell chronic lymphocytic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2006Davide Bagnara Summary Intraclonal diversification of immunoglobulin (Ig) variable (V) genes was evaluated in leukaemic cells from a B-cell chronic lymphocytic leukaemia (B-CLL) case over a 2-year period at four time points. Intraclonal heterogeneity was analysed by sequencing 305 molecular clones derived from polymerase chain reaction amplification of B-CLL cell IgV heavy (H) and light (C) chain gene rearrangements. Sequences were compared with evaluating intraclonal variation and the nature of somatic mutations. Although IgV intraclonal variation was detected at all time points, its level decreased with time and a parallel emergence of two more represented VHDJH clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one VLJL rearrangement became more represented over time. Analyses of somatic mutations suggest antigen selection and impairment of negative selection of neoplastic cells. In addition, a genealogical tree representing a model of clonal evolution of the neoplastic cells was created. It is of note that, during the period of study, the patient showed clinical progression of disease. We conclude that antigen stimulation and somatic hypermutation may participate in disease progression through the selection and expansion of neoplastic subclone(s). [source] Multicolour fluorescence in situ hybridization analysis of t(14;18)-positive follicular lymphoma and correlation with gene expression data and clinical outcomeBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2003Valia S. Lestou Summary. In order fully to identify secondary chromosomal alterations, such as duplications, additions and marker chromosomes that remained unresolved by G banding, 60 cases of t(14;18)-positive follicular lymphoma (FL) were analysed by multicolour karyotyping techniques [multicolour fluorescence in situ hybridization (MFISH)/multicolour banding for chromosome 1 (MBAND1)]. A total of 165 additional structural chromosomal aberrations were delineated. An increased frequency of chromosomal gains involving X, 1q, 2, 3q27-q29, 5, 6p11-p21, 7, 8, 11, 12, 14q32, 17q, 18 and 21 and deletions of 1p36, 3q28-q29, 6q, 10q22-q24 and 17p11-p13 was revealed by the MFISH/MBAND1 analysis. Balanced translocations other than t(14;18) were uncommon, whereas unbalanced translocations were numerous. Deletion of 1p36 and duplication of 1p33-p35, 1p12-p21 and 1q21-q41 were regularly involved in chromosome 1 alterations, seen in 53% of the cases. A strong correlation was demonstrated between gains of individual chromosomal bands and increased gene expression, including 1q22/MNDA, 6p21/CDKN1A, 12q13-q14/SAS, 17q23/ZNF161, 18q21/BCL2 and Xq13/IL2RG. Unfavourable overall survival was associated with del(1)(p36) and dup(18q). These data support the notion that translocation events are primarily responsible for FL disease initiation, whereas the unbalanced chromosomal gains and losses that mirror the gene expression patterns characterize clonal evolution and disease progression, and thus provide further insights into the biology of FL. [source] p53 intronic point mutation, aberrant splicing and telomeric associations in a case of B-chronic lymphocytic leukaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2000Teresa Bromidge We report a case of chronic lymphocytic leukaemia (CLL) with telomeric associations and a p53 intronic point mutation. Karyotypic analysis revealed clonal and non-clonal telomeric associations, accompanied by clonal cytogenetic abnormalities and also in isolation. The p53 mutation, which occurred at the invariant base pair ,2 of the splice acceptor site in intron 7 resulted in the abolition of correct splicing of exon 7 to exon 8. Multiple aberrant splice products were characterized, all of which differed from wildtype in the DNA binding domain. Fluorescence in situ hybridization demonstrated that the clone retained two copies of the p53 gene and wild-type p53 transcript was detected on cloning of reverse transcriptase polymerase chain reaction (RT-PCR) product, indicating that one wild-type allele remained. However, a plasmid clone with correct splicing at the exon 7/8 boundary, but with a 21 bp deletion in exon 8, was also found at low frequency. This finding indicates clonal evolution, resulting in complete loss of wild-type p53. The intronic point mutation was not present in DNA extracted from cervical tissue indicating that it was a leukaemic phenomenon. This is the first case of an intronic point mutation to be reported in CLL. This mutation led to chaotic p53 expression and, interestingly, occurred in a case showing telomeric associations, a rare phenomenon in B-CLL. [source] Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy,CANCER, Issue 11 2010Dushyant Verma MD Abstract BACKGROUND: Clonal evolution is frequently detected in patients developing resistance to imatinib. The outcome of patients with clonal evolution treated with second generation tyrosine kinase inhibitors is not known. METHODS: The authors analyzed the outcome of 177 CML patients after second tyrosine kinase inhibitor therapy. RESULTS: Ninety-five patients were in chronic phase, 30 had clonal evolution, 28 were in accelerated phase (AP), and 24 were in AP plus clonal evolution. Major cytogenetic response rates were 58%, 54%, 28%, and 13%; 2-year overall survival (OS) rates were 86%, 73%, 68%, and 33%; and 2-year event-free survival (EFS) rates were 69%, 67%, 31%, and 8%, respectively. The hematologic and cytogenetic response rates, OS, and EFS were no different between patients in chronic phase with clonal evolution and patients with chronic phase and no clonal evolution. However, clonal evolution had a significant adverse impact when associated with other features of AP. On multivariate analysis, clonal evolution had no independently significant effect on achieving major cytogenetic response on the second generation tyrosine kinase inhibitors. The factors predicting increasing major cytogenetic response to second generation tyrosine kinase inhibitors were prior achievement of major cytogenetic response with imatinib, higher hemoglobin levels, no splenomegaly, lower percentage of Philadelphia chromosome-positive metaphases, and no prior chemotherapy. CONCLUSIONS: Clonal evolution constitutes a heterogeneous entity with variable outcome with second generation tyrosine kinase inhibitors, with trisomy 8, chromosome 17, and complex abnormalities having the worst outcome, regardless of the number of metaphases involved. The molecular events behind these abnormalities and potential therapeutic approaches directed at them need to be defined. Cancer 2010. © 2010 American Cancer Society. [source] High throughput comparative genomic hybridization array analysis of multifocal urothelial cancersCANCER SCIENCE, Issue 8 2006Hiroaki Kawanishi The purpose of this study was to examine genetic alterations occur during synchronous or metachronous multifocal development of urothelial cancers on the whole genome using a comparative genomic hybridization (CGH) array. We used 10 tumor pairs (2 tumors for each patient), in which we had previously defined a clonal relationship by microsatellite analysis. For CGH array analysis, Vysis GenoSensor Array 300 kit was used. An unsupervised hierarchical cluster analysis revealed that the tumors from one patient were clustered together independent of the tumors of all other patients. On the other hand, many genetic divergences among multifocal urothelial cancers were newly found by a CGH array analysis. The concordant genetic alteration patterns of the chromosomal arm in tumor pairs were most frequently observed in 9p, 9q, 8p, 7p, 7q and 11q, while discordant patterns were most frequently found in 15q, 20q, 2q, 10p and 11q. Investigation using a CGH array showed that genetically stable multifocal tumors were less frequent, and that a large percentage of urothelial cancers accumulate genetic alterations during multifocal development by clonal evolution. We might have to consider these genetic accumulations during multifocal development when designing strategies for prevention and detection of recurrent multifocal urothelial cancers. CGH array can be a powerful tool for genetic analysis of multifocal urothelial cancer. (Cancer Sci 2006; 97: 746,752) [source] | |||||||||||||||||||||||||