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FEBS letters 06/2011; 585(13):1993. · 3.54 Impact Factor
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Jean-Pierre Issa
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ABSTRACT: The human genome contains large areas with hypervariable DNA methylation that are associated with deregulation of gene expression. This epigenetic variation may be necessary for differentiation, but it also provides a mechanism for Darwinian evolution at the cellular level that may underlie age-related diseases such as cancer.
Nature Genetics 01/2011; 43(8):724-6. · 35.53 Impact Factor
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ABSTRACT: The prognosis of patients with myelodysplastic syndrome (MDS) after decitabine failure is not known.
Data from 87 patients with MDS (n=67) and chronic myelomonocytic leukemia (n=.20) after failure of decitabine regimens were reviewed.
After a median follow-up of 21 months from decitabine failure, 13 (15%) patients remained alive; the median survival was 4.3 months, and the estimated 12-month survival rate was 28%. The estimated 12-month survival rates were 27%, 33%, and 33%, respectively, for patients with high-risk, intermediate-2-risk, and intermediate-1-risk disease (P=.99) by the International Prognostic Scoring System. The estimated 12-month survival rates were 100%, 54%, 41%, and 18%, respectively, for patients with low-risk, intermediate-1-risk, intermediate-2-risk, and high-risk disease according to The University of Texas M. D. Anderson Cancer Center risk model (P=.01).
The outcome of patients after decitabine failure is poor and appears to be predictable after decitabine failure.
Cancer 08/2010; 116(16):3830-4. · 4.77 Impact Factor
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ABSTRACT: The management of the myelodysplastic syndromes (MDS) requires insight into the complex biology of the disease. Despite this challenge, two recent developments have contributed significantly to advancements in the treatment of MDS: (i) improvements in classification systems and prognostic models; and (ii) the emergence of US FDA-approved agents such as lenalidomide, azacitidine and decitabine. Prior to these developments, supportive care measures consisting of blood and platelet transfusions, haematopoietic growth factors and antimicrobials remained standard of care for the treatment of MDS. As a result of these developments, clinicians are able to provide patient-tailored therapy for specific MDS subgroups. Clinical trials addressing combination therapies with multiple investigational agents as well as novel combination regimens are ongoing. This review focuses on supportive care modalities, the approved agents indicated for the treatment of MDS and future directions for the treatment of MDS, including agents under clinical investigation.
Drugs 07/2010; 70(11):1381-94. · 4.23 Impact Factor
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Bernard Kwabi-Addo,
Songping Wang,
Woonbok Chung,
Jaroslav Jelinek,
Steven R Patierno,
Bi-Dar Wang,
Ramez Andrawis,
Norman H Lee,
Victor Apprey, Jean-Pierre Issa,
Michael Ittmann
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ABSTRACT: Aberrant DNA methylation changes are common somatic alterations in prostate carcinogenesis. We examined the methylation status of six genes in prostate tissue specimens from African American (AA) and Caucasian (Cau) males.
We used pyrosequencing to quantitatively measure the methylation status of GSTP1, AR, RARbeta2, SPARC, TIMP3, and NKX2-5. Real-time PCR was used to determine gene expression, and gene reactivation was analyzed by 5-aza-2'-deoxycytidine and/or trichostatin A treatment.
Statistical analysis showed significantly higher methylation in the prostate cancer tissue samples in comparison with matched normal samples for GSTP1 (P = 0.0001 for AA; P = 0.0008 for Cau), RARbeta2 (P < 0.001 for AA and Cau), SPARC (P < 0.0001 for AA and Cau), TIMP3 (P < 0.0001 for AA and Cau), and NKX2-5 (P < 0.0001 for AA; P = 0.003 for Cau). Overall, we observed significant differences (P < 0.05) in the methylation level for all genes, except GSTP1, in the AA samples in comparison with the Cau samples. Furthermore, regression analysis revealed significantly higher methylation for NKX2-5 (P = 0.008) and TIMP3 (P = 0.039) in normal prostate tissue samples from AA in comparison with Cau, and a statistically significant association of methylation with age for NKX2-5 (P = 0.03) after adjusting for race.
Our findings show higher methylation of several genes in prostate tissue samples from AA in comparison with Cau and may potentially contribute to the racial differences that are observed in prostate cancer pathogenesis.
Clinical Cancer Research 07/2010; 16(14):3539-47. · 7.74 Impact Factor
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G Nicolas Batty,
Hagop Kantarjian, Jean-Pierre Issa,
Elias Jabbour,
Fabio P S Santos,
Deborah McCue,
Guillermo Garcia-Manero,
Sherry Pierce,
Susan O'Brien,
Jorge E Cortés,
Farhad Ravandi
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ABSTRACT: To our knowledge, the feasibility of therapy with hypomethylating agents (HAs) in patients with renal insufficiency (RI) has not been examined.
We reviewed 41 patients with a diagnosis of acute myeloid leukemia (n = 17), myelodysplastic syndromes (n = 15), and chronic myelomonocytic leukemia (n = 9) who had RI and were receiving therapy with azacitidine or decitabine. The median number of administered cycles was 3. Most patients (39; 95%) received a standard dose of the drugs at the initiation of therapy. Nine patients (22%) required treatment interruptions or discontinuation, and 10 patients (24%) required dose reductions.
The overall response rate was 63%, and 4 patients (10%) achieved a complete response. Twenty patients (51%) experienced grade 3 or 4 myelosuppression-related toxicities. Hospitalization was required in 68% of the patients. Among 12 patients with an estimated glomerular filtration rate of 29 mL per minute or less, 6 required dose reductions attributable to myelosuppression (n = 3) or to worsening renal function (n = 3). The overall survival (OS) at 18 months was 12%, and the median OS was 8.6 months.
The use of HA in patients with RI is feasible, but is associated with a higher incidence of toxicity. Dose adjustments and the use of growth factor may be necessary for some patients.
Clinical lymphoma, myeloma & leukemia 06/2010; 10(3):205-10.
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Jean-Pierre Issa
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ABSTRACT: Epigenetic mechanisms, such as DNA methylation and histone modifications, drive stable, clonally propagated changes in gene expression and can therefore serve as molecular mediators of pathway dysfunction in neoplasia. Myelodysplastic syndrome (MDS) is characterized by frequent epigenetic abnormalities, including the hypermethylation of genes that control proliferation, adhesion, and other characteristic features of this leukemia. Aberrant DNA hypermethylation is associated with a poor prognosis in MDS that can be accounted for by more rapid progression to acute myeloid leukemia. In turn, treatment with drugs that modify epigenetic pathways (DNA methylation and histone deacetylation inhibitors) induces durable remissions and prolongs life in MDS, offering some hope and direction in the future management of this deadly disease.
Hematology/oncology clinics of North America 04/2010; 24(2):317-30. · 2.05 Impact Factor
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ABSTRACT: Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias and a propensity to transform into acute myeloid leukemia. There are few treatment options available for patients with MDS. Studies into the molecular biology of MDS have demonstrated abnormal patterns of DNA methylation that lead to silencing of tumor-suppressor genes. Hypomethylating agents are compounds that have the potential to reverse the aberrant DNA methylation and increase the expression of silenced genes, leading to cellular differentiation and/or apoptosis. Decitabine is a cytidine analogue that has activity as a hypomethylating agent and has been evaluated in the therapy of patients with high-risk MDS. Several studies have confirmed the clinical activity of low-dose decitabine in patients with high-risk MDS, leading to responses in approximately 50% of patients, with low treatment-related mortality. Responses have even been seen in patients with high-risk cytogenetic abnormalities, and some studies have demonstrated increased re-expression of genes that were previously silenced by hypermethylation, such as CDKN2B/p15INK4B. There are still some issues concerning the ideal dose and schedule of decitabine for treating patients with MDS. This article focuses on the most recent clinical studies of decitabine for therapy of MDS.
Expert Review of Anti-infective Therapy 01/2010; 10(1):9-22. · 2.65 Impact Factor
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ABSTRACT: Cytarabine resistance characterizes relapsed and refractory acute myelogenous leukemia (AML). Restoration of cytarabine sensitivity can potentially improve treatment outcome in this setting. Acquired hypermethylation of gene promoters and associated silencing of gene expression has been implicated in chemo resistance, and drug-induced hypomethylation can improve sensitivity to cytarabine in vitro. We conducted an adaptively randomized study of a combination of azacitidine, a hypomethylating agent, and cytarabine in 34 patients with AML. The combination administered in a concomitant fashion is safe at full doses of azacitidine and cytarabine, without unexpected toxicities. However, in this advanced AML population, it was difficult to deliver more than one cycle of therapy, and minimal anti-leukemia activity was seen in patients with relapsed/refractory disease. Complete remission was achieved in 2 of 6 minimally pre-treated patients. We conclude that the combination of azacitidine and cytarabine is feasible but has limited activity in relapsed/refractory AML.
Leukemia & lymphoma 12/2009; 51(1):73-8. · 2.40 Impact Factor
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ABSTRACT: DNA methylation of promoter CpG islands is strongly associated with gene silencing and is known as a frequent cause of loss of expression of tumor suppressor genes, as well as other genes involved in tumor formation. DNA methylation of driver genes is very likely outnumbered by the number of methylated passenger genes, though these can be useful as tumor markers. Much of what is known about the importance of DNA methylation in cancer was gained through small- and moderate-scale analysis of gene promoters and tumor samples. A much better understanding of the role of DNA methylation in cancer, either as a marker of disease or as an active driver of tumorigenesis, will likely be gained from genome-wide studies of this modification in normal and malignant cells. This goal has become more attainable with the recent introduction of large-scale genome analysis methodologies and these have been modified to allow for investigation of DNA methylation. Several research groups have been formed to coordinate efforts and apply these methodologies to decipher the methylome of healthy and diseased tissues. In this article we review technological advances in genome-wide methylation profiling.
Genome Medicine 11/2009; 1(11):106.
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Farhad Ravandi, Jean-Pierre Issa,
Guillermo Garcia-Manero,
Susan O'Brien,
Sherry Pierce,
Jianqin Shan,
Gautam Borthakur,
Srdan Verstovsek,
Stefan Faderl,
Jorge Cortes,
Hagop Kantarjian
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ABSTRACT: Outcome of patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) with chromosome 5 and 7 abnormalities (excluding del 5[q]) has been poor, with <10% of patients alive at 2 years.
The authors investigated whether treatment with hypomethylating agents (5-azacytidine/decitabine) leads to an improved outcome. Between January 2004 and December 2007, 81 patients (37 [46%] with AML [>or=20% blasts]; 44 [54%] with high-risk MDS) with chromosome 5 and 7 abnormalities were treated with hypomethylating agents as their initial therapy. These included 68 patients with complex (>or=3) abnormalities and 13 with <3 aberrations. During the same period, 151 patients (126 with AML, 25 with MDS) with chromosome 5 and 7 abnormalities (128 complex, 23 noncomplex) were treated with intensive chemotherapy (including cytarabine-based regimens in 72% and other regimes in 28%).
The median ages for the 2 groups were 66 years and 61 years, respectively (ranges, 37-85 years and 19-89 years). Thirty-three (41%) patients in the hypomethylating group achieved complete remission (CR) versus 53 (35%) in the chemotherapy group (P=.395). With a median follow-up of 51 weeks (range, 12-101 weeks) and 40 weeks (range, 5-128 weeks), 22 of 33 patients in the hypomethylating group and 33 of 53 patients in the chemotherapy group had developed disease recurrence. The median CR duration was 45 weeks and 23 weeks, respectively (P=.153). The overall survival was superior for the hypomethylating group compared with the chemotherapy group (P=.019).
Treatment with hypomethylating agents may be superior to chemotherapy in patients with chromosome 5 and 7 abnormalities.
Cancer 09/2009; 115(24):5746-51. · 4.77 Impact Factor
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Hagop Kantarjian,
Susan O'Brien,
Farhad Ravandi,
Gautam Borthakur,
Stefan Faderl,
Carlos Bueso-Ramos,
Lynne Abruzzo,
Sherry Pierce,
Jianqin Shan, Jean-Pierre Issa,
Guillermo Garcia-Manero
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ABSTRACT: To define the prognosis in myelodysplastic syndrome (MDS) and deletion 5q with or without other cytogenetic abnormalities.
Patients with MDS (<20% blasts) and evaluable cytogenetic studies (1966-present) were reviewed. Outcome of patients with deletion 5q or with loss of chromosome 5 (monosomy 5) was analyzed.
Of 2743 patients analyzed, 287 (10%) had deletion 5q and 216 (8%) had monosomy 5 abnormalities. The median survival was 9 months with deletion 5q, 6 months with monosomy 5, and 17 months without a chromosome 5 abnormality. Considering patients with deletion 5q, the median survival was 33 months with deletion 5q alone, 17 months with deletion 5q and 1 additional abnormality, but only 6 months to 12 months with deletion 5q and > or =2 abnormalities or chromosome 7 abnormality. Only 93 patients (3.4% of total) had lower risk MDS (international prognostic scoring system low or intermediate 1) and deletion 5q; their median survival was 29 months (2-year survival 60%), and ranged from 13-41 months depending on the presence or absence of additional chromosomal abnormalities. Among 198 patients with MDS with deletion 5q and <10% blasts (a subset now often offered lenalidomide), the median survival was 12 months. Monosomy 5 was significantly more frequently associated with advanced MDS and with other chromosomal abnormalities.
This study provided baseline expectations of outcome in different MDS subsets and deletion 5q.
Cancer 08/2009; 115(22):5202-9. · 4.77 Impact Factor
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ABSTRACT: By hypomethylating genes, decitabine may up-regulate factors required for chemotherapeutic cytotoxicity. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1.
Thirty-one patients with refractory malignancies received decitabine 2.5 to 10 mg/m(2) on days 1 to 5, and 8 to 12 or 15 to 20 mg/m(2) on days 1 to 5. Tumor was assessed for DNA methylation (by LINE assays), apoptosis, necrosis, mitoses, Ki67, DNA methyltransferase (DNMT1), CTR1, and p16.
Febrile neutropenia was dose limiting. One thymoma patient responded. Decitabine decreased tumor DNA methylation (from median 51.2% predecitabine to 43.7% postdecitabine; P = 0.01, with effects at all doses) and in peripheral blood mononuclear cells (from 65.3-56.0%). There was no correlation between tumor and peripheral blood mononuclear cells. Patients starting decitabine < or =3 versus >3 months after last prior cytotoxic or targeted therapy had lower predecitabine tumor CTR1 scores (P = 0.02), higher p16 (P = 0.04), and trends (P = 0.07) toward higher tumor methylation and apoptosis. Decitabine decreased tumor DNMT1 for scores initially >0 (P = 0.04). Decitabine increased tumor apoptosis (P < 0.05), mitoses (if initially low, P = 0.02), and CTR1 (if initially low, P = 0.025, or if < or =3 months from last prior therapy, P = 0.04). Tumor CTR1 scores correlated inversely with methylation (r = -0.41, P = 0.005), but CTR1 promoter was not hypermethylated. Only three patients had tumor p16 promoter hypermethylation. P16 scores did not increase. Higher blood pressure correlated with lower tumor necrosis (P = 0.03) and a trend toward greater DNA demethylation (P = 0.10).
Exposure to various cytotoxic and targeted agents might generate broad pleiotropic resistance by reducing CTR1 and other transporters. Decitabine decreases DNA methylation and augments CTR1 expression through methylation-independent mechanisms.
Clinical Cancer Research 07/2009; 15(11):3881-8. · 7.74 Impact Factor
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Ana Aparicio,
Brittany North,
Lindsey Barske,
Xuemei Wang,
Valentina Bollati,
Daniel Weisenberger,
Christine Yoo,
Nizar Tannir,
Erin Horne,
Susan Groshen,
Peter Jones,
Allen Yang, Jean-Pierre Issa
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ABSTRACT: Multiple clinical trials are investigating the use of the DNA methylation inhibitors azacitidine and decitabine for the treatment of solid tumors. Clinical trials in hematological malignancies have shown that optimal activity does not occur at their maximum tolerated doses but selection of an optimal biological dose and schedule for use in solid tumor patients is hampered by the difficulty of obtaining tumor tissue to measure their activity. Here we investigate the feasibility of using plasma DNA to measure the demethylating activity of the DNA methylation inhibitors in patients with solid tumors. We compared four methods to measure LINE-1 and MAGE-A1 promoter methylation in T24 and HCT116 cancer cells treated with decitabine treatment and selected Pyrosequencing for its greater reproducibility and higher signal to noise ratio. We then obtained DNA from plasma, peripheral blood mononuclear cells, buccal mucosa cells and saliva from ten patients with metastatic solid tumors at two different time points, without any intervening treatment. DNA methylation measurements were not significantly different between time point 1 and time point 2 in patient samples. We conclude that measurement of LINE-1 methylation in DNA extracted from the plasma of patients with advanced solid tumors, using Pyrosequencing, is feasible and has low within patient variability. Ongoing studies will determine whether changes in LINE-1 methylation in plasma DNA occur as a result of treatment with DNA methylation inhibitors and parallel changes in tumor tissue DNA.
Epigenetics: official journal of the DNA Methylation Society 05/2009; 4(3):176-84. · 4.58 Impact Factor
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ABSTRACT: Increased survival is a common goal of cancer clinical trials. Owing to the long periods of observation and follow-up to assess patient survival outcome, it is difficult to use outcome-adaptive randomization in these trials. In practice, often information about a short-term response is quickly available during or shortly after treatment, and this short-term response is a good predictor for long-term survival. For example, complete remission of leukemia can be achieved and measured after a few cycles of treatment. It is a short-term response that is desirable for prolonging survival. We propose a new design for survival trials when such short-term response information is available. We use the short-term information to 'speed up' the adaptation of the randomization procedure. We establish a connection between the short-term response and the long-term survival through a Bayesian model, first by using prior clinical information, and then by dynamically updating the model according to information accumulated in the ongoing trial. Interim monitoring and final decision making are based upon inference on the primary outcome of survival. The new design uses fewer patients, and can more effectively assign patients to the better treatment arms. We demonstrate these properties through simulation studies.
Statistics in Medicine 04/2009; 28(12):1680-9. · 1.88 Impact Factor
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ABSTRACT: In plants and animals, gene expression can be altered by changes not to DNA itself but rather chemical modifications either to DNA or to histones that interact with DNA. These so called epigenetic modifications persist through cell cycle. Rapidly advancing technologies, such next generation DNA sequencing, have dramatically increased our ability to survey epigenetic markers genomewide. These techniques are revealing in great details massive epigenetic changes in cancer. Analysis of next generation sequencing data present a formidable computational challenge. We will discuss methods to address these challenges in the context of analyzing histone modifications and DNA methylation data. Several techniques useful in epigenetic data analysis will be discussed, mapping tags to reference genome incorporating all known SNPs, analysis of chIP-seq data, as well as restriction enzyme-based DNA methylation analysis.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 01/2009; 2009:6730.
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Jean-Pierre Issa
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ABSTRACT: Combined genetic and epigenetic analysis of sporadic colon cancer suggest that it can no longer be viewed as a single disease. There are at least three different subsets with distinct clinico-pathologic features, with important implications for preventions, screening, and therapy.
Clinical Cancer Research 11/2008; 14(19):5939-40. · 7.74 Impact Factor
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Jean-Pierre Issa
Cancer Prevention Research 10/2008; 1(4):219-22. · 4.91 Impact Factor
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Hagop Kantarjian MD,
O&apos,
Susan Brien,
Jorge Cortes,
William Wierda,
Stefan Faderl,
Guillermo Garcia‐Manero, Jean‐Pierre Issa,
Elihu Estey,
Michael Keating,
Emil J. Freireich,
Hagop Kantarjian,
Susan O'Brien
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ABSTRACT: Major therapeutic progress has been accomplished in leukemia and myelodysplastic syndrome (MDS) over the past 40 years, which may not be fully appreciated by the larger medical community. The objective of this review was to briefly highlight the treatment breakthroughs in leukemia and MDS. Therapeutic progress happened through better understanding of disease pathophysiologies and rational development of targeted agents, like imatinib mesylate in chronic myeloid leukemia (CML), and through astute, empirical discoveries in the clinic, like all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia (APL) and chlorodeoxyadenosine in hairy cell leukemia (HCL). Today, the 5- to 10-year survival rates in patients with APL and HCL exceed 80%. In patients with CML, imatinib therapy has been associated with estimated 5- to 7-year survival rates from 85% to 90%. In patients with adult acute lymphocytic leukemia, modern intensive regimens have improved the 5-year survival rates from 20% up to 40%. In patients with chronic lymphocytic leukemia, chemoimmunotherapy recently produced high rates of quality responses and improved long-term outcome. In younger patients with acute myeloid leukemia (AML), the 5-year survival rates range from 40% to 50%, although elderly AML remains a therapeutic challenge. In patients with MDS, it was recently demonstrated that epigenetic therapy with hypomethylating agents improved survival. Much therapeutic progress has been witnessed in leukemia and MDS, and much more is expected to occur soon. Cancer 2008;113(7 suppl):1933–52. © 2008 American Cancer Society.
Cancer 09/2008; 113(S7):1933 - 1952. · 4.77 Impact Factor
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Tadeusz Majewski,
Sangkyou Lee,
Joon Jeong,
Dong-Sup Yoon,
Andrzej Kram,
Mi-Sook Kim,
Tomasz Tuziak,
Jolanta Bondaruk,
Sooyong Lee,
Weon-Seo Park, [......],
Henry T Lynch,
Adi Gazdar,
Menashe Bar-Eli,
Xifeng F Wu,
David J McConkey,
Keith Baggerly, Jean-Pierre Issa,
William F Benedict,
Steven E Scherer,
Bogdan Czerniak
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ABSTRACT: The search for the genomic sequences involved in human cancers can be greatly facilitated by maps of genomic imbalances identifying the involved chromosomal regions, particularly those that participate in the development of occult preneoplastic conditions that progress to clinically aggressive invasive cancer. The integration of such regions with human genome sequence variation may provide valuable clues about their overall structure and gene content. By extension, such knowledge may help us understand the underlying genetic components involved in the initiation and progression of these cancers. We describe the development of a genome-wide map of human bladder cancer that tracks its progression from in situ precursor conditions to invasive disease. Testing for allelic losses using a genome-wide panel of 787 microsatellite markers was performed on multiple DNA samples, extracted from the entire mucosal surface of the bladder and corresponding to normal urothelium, in situ preneoplastic lesions, and invasive carcinoma. Using this approach, we matched the clonal allelic losses in distinct chromosomal regions to specific phases of bladder neoplasia and produced a detailed genetic map of bladder cancer development. These analyses revealed three major waves of genetic changes associated with growth advantages of successive clones and reflecting a stepwise conversion of normal urothelial cells into cancer cells. The genetic changes map to six regions at 3q22-q24, 5q22-q31, 9q21-q22, 10q26, 13q14, and 17p13, which may represent critical hits driving the development of bladder cancer. Finally, we performed high-resolution mapping using single nucleotide polymorphism markers within one region on chromosome 13q14, containing the model tumor suppressor gene RB1, and defined a minimal deleted region associated with clonal expansion of in situ neoplasia. These analyses provided new insights on the involvement of several non-coding sequences mapping to the region and identified novel target genes, termed forerunner (FR) genes, involved in early phases of cancer development.
Laboratory Investigation 08/2008; 88(7):694-721. · 3.64 Impact Factor
