Secondary Abnormalities Research Articles

Genetic lesions in a preleukemic aplasia phase in a child with acute lymphoblastic leukemia

In a small fraction ( approximately 2%) of cases of childhood acute lymphoblastic leukemia (ALL) clinical presentation of leukemia is preceded, some 2-9 months earlier, by a transient, remitting phase of nonclassical aplastic anemia, usually in connection with infection. The potential "preleukemic" nature of this prodromal phase has not been fully explored. We have retrospectively analyzed the blood and bone marrow of a child who presented with aplastic anemia 9 months before the development of ETV6-RUNX1 fusion gene positive ALL. High resolution SNP genotyping arrays identified 11 regions of loss of heterozygosity, with and without concurrent copy number changes, at the presentation of ALL. In all cases of copy number change, the deletion or gain identified by single nucleotide polymorphism (SNP) analysis was confirmed in the ALL blasts by FISH. Retrospective analysis of aplastic phase bone marrow showed that the ETV6-RUNX1 fusion was present along with all of the additional genetic changes assessed, albeit subclonal to ETV6-RUNX1. These data identify for the first time the leukemic genotype of an aplasia preceding clinical ALL and indicate that multiple secondary genetic abnormalities can contribute to a dominant subclone several months before a diagnosis of ALL. These data have implications for the biology of ALL and for management of similar patients.

Intellectual disability: definition, etiological factors, classification, diagnosis, treatment and prognosis

ETIOLOGY AND CLASSIFICATION: Causal factors related with cognitive disability are multiples and can be classified as follows: Genetic, acquired (congenital and developmental), environmental and sociocultural. Likewise, in relation to the classification, cognitive disability has as a common denominator a subnormal intellectual functioning level; nevertheless, the extent to which an individual is unable to face the demands established by society for the individuals age group has brought about four degrees of severity: Mild, moderate, severe and profound. The clinical history must put an emphasis on healthcare during the prenatal, perinatal and postnatal period and include the results of all previous studies, including a genealogical tree for at least three generations and an intentional search for family antecedents of mental delay, psychiatric illnesses and congenital abnormalities. The physical exam should focus on secondary abnormalities and congenital malformations, somatometric measurements and neurological and behavioral phenotype evaluations. If it is not feasible to establish a clinical diagnosis, it is necessary to conduct high-resolution cytogenetic studies in addition to metabolic clinical evaluations. In the next step, if no abnormal data are identified, submicroscopic chromosomal disorders are evaluated. Intellectual disability is not curable; and yet, the prognostic in general terms is good when using the emotional wellbeing of the individual as a parameter. Intellectual disability should be treated in a comprehensive manner. Nevertheless, currently, the fundamental task and perhaps the only one that applies is the detection of the limitation and abilities as a function of subjects age and expectations for the future, with the only goal being to provide the support necessary for each one of the dimensions or areas in which the persons life is expressed and exposed.

C-MYC translocation in t(14;18) positive follicular lymphoma at presentation: An adverse prognostic indicator?

Follicular lymphoma (FL) is a common subtype of low grade B-cell non-Hodgkin lymphoma (NHL). Although this form of lymphoma often pursues an indolent course, in some cases it may behave in a more aggressive manner. Clinical and histological parameters have been shown to correlate with an adverse prognosis but a number of cytogenetic abnormalities may also be associated with aggressive disease. Although, the t(14;18) in itself does not affect outcome in cases of FL, secondary abnormalities that occur in a complex polyploid karyotype may identify cases with a poor prognosis. It is unusual to find both t(14;18) and C-MYC translocation in the same tumour; those cases in which it has been described include examples of high-grade B-cell NHL (either de novo or transformed FL) or B-cell acute lymphoblastic lymphoma. In this report, three cases of FL are described in which both t(14;18) and a C-MYC translocation were identified at presentation. We also summarize four further cases from the literature. This is a small series but one which raises the possibility that the presence of a C-MYC translocations at presentation may identify a particularly aggressive subtype of FL. Further studies are required to investigate the true incidence of this aberration, the impact on C-MYC regulation, clinical course and response to treatment.

Disruption of the ETV6 gene as a consequence of a rare translocation (12;12)(p13;q13) in treatment-induced acute myeloid leukemia after breast cancer

We describe a case of treatment-induced acute myeloid leukemia M2 after breast cancer with a rare reciprocal t(12;12)(p13;q13) as a secondary cytogenetic abnormality in addition to the t(11;19)(q23;p13.1). Fluorescence in situ hybridization analysis revealed that both ETV6 genes (previously TEL) were located on the same der(12)t(12;12) as a result of t(12;12). Interestingly, the translocated ETV6 gene was disrupted, indicating the breakpoint on the large der(12)t(12;12) to be within the ETV6 gene and thus the possible formation of a new fusion gene. CHOP gene at 12q13, was found to be translocated intact to the other homologue chromosome 12, indicating that the breakpoint on the small der(12) is proximal to CHOP. To the best of our knowledge, our patient represents the first report of the rare t(12;12)(p13;q13) described in treatment-induced leukemia and the possible formation of a new fusion gene.

Amplification of BCR–ABL and t(3;21) in a patient with blast crisis of chronic myelogenous leukemia

The Philadelphia (Ph) chromosome, or t(9;22), is the hallmark of chronic myelogenous leukemia (CML). It results in juxtaposition of the 5′ part of the BCR gene on chromosome 22 to the 3′ part of the ABL1 gene (previously ABL) on chromosome 9. CML is clinically characterized by three distinct phases: chronic, accelerated, and blast phase. Blast crisis is characterized by the rapid expansion of a population of differentiation arrested blast cells (myeloid or lymphoid cells population), with secondary chromosomal abnormalities present. We report a case of myeloid blast crisis of CML resistant to imatinib mesylate and chemotherapy. By use of cytogenetic, fluorescence in situ hybridization, and comparative genomic hybridization methods, we identified a cluster of BCR–ABL amplification on inverted duplication of the Ph chromosome with t(3;21)(q26;q22) and increased genomic levels of the RUNX1 gene (previously AML1). The t(3;21)(q26;q22) is a recurrent chromosomal abnormality in some cases of CML blast phase and in treatment-related myelodysplastic syndrome and acute myeloid leukemia. Amplification or copy number increase of RUNX1 has been reported in childhood acute lymphoblastic leukemia. Our study indicated that the progenitor of CML was BCR–ABL dependent through the amplification of Ph chromosome as a mechanism of resistance to imatinib therapy. The coexistence of BCR–ABL and t(3;21)(q26;q22) with RUNX1 rearrangement might play a pivotal role in the CML blast transformation.

Clonal evolution with + 11q 13, t(1;7) and t(1;4) at relapse in a patient with Ph positive acute lymphocytic leukemia (ALL) treated with single agent front line imatinib followed by dasatinib

Imatinib, a selective ABL kinase inhibitor has improved therapeutic outcome in patients with Philadelphia positive chronic or acute leukemia. In the present study, we describe a 56-year-old male with Philadelphia chromosome positive acute lymphocytic leukemia (ALL) who was treated with up-front single agent imatinib and achieved complete hematologic, cytogenetic and molecular remission. At relapse 11 months later, new chromosomal translocations involving chromosomes 1, 7 and 4 and cryptic addition to chromosome 11 were identified in Ph + cells and the patient had rapid deterioration with progressive disease. The significance of additional chromosomal abnormalities in imatinib treated patients and secondary chromosomal abnormalities in Philadelphia positive chronic myeloid leukemia and ALL are discussed briefly in this report.

Effective Telomerase Inhibition Via Expression of Dominant-Negative HTERT Leads to Altered Growth Kinetics, Elevated Apoptosis and Increased Radiosensitivity of Bcr-Abl-Positive K562 Cells In Vitro.

Disease progression in CML is associated with accelerated telomere shortening caused by increased turnover of Bcr-Abl positive cells. We have recently proposed a model in which continuous telomere shortening is correlated with increasing genetic instability in Bcr-Abl-positive cells thus facilitating the acquisition of secondary genetic abnormalities and, as a consequence clonal succession and eventually clinical progression of the disease. Based on this hypothesis, telomerase upregulation in late stage disease is a prerequisite for prevention of replication-induced senescence in Bcr-Abl positive cells. As a consequence, treatment of CML with Telomerase inhibitors (TI) represents an attractive strategy aiming at the potential eradication of cycling CML stem cells. Therefore, we have exploited both pharmacological (small molecule inhibitor) and genetic strategies (dominant negative hTERT mutants, DN-hTERT) of telomerase inhibition in CML cells in vitro We first treated K562 cells with the pharmacological telomerase inhibitor BIBR1532 in vitro. After around 400 population doublings (PD), no differences in growth kinetics nor signs of senescence or apoptosis were observed in BIBR1532 treated cells despite of significant telomere shortening (22 base pairs (bp) per PD) compared to control cells. Furthermore, neither significant differences in mRNA expression of telomere/telomerase-associated proteins, nor accumulation of double strand breaks (DSBs) under irradiation was observed in treated cells with short telomeres as opposed to untreated control cells. The very slow shortening rate of 22bp/PD plus the lack of stigmata pointing to induction of senescence in K562 cells lead to the assumption that telomerase activity is not complete inhibited by the compound. In order to verify the potency of telomerase directed treatments in CML, we therefore expressed DN-hTERT in K562 cells. Integration of DN-hTERT led to a significant decrease in telomerase activity (measured by RQ-TRAP). Furthermore, DN-hTERT expressing cells underwent accelerated telomere shortening at a substantially higher rate (>100 bp/PD) from 15kb to around 4kb within 110 days of culture. In contrast to BIBR1532-treated cells, DN-hTERT expressing K562 cells slowed down growth kinetic in comparison to control cells after 80 days of culture. By using Annexin 5 staining, 25% of apoptotic cells could be detected in cells with critically short telomeres as compared to control cells (<3%). Finally, a significantly increased accumulation of double strand breaks (DSBs) detected by gammaH2AX foci after exposure to irradiation was observed in DN-hTERT K562 cells as compared to control cells pointing to an impaired DNA repair machinery in Bcr-Abl positive cells with disrupted telomere maintenance. In summary, the data suggest that pharmacological telomerase inhibition by BIBR1532 is insufficient to induce telomere-mediated senescence in Bcr-Abl-positive cells. However, accelerated telomere shortening, slowing down of growth kinetics, elevated apoptosis and increased radiosensitivity induced by expression of DN-hTERT indicate a therapeutic potential for telomerase-directed treatment strategies in CML.

Clinical and Pathologic Analysis of 16 Cases of Relapsed Chronic Myeloid Leukemia After Stem Cell Transplantation

Chronic myeloid leukemia (CML) is a myeloproliferative disease that originates in an abnormal pluripotent bone marrow stem cell and is characteristically associated with the Philadelphia chromosome and/or the bcr/abl fusion gene. Despite the exciting success of the bcr/abl tyrosine kinase-specific inhibitor imatinib for CML treatment, hematopoietic stem cell (bone marrow or peripheral blood stem cell) transplantation (HCT) remains the only "curative" approach for the majority of patients. Although HCT outcomes for patients with CML have improved considerably during the past 2 decades, relapse after HCT may occur. We analyzed the clinical and pathologic features of 16 cases of hematologically relapsed CML after HCT during a 5-year period at City of Hope National Medical Center, Duarte, CA. The results of our analysis showed that relapsed CML after HCT frequently manifested with advanced disease with a more aggressive clinical course and was often refractory to therapy. The frequency of acute leukemic transformation at time of relapse was largely associated with pre-HCT disease status and acquired secondary cytogenetic abnormalities. Disease mortality in patients with relapsed CML after HCT was closely associated with advanced disease and HCT-related complications.

Imbalances of chromosomes 4, 9, and 12 are recurrent in the thecoma-fibroma group of ovarian stromal tumors

Traditional cytogenetic studies of ovarian stromal tumors are few, although trisomy 12 has been frequently documented with fluorescence in situ hybridization (FISH). In the current study, karyotypic analysis of four ovarian stromal tumors and a review of the literature suggest that numerical abnormalities of chromosomes 4 and 9 might also be important, possibly as secondary changes. To determine the frequency of 4, 9, and 12 aneuploidy in a larger group of ovarian tumors, FISH studies were performed on eight fibromas, three thecomas, one fibrothecoma, and five cellular fibromas. Trisomy 12 was identified in all five cellular fibromas as well as in two fibromas and the fibrothecoma. Gain of chromosome 9 was confined to the cellular fibromas. Loss of chromosomes 4 and/or 9 was prominent in the fibromas. These findings confirm the presence of trisomy 12 as a nonrandom chromosomal abnormality in ovarian stromal tumors. Moreover, these conventional and molecular cytogenetic data indicate that gain of chromosome 9 in addition to gain of chromosome 12 is prominent in cellular fibroma. In contrast, loss of chromosomes 4 and/or 9 are recurrent in fibroma. In summary, imbalances of chromosomes 4 and 9 appear to represent important secondary abnormalities in the thecoma-fibroma ovarian tumor group.

Secondary abnormalities of neurotransmitters in infants with neurological disorders

Neurotransmitters are essential in young children for differentiation and neuronal growth of the developing nervous system. We aimed to identify possible factors related to secondary neurotransmitter abnormalities in pediatric patients with neurological disorders. We analyzed cerebrospinal fluid (CSF) and biogenic amine metabolites in 56 infants (33 males, 23 females; mean age 5.8mo [SD 4.1mo] range 1d-1y) with neurological disorders whose aetiology was initially unknown. Patients were classified into three clinical phenotypes: epileptic encephalopathy, severe motor impairment, and non-specific manifestations. All patients showed normal results for screening of inborn errors of metabolism. We report clinical, neuroimaging, and follow-up data. Among the patients studied, 10 had low homovanillic acid (HVA) levels and in four patients, 5-hydroxyindoleacetic acid (5-HIAA) was also reduced. Patients with neonatal onset had significantly lower levels of HVA than a comparison group. HVA deficiency was also associated with severe motor impairment and the final diagnosis related to neurodegenerative disorders. 5-HIAA values tended to be decreased in patients with brain cortical atrophy. The possibility of treating patients with L-Dopa and 5-hydroxytryptophan, in order to improve their neurological function and maturation, may be considered.

Loss of pregnancy‐associated plasma protein A extends lifespan in mice

Genetic deletion in mice of pregnancy-associated plasma protein A (PAPP-A), a recently identified metalloproteinase in the insulin-like growth factor system, extends by 30-40% both mean and maximum lifespan with no reduction in food intake or secondary endocrine abnormalities. Furthermore, these mice have markedly reduced incidence of spontaneous tumors. The findings implicate PAPP-A as a critical regulator of lifespan and age-related diseases, and suggest PAPP-A as a possible target to promote longevity.

Inactivation of RB1 in mantle-cell lymphoma detected by nonsense-mediated mRNA decay pathway inhibition and microarray analysis

AbstractMantle-cell lymphoma (MCL) is genetically characterized by the translocation t(11;14)(q13;q32) and a high number of secondary chromosomal abnormalities. To identify genes inactivated in this lymphoma, we examined 5 MCL cell lines following a strategy previously described in tumors with microsatellite instability that is based on the combined inhibition of the nonsense-mediated mRNA decay pathway and gene-expression profiling. This approach, together with the design of a conservative algorithm for analysis of the results, allowed the identification of 3 genes carrying premature stop codons. These genes were p53 with a mutation previously described in JEKO-1, the leukocyte-derived arginine aminopeptidase (LRAP) gene in REC-1 that showed a new splicing isoform generating a premature stop codon, and RB1 in UPN-1 that contained an intragenic homozygous deletion resulting in a truncated transcript and total loss of protein expression. The new LRAP isoform was detected also in 2 primary MCLs, whereas inactivating intragenic deletions of RB1 were found in the primary tumor from which UPN-1 was derived and 1 additional blastoid MCL. These tumors carried a concomitant inactivation of p53, whereas p16INK4a was wild type. These results indicate for the first time that RB1 may be inactivated in aggressive MCL by intragenic deletions.

PO13-334 REGRESSION OF NORMOLIPEMIC XANTHELASMA PALPEBRARUM ASSOCIATED WITH INFLAMMATORY STATE IN CASTLEMAN'S DISEASE

PO13-334 REGRESSION OF NORMOLIPEMIC XANTHELASMA PALPEBRARUM ASSOCIATED WITH INFLAMMATORY STATE IN CASTLEMAN'S DISEASE

Erratum: Deletion of 11q23 is a highly specific nonrandom secondary genetic abnormality of ETV6/RUNX1-rearranged childhood acute lymphoblastic leukaemia

Correction to: Leukemia (2007) 21, 584–586. doi:10.1038/sj.leu.2404507 Owing to a typesetting error, on page 1, second paragraph, the number ‘6’ was omitted in error, and this should have read ETV6/RUNX1+ instead of ETV/RUNX1+. The Publisher would like to apologize for any inconvenience this may have caused.

Acute myeloid leukemia developing during imatinib mesylate therapy for chronic myeloid leukemia in the absence of new cytogenetic abnormalities

The BCR/ABL tyrosine kinase inhibitor imatinib mesylate produces a high rate of cytogenetic responses in patients with Philadelphia (Ph)-positive chronic myeloid leukemia (CML), but secondary clonal chromosome abnormalities may develop in Ph-negative cells, and acute myeloid leukemia (AML) has been reported in patients with secondary chromosome abnormalities. We report a patient who developed AML during imatinib treatment of Ph-positive CML despite a cytogenetic response and absence of secondary chromosome abnormalities. Thus, development of AML as a rare event in CML patients with cytogenetic responses to imatinib therapy does not depend on the development of secondary cytogenetic abnormalities.

Enzyme, cell and gene‐based therapies for metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is a demyelinating storage disease caused by deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Lack of ARSA activity leads to the accumulation of galactosylceramide-3-O-sulfate (sulfatide) in the central and peripheral nervous systems. Based on the age at onset, the disease is usually classified into three forms: the late-infantile form, which manifests in the second year of life; the juvenile variants (onset between 4 and 12 years), which are subdivided into early-juvenile (EJ, onset before 6 years) and late-juvenile (LJ, onset after 6 years); and the adult form (onset after 12 years of age). Currently, there is no efficient therapy for the late-infantile form of MLD (50% of the patients), death occurring within a few years after onset of neurological symptoms. Allogeneic haematopoietic cell transplantation (HCT), when performed at a very early stage of the disease, may improve selected patients with juvenile or adult forms of MLD. As with other lysosomal storage diseases, the physiopathology of MLD is poorly understood. Demyelination is the main pathological finding, but substantial storage of sulfatides in neurons also occurs, and may contribute to the clinical phenotype. The physiopathological process leading to neuronal and glial cell degeneration and apoptosis involves accumulation of undegraded sulfatides but also secondary abnormalities (storage/mislocalization of unrelated lipids, inflammatory processes). This review summarizes the recent advances in the understanding of the physiopathology of MLD and the new therapeutic perspectives currently under preclinical investigation, including enzyme replacement therapy, gene therapy and cell therapy.

Cytogenetic patterns in ETV6/RUNX1‐positive pediatric B‐cell precursor acute lymphoblastic leukemia: A Nordic series of 245 cases and review of the literature

Between 1992 and 2004, 1,140 children (1 to<15 years) were diagnosed with B-cell precursor acute lymphoblastic leukemia (ALL) in the Nordic countries. Of these, 288 (25%) were positive for t(12;21)(p13;q22) [ETV6/RUNX1]. G-banding analyses were successful in 245 (85%); 43 (15%) were karyotypic failures. The modal chromosome numbers, incidence, types, and numbers of additional abnormalities, genomic imbalances, and chromosomal breakpoints in the 245 karyotypically informative cases, as well as in 152 previously reported cytogenetically characterized t(12;21)-positive ALLs in the same age group, were ascertained. The most common modal numbers among the 397 cases were 46 (67%), 47 (16%), 48 (6%), and 45 (5%). High-hyperdiploidy, triploidy, and tetraploidy were each found in approximately 1%; none had less than 40 chromosomes. Secondary chromosomal abnormalities were identified by chromosome banding in 248 (62%) of the 397 ALLs. Of these, 172 (69%) displayed only unbalanced changes, 14 (6%) only balanced aberrations, and 26 (10%) harbored both unbalanced and balanced abnormalities; 36 (15%) were uninformative because of incomplete karyotypes. The numbers of secondary changes varied between 1 and 19, with a median of 2 additional aberrations per cytogenetically abnormal case. The most frequent genomic imbalances were deletions of 6q21-27 (18%), 8p11-23 (6%), 9p13-24 (7%), 11q23-25 (6%), 12p11-13 (27%), 13q14-34 (7%), loss of the X chromosome (8%), and gains of 10 (9%), 16 (6%), and 21 (29%); no frequent partial gains were noted. The chromosome bands most often involved in structural rearrangements were 3p21 (2%), 5q13 (2%), 6q12 (2%), 6q14 (2%), 6q16 (2%), 6q21 (10%), 6q23 (6%), 6q25 (3%), 9p13 (2%), 11q13 (2%), 11q23 (2%), 12p11 (6%), 12p12 (7%), 12p13 (25%), 21q10 (6%), and 21q22 (6%). Considering that the t(12;21) is known to arise in utero and that the postnatal latency period is protracted, additional mutations are most likely necessary for overt ALL. The frequently rearranged chromosome regions may harbor genes of importance for the transformation and/or progression of an initial preleukemic t(12;21)-positive clone.

Postoperative Anti-Tgf-β2 Antibody Therapy Improves Intracranial Volume and Craniofacial Growth in Craniosynostotic Rabbits

Postoperative resynostosis and secondary craniofacial growth abnormalities are common sequelae after craniofacial surgery. It has been suggested that an overexpression of transforming growth factor-beta2 (Tgf-beta2) may be related to craniosynostosis and contribute to postoperative resynostosis. Interference with Tgf-beta2 function using neutralizing antibodies may inhibit resynostosis and improve postoperative craniofacial growth; the present study was designed to test this hypothesis. Twenty-nine New Zealand white rabbits with bilateral coronal suture synostosis were used: 1) suturectomy controls (n=9); 2) suturectomy with nonspecific, control IgG antibody (n=9); and 3) suturectomy with anti-Tgf-beta2 antibody (n=11). At 10 days of age, a 3 mm x 15-mm coronal suturectomy was performed. The sites in groups 2 and 3 were immediately filled with 0.1 cc of a slow resorbing collagen gel mixed with either IgG (100 microg/suture) or anti-Tgf-beta2 (100 microg/suture). Three-dimensional computed tomography scan reconstructions of the skulls and cephalographs were obtained at 10, 25, 42, and 84 days of age. Computed tomography scan data revealed patent suturectomy sites and significantly (P<0.05) greater intracranial volumes by 84 days of age in rabbits treated with anti-Tgf-beta2 compared with controls. Cephalometric analysis revealed significant (P<0.05) differences in craniofacial, cranial vault, and cranial base growth by 84 days of age in rabbits treated with anti-Tgf-beta2 compared with controls. These data support the initial hypothesis that interference with Tgf-beta2 function inhibited postoperative resynostosis and improved cranial vault growth in this rabbit model. Thus, this biologically based therapy may be a potential surgical adjunct in the treatment of infants with craniosynostosis.

Incidence and Clinical Significance of Sex Chromosome Losses in Bone Marrow of Patients with Hematologic Diseases

Loss of sex chromosomes in bone marrow is observed both in elderly persons as an aging phenomenon and in patients with hematologic malignancies. The purpose of this study was to evaluate the incidence and clinical significance of sex chromosome losses in patients with hematologic diseases, comparing the characteristics between patients with sole and secondary sex chromosome losses in conjunction with other chromosomal abnormalities. Study group included 868 patients with hematologic diseases between June 1998 and May 2006. The cells of bone marrow aspirates were processed using unstimulated culture methods such as direct, 24-hr and/or 48-hr culture. Sex chromosome losses were included in the karyotype, when X or Y chromosome loss is observed in more than 2 metaphase cells. The sex chromosome losses in bone marrow were found in 5.1% of the patients and 1.8% showed sex chromosome losses as a sole chromosomal abnormality. According to the disease categories, the incidences of sex chromosome losses were as follows: acute myelogenous leukemia (AML), 9.5%; acute lymphoblastic leukemia, 0%; myelodysplastic syndrome, 6.0%; chronic myelogenous leukemia 3.6%; myeloproliferative disorders, 1.3%; multiple myeloma (MM), 13.0%; chronic lymphocytic leukemia, 0%; malignant lymphoma, 3.8%; and benign hematologic diseases 2.2%. The patients with sex chromosome losses as a sole chromosomal abnormality were all male and median age was higher than that of patients with sex chromosome losses as a secondary abnormality (64 vs. 58 yr, P=0.02). The proportion of metaphase cells with sex chromosome losses was significantly lower in patients with sex chromosome losses as a sole chromosomal abnormality (40% vs. 100%, P<0.0001). The changes of sex chromosome loss were correlated with the disease status of AML and MM. These results suggest that secondary sex chromosome losses in conjunction with other chromosomal abnormalities seem to be one of the clonal abnormalities, whereas sex chromosome losses as a sole change seem to be an aging phenomenon, but further studies are needed.

Non-Hodgkin lymphoma with t(14;18): clonal evolution patterns and cytogenetic–pathologic–clinical correlations

The pattern and frequency of secondary chromosome abnormalities in t(14;18)-carrying non-Hodgkin lymphomas (NHL) were evaluated for differences in relation to histologic NHL subtype and patients' outcome. One hundred and forty-nine NHL patients with t(14;18) and complete cytogenetic, morphologic, and clinical information were selected. One hundred and twelve cases were follicular lymphoma (FL) and 37 were diffuse large B-cell lymphoma (DLBCL). One hundred and forty cases showed secondary aberrations (94%, median = 6.0). The most frequent were losses from chromosome arms 1p and 6q and +7 (26%). Loss from 1q, +7, and +12 were more frequent in DLBCL than in FL. Loss from 1p, Xp, and -16 were more frequent in FL grade 3 than in FL grades 1 and 2. Patients with <6.0 secondary cytogenetic aberrations had better prognosis than did those with a higher number of aberrations. Trisomy 21 was associated with shorter patient survival. FLIPI score, the number of secondary chromosomal aberrations, and +21 were all of independent prognostic value in Cox multivariate analysis. FL grade 1-3a patients that had received chemotherapy, showed a higher frequency of i(6p) and loss from 6q. Secondary chromosomal aberrations showed some correlation with the morphologic subgroups of t(14;18)-NHL. Trisomy 21 and the presence of >6.0 secondary cytogenetic aberrations both correlated with shorter overall survival.