Novel and Uncommon Chromosome Aberrations in Chronic Lymphocytic Leukemia: Cytogenetic, FISH and Clinical Evaluation

The identification of the non-random genetic alterations associated with cancer has great importance not only to basic research but also to disease management as diagnostic and prognostic markers. In contrast to other types of lymphomas, translocations are rare events in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and not any CLL/SLL-specific translocation has been found yet. Moreover, translocations have been reported to be a prognostic marker for an unfavorable clinical outcome. The purpose of our study was to contribute to the understanding of the chromosome alterations associated with this group of lymphoid malignancies. The combination of conventional cytogenetics with FISH (fluorescence in situ hybridization) analysis allowed us a more accurate definition of the genomic aberrations involved in CLL/SLL. Novel and uncommon chromosome rearrangements were found in our series. In the present work, we describe the cytogenetic and FISH analyses of 12 CLL/SLL patients out of 150 cases with successful cytogenetic study, that interestingly showed in their karyotypes new or infrequent clonal chromosome rearrangements, all of them associated to adverse clinical course with partial or null response to different chemotherapeutic agents. We identified 16 different chromosome rearrangements and translocations were the most frequent aberration (7/16; 43,8%). Some of these findings were recently reported by us as a new alterations in SLL/CLL patients: t(2;17)(p21;q23); der(17)t(12;17)(q13;q25); der(14)(t(11;14)(q13;q24), t(5;12;19)(q15;p11;q13); psu dic (17;2)(p11.2;p21), psu dic (12;21)(q24;q10), t(10;14)(q22;q32), del(3)(p11) and del(5)(q15). Translocation t(11;13)(p15;q22) and del(18)(p11) were not previously described, meanwhile, dic(17;18)(p11.2;p11.2), dup(12)(q13q24), del(7)(q34), t(2;14)(p11;q32) and del(7)(q11) were infrequently reported in the literature. Translocation t(2;17)(p21;q23) is recurrent in our series and t(2;14)(p11;q32) became recurrent from our data. Chromosomes 17, 2, 12 and 14 were the most frequently involved. Twenty one different breakpoints were found and 38.1% (8/21) of them, such as 2p21, 5q15, 17p11.2, 17q23, 12q13, 12q24, 14q32 and 18p11 were recurrent in our series. All but one patient of our series showed an unfavorable clinical outcome. A detailed analysis and a review of the cytogenetic and molecular cytogenetics findings in CLL/SLL were performed. Our findings may facilitate the understanding of genetic events associated with development and progression of CLL/SLL and may have implications in the clinical management of patients with this disease.Fil: Cerretini, Roxana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Chena, Christian. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Slavutsky, Irma Rosa. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Secondary genomic alterations in follicular lymphomas

Follicular lymphoma (FL) is the second most common subtype of B-cell non-Hodgkin lymphoma (NHL) in the Western world. It is genetically characterized by t(14;18)(q32;q21) translocation that determines the juxtaposition of BCL2 gene in 18q21.3 with the immunoglobulin in heavy chain (IGH) gene at 14q32.33. This translocation is observed in 70%-80% of cases and, by itself is not sufficient to explain either FL biology or clinical outcome. Additional changes are necessary to generate a fully malignant clonal proliferation. Many of these secondary genetic aberrations are visible in the clonal karyotype, but the sequence by which they arise and their influence on clinical behaviour has not been determined yet. In the present study, we analyzed 12 cases with diagnosis of FL with abnormal karyotypes in order to identify secondary genetic alterations associated with t(14;18)(q32;q21)-positive and negative subsets. Cytogenetic, FISH (fluorescence in situ hybridization) and molecular studies were used to a more accurate definition of these rearrangements. By classical cytogenetics, translocation t(14;18)(q32;q21) was observed in 7 (58.3%) cases. FISH and molecular studies demonstrated that BCL2/IGH rearrangements were also present in other 2 (16,7%) cases and the remainder 3 (25%) were negative patients. Seventy five percent of secondary alterations of this series were unbalanced rearrangements with loss of chromosome regions. As a whole, chromosome 1 was the most frequently involved in structural rearrangements followed by chromosomes 3 and 6. Overall, t(3;14)(q27;q32), dup(1)(q21q32), del(6)(q21) and del(6)(q23) were recurrent in our series. Translocations at 3q27 and genomic gains on 1q21-q32 were more frequent in t(14;18)(q32;q211) positive subset. The most common breakpoints were 3q27, 1q21 and 1q32 other than 14q32 and 18q21. Fourteen novel rearrangements associated and non associated to t(14;18)(q32;q21) translocation were described. Trisomies 21, 2, 20, 12 and 9 and monosomy 13 were recurrent in our series. According to the literature, our patients showed a great karyotypic instability with different types of chromosome aberrations that appeared to be involved in tumor development and disease progression. These genomic abnormalities reflect the heterogeneity of this pathology. They do not occur randomly and some of them target genes important for the survival and tumor progression. So, it is important to go on with this type of studies in order to know the biological basis of clinical heterogeneity among FL patients that could lead to development of novel therapeutics.Fil: Cerretini, Roxana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Noriega, Maria Fernanda. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Slavutsky, Irma Rosa. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

New chromosome abnormalities and lack of BCL-6 gene rearrangements in Argentinean diffuse large B-cell lymphomas

Objectives: Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphomas. Cytogenetic studies have revealed a broad spectrum of clonal genetic abnormalities and complex karyotypes. The purpose of this study was to contribute to the understanding of the genomic alterations associated with this group of lymphomas. Methods: Cytogenetic, fluorescence in situ hybridization (FISH) and molecular analyses were performed in 30 cases with DLBCL: 20 de novo DLBCL (dn-DLBCL) and 10 DLBCL secondary to follicular lymphoma (S-DLBCL). Results: A total of 37 different structural chromosomal rearrangements were found: 27% translocations, 54% deletions, and 19% other alterations. Chromosomes 8, 6, 2, and 9 were the most commonly affected. Interestingly, translocation t(3;14)(q27;q32) and/or BCL-6 gene rearrangements were not observed either by cytogenetic studies or by FISH analysis. Fifteen novel cytogenetic alterations were detected, among them translocations t(2;21)(p11;q22) and t(8;18)(q24;p11.3) appeared as sole structural abnormalities. Translocation t(14;18)(q32;q21) and/or BCL-2-IGH gene rearrangements were the genomic alterations most frequently observed: 50% of S-DLBCL and 30% of dn-DLBCL. Deletions del(4)(q21), del(6)(q27), del(8)(q11), and del(9)(q11) were recurrent. The most common gains involved chromosome regions at 12q13-q24, 7q10-q32, and 17q22-qter; 6q was the most frequently deleted region, followed by losses at 2q35-qter, 7q32-qter, and 9q13-qter. Four novel regions of loss were identified: 5q13-q21, 2q35-qter (both recurrent in our series), 4p11-p12, and 17q11-q12. Conclusions: These studies emphasize the value of combining conventional cytogenetics with FISH and molecular studies to allow a more accurate definition of the genomic aberrations involved in DLBCL. © 2006 Blackwell Munksgaard.Fil: Cerretini, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Noriega, Maria Fernanda. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Narbaitz, Marina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentin

Evaluation of constitutional chromosome aberrations in hematologic disorders

We have reviewed 4164 patients with various hematologic disorders cytogenetically studied in our laboratory during the last 25 years to analyze the frequency of constitutional chromosome aberrations (CCA) and to evaluate their association with hematologic malignancies. Our population of patients included 1133 pediatric patients and 3031 adults. Twenty-four (0.58%) cases showed CCA. They included four patients with Robertsonian translocations, one patient with a balanced translocation, two patients with sex chromosome abnormalities, and 17 cases with Down syndrome (DS). Nonsignificant differences among the frequency of patients with CCA from our hematologic series and those observed in the two largest combined surveys of livebirth published (0.65-0.84%) were found. The incidence of DS patients in our population (0.41%) was approximately three times higher than of that observed at birth (0.12-0.17%; P<0.001). The total incidence of constitutional chromosome abnormalities in the non-DS hematologic patients was 0.168% (7 of 4164) lower than of that observed in the newborn population (0.51-0.67%; P<0.001). Nonsignificant differences were found when the incidences of structural aberrations and sex chromosome anomalies were individually compared with the data of the overall population. Our results suggest that the presence of a CCA, other than DS, would not predispose patients to hematologic malignancies. © 2002 Elsevier Science Inc. All rights reserved.Fil: Cerretini, Roxana. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; ArgentinaFil: Acevedo, Susana Haydee. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Chena, Christian. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Belli, Carolina Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentin

Microcephaly, characteristic facies, joint abnormalities, and deficient leucocyte chemotaxis: a further case of the syndrome of Say et al

Fil: Perandones, Claudia. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Cerretini, Roxana Inés. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Vargas Vera, R. M. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Aranda, Eliseo Isaac. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Alba, Liliana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.Fil: Pivetta, Omar H. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina.We report on a 13 year old boy with microcephaly, sloping forehead, prominent nose, scoliosis, and flexion contractures involving the elbows and knees. The patient showed severe mental and growth retardation. Since birth and up to the present he has suffered from multiple and varied infections. Immunological studies showed a marked decrease in leucocyte chemotaxis. Clinical and laboratory findings confirm the similarity of this case to the two brothers described by Say et al. We have not found any descriptions of similar patients. The purpose of this paper is to contribute to the phenotypic delineation of this syndrome and to highlight the need for immunological investigation in patients with multiple congenital malformations

TRIO-related intellectual disability with microcephaly: a case report of a patient with novel clinical findings

Fil: Bevilacqua, Florencia. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica. Departamento de Diagnóstico Médico; Argentina.Fil: Alberto, Guillermo. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica. Departamento de Diagnóstico Médico; Argentina.Fil: Duarte, Santiago Pablo. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica. Departamento de Diagnóstico Médico; Argentina.Fil: Serra, Marina. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica. Departamento de Diagnóstico Médico; Argentina.Fil: Basterra, Julieta. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica. Departamento de Diagnóstico Médico; Argentina.Fil: Espeche, Lucía. Department of Clinical GeneticsFil: Cerretini, Roxana Inés. Department of Clinical GeneticsFil: Solari, Andrea Paula. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica. Departamento de Diagnóstico Médico; Argentina

Germline pathogenic variants in BRCA1, BRCA2, PALB2 and RAD51C in breast cancer women from Argentina

Fil: Cerretini, R. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica Dr. Eduardo Castilla; Argentina.Fil: Mercado, G. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica Dr. Eduardo Castilla; Argentina.Fil: Morganstein, Josh. Women’s College Research InstituteWomen’s College Hospital; CanadaFil: Schiaffi, Jorge. Sección de Patología Mamaria. Servicio de Ginecología Hospital Bernardino Rivadavia; Buenos Aires; ArgentinaFil: Reynoso, M. Servicio de Ginecología. Hospital Evita de Lanús; Buenos Aires; ArgentinaFil: Montoya, D. Servicio de Patología Mamaria. Instituto de Oncología Dr. Angel H Roffo; Buenos Aires; ArgentinaFil: Valdez, R. Servicio de Genética. Hospital Militar Central; Buenos Aires; ArgentinaFil: Narod, SA. Dalla Lana School of Public Health. University of Toronto; Toronto; CanadáFil: Akbari, MR. Women’s College Research Institute. Women’s College Hospital; CanadaEach year, 17,000 new breast cancer cases are diagnosed in Argentina, and 5400 women die of breast cancer. The contribution of cancer-related mutations to the incidence of breast cancer in Argentina has not yet been explored

Inversions of chromosomes 2 and 6 in mantle cell lymphoma. Cytogenetic, FISH, and molecular studies

Inversions are infrequent events in hematological malignancies. We here report the cytogenetic, fluorescence in situ hybridization (FISH), and molecular studies of 2 patients diagnosed with mantle cell lymphoma (MCL) that showed inversions of chromosomes 2 and 6 as part of complex karyotypes. Both patients showed a cytogenetically identical inv(6)(p23q11) detected as a secondary aberration. In addition, both patients had a derivative chromosome 2 which originated by partial deletion of the short arm and a pericentric inversion with different breakpoints on the long arm: der(2)del(2)(p21)inv(2)(p21q11) and der(2)del(2)(p21)inv(2)(p21q13), respectively. The presence of t(11;14)(q13;q32) was confirmed by interphase FISH and by molecular study. Residual normal cells were found in both cases. The patients showed a different clinical evolution with a poor outcome for one case and a favorable course of the disease for the other one. The review of the literature in MCL showed a total of 9 inversions affecting different chromosomes. Considering that inversions are very infrequent events in MCL, our findings could be important for detecting genes potentially involved in development and/or progression of this aggressive non-Hodgkin lymphoma subtype. © 2006 Elsevier Inc. All rights reserved.Fil: Pedrazzini, Estela Marta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Cerretini, Roxana. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; ArgentinaFil: Noriega, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Narbaitz, Marina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Palacios, María Fernanda. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Negri, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Provincia de Entre Rios. Hospital San Martin; ArgentinaFil: Bengió, Raquel. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; Argentin

Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina

Fil: Bañares, Virginia G. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina. Departamento de Genética Experimental; Argentina.Fil: Corral, Pablo. Universidad FASTA. Facultad de Medicina. Departamento Investigación; Argentina.Fil: Medeiros, Ana Margarida. Instituto Nacional de Saúde Dr Ricardo Jorge. Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis. Grupo de Investigação Cardiovascular. University of Lisbon. BioISI - Biosystems & Integrative Sciences Institute. Faculty of Sciences; Portugal.Fil: Araujo, Maria Beatriz. Hospital Garrahan. Servicio de Nutrición, Ciudad Autónoma de Buenos Aires; Argentina.Fil: Lozada, Alfredo. Universidad Austral. Clínica de Lípidos; Argentina.Fil: Bustamante, Juan. IQUIBICEN-CONICET. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; Argentina.Fil: Cerretini, Roxana. ANLIS Dr.C.G.Malbrán. Centro Nacional de Genética Médica; Argentina. Departamento de Genética Experimental; Argentina.Fil: Lopez, Graciela I. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica. Laboratorio de Lípidos y Aterosclerosis; Argentina; Universidad de Buenos Aires, Instituto de Fisiopatologia y Bioquímica Clinica - INFIBIOC; Argentina.Fil: Bourbon, Mafalda. Instituto Nacional de Saúde Dr Ricardo Jorge. Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis. Grupo de Investigação Cardiovascular. University of Lisbon. BioISI - Biosystems & Integrative Sciences Institute. Faculty of Sciences; Portugal.Fil: Schreier, Laura E. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica. Laboratorio de Lípidos y Aterosclerosis; Argentina; Universidad de Buenos Aires, Instituto de Fisiopatologia y Bioquímica Clinica - INFIBIOC; Argentina.Background: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol and early cardiovascular disease. As cardiovascular disease is a leading cause of mortality in Argentina, early identification of patients with FH is of great public health importance. Objective: The aim of our study was to identify families with FH and to approximate to the characterization of the genetic spectrum mutations of FH in Argentina. Methods: Thirty-three not related index cases were selected with clinical diagnosis of FH. Genetic analysis was performed by sequencing, multiplex ligation-dependent probe amplification, and bioinformatics tools. Results: Twenty genetic variants were identified among 24 cases (73%), 95% on the low-density lipoprotein receptor gene. The only variant on APOB was the R3527Q. Four were novel variants: c.-135C>A, c.170A>C p.(Asp57Ala), c.684G>C p.(Glu228Asp), and c.1895A>T p.(Asn632Ile); the bioinformatics' analysis revealed clear destabilizing effects for 2 of them. The exon 14 presented the highest number of variants (32%). Four variants were observed in more than 1 case and the c.2043C>A p.(Cys681*) was carried by 18% of index cases. Two true homozygotes, 3 compound heterozygotes, and 1 double heterozygote were identified. Conclusion: This study characterizes for the first time in Argentina genetic variants associated with FH and suggest that the allelic heterogeneity of the FH in the country could have 1 relative common low-density lipoprotein receptor mutation. This knowledge is important for the genotype-phenotype correlation and for optimizing both cholesterol-lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of FH in Argentina. Keywords: APOB; Argentina; Cardiovascular disease; Cardiovascular disease prevention; Cholesterol; Familial hypercholesterolemia; Genetic variants; LDLR gene; Mutations; Public health