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Cancer Genet Cytogenet, 193(2), 123--126
September, 2009

A case of childhood acute myeloid leukemia AML (M5) with a neocentricchromosome neo(1)(qter-->q23 approximately 24::q23 approximately24-->q43-->neo-->q43-->qter) and tetrasomy of chromosomes 8 and 21.

de Figueiredo, Amanda Faria, Hasmik Mkrtchyan, Thomas Liehr, Eliane Maria Soares Ventura, de Jesus Marques-Salles, Terezinha, Neide Santos, Raul Corr{\^e}a Ribeiro, Eliana Abdelhay, Maria Luiza Macedo Silva

Hyperdiploidy is rarely observed in childhood acute myeloid leukemia (AML). Described here is the case of a 2(1/2)-year-old girl with AML-M5 and 51 chromosomes characterized by double tetrasomy of chromosomes 8 and 21 and also a neocentric derivative chromosome neo(1)(qter-->q23 approximately 24::q23 approximately 24-->q43-->neo-->q43-->qter). Little is known about the prognostic significance of these chromosomal abnormalities in childhood AML. In the actual case, complete remission was achieved after chemotherapy, which continued for 7 months. No acquired neocentric chromosome 1 has been described previously, even though neocentromere formation has been reported for other chromosomes in neoplasms.

J Natl Cancer Inst, 101(10), 736--750
May, 2009

Ki67 index, HER2 status, and prognosis of patients with luminal Bbreast cancer.

Maggie C U. Cheang, Stephen K. Chia, David Voduc, Dongxia Gao, Samuel Leung, Jacqueline Snider, Mark Watson, Sherri Davies, Philip S. Bernard, Joel S. Parker, Charles M. Perou, Matthew J. Ellis, Torsten O. Nielsen

Gene expression profiling of breast cancer has identified two biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer: luminal A and luminal B. Luminal B tumors have higher proliferation and poorer prognosis than luminal A tumors. In this study, we developed a clinically practical immunohistochemistry assay to distinguish luminal B from luminal A tumors and investigated its ability to separate tumors according to breast cancer recurrence-free and disease-specific survival.Tumors from a cohort of 357 patients with invasive breast carcinomas were subtyped by gene expression profile. Hormone receptor status, HER2 status, and the Ki67 index (percentage of Ki67-positive cancer nuclei) were determined immunohistochemically. Receiver operating characteristic curves were used to determine the Ki67 cut point to distinguish luminal B from luminal A tumors. The prognostic value of the immunohistochemical assignment for breast cancer recurrence-free and disease-specific survival was investigated with an independent tissue microarray series of 4046 breast cancers by use of Kaplan-Meier curves and multivariable Cox regression.Gene expression profiling classified 101 (28\%) of the 357 tumors as luminal A and 69 (19\%) as luminal B. The best Ki67 index cut point to distinguish luminal B from luminal A tumors was 13.25\%. In an independent cohort of 4046 patients with breast cancer, 2847 had hormone receptor-positive tumors. When HER2 immunohistochemistry and the Ki67 index were used to subtype these 2847 tumors, we classified 1530 (59\%, 95\% confidence interval [CI] = 57\% to 61\%) as luminal A, 846 (33\%, 95\% CI = 31\% to 34\%) as luminal B, and 222 (9\%, 95\% CI = 7\% to 10\%) as luminal-HER2 positive. Luminal B and luminal-HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories. Of particular relevance are women who received tamoxifen as their sole adjuvant systemic therapy, among whom the 10-year breast cancer-specific survival was 79\% (95\% CI = 76\% to 83\%) for luminal A, 64\% (95\% CI = 59\% to 70\%) for luminal B, and 57\% (95\% CI = 47\% to 69\%) for luminal-HER2 subtypes.Expression of ER, progesterone receptor, and HER2 proteins and the Ki67 index appear to distinguish luminal A from luminal B breast cancer subtypes.

Hum Mol Genet, 18(6), 1017--1027
March, 2009

Telomere elongation involves intra-molecular DNA replication in cellsutilizing alternative lengthening of telomeres.

Alessandra Muntoni, Axel A. Neumann, Mark Hills, Roger R. Reddel

Alternative lengthening of telomeres (ALT) is a telomere length maintenance mechanism based on recombination, where telomeres use other telomeric DNA as a template for DNA synthesis. About 10\% of all human tumors depend on ALT for their continued growth, and understanding its molecular details is critically important for the development of cancer treatments that target this mechanism. We have previously shown that telomeres of ALT-positive human cells can become lengthened via inter-telomeric copying, i.e. by copying the telomere of another chromosome. The possibility that such telomeres could elongate by using other sources of telomeric DNA as copy templates has not been investigated previously. In this study, we have determined whether a telomere can become lengthened by copying its own sequences, without the need for using another telomere as a copy template. To test this, we transduced an ALT cell line with a telomere-targeting construct and obtained clones with a single tagged telomere. We showed that the telomere tag can be amplified without the involvement of other telomeres, indicating that telomere elongation can also occur by intra-telomeric DNA copying. This is the first direct evidence that the ALT mechanism involves more than one method of telomere elongation.

Cancer Genet Cytogenet, 189(1), 59--62
February, 2009

A new chromosomal three-way rearrangement involving MLL masked bya t(9;19)(p11;p13) in an infant with acute myeloid leukemia.

de Jesus Marques-Salles, Terezinha, Thomas Liehr, Hasmik Mkrtchyan, Susana C Raimondi, de Souza, Mariana Tavares, de Figueiredo, Amanda Faria, Soraia Rouxinol, Fernanda C Jordy Macedo, Eliana Abdelhay, Neide Santos, Maria Luiza Macedo Silva

Infants diagnosed with acute myelogenous leukemia (AML) are likely to have subtypes M4 or M5 characterized by 11q23 abnormalities like a t(9;11)(p22;q23). Detection of all possible types of chromosomal abnormalities, including mixed lineage leukemia (MLL) gene rearrangements at 11q23, is of importance for the identification of biological subgroups, which might differ in drug resistance and/or clinical outcome. Here, we report the clinical, conventional banding and molecular cytogenetics data of a 6-month-old boy with an AML-M5 presenting with a unique cryptic rearrangement involving the MLL gene: a three-way t(9;19;11)(p11.2;p13.1;q23).

EMBO J, 28(7), 799-809

Control of telomere length by a trimming mechanism that involves generation of t-circles

HA Pickett, AJ Cesare, RL Johnston, AA Neumann, RR Reddel

Telomere lengths are maintained in many cancer cells by the ribonucleoprotein enzyme telomerase but can be further elongated by increasing telomerase activity through the overexpression of telomerase components. We report here that increased telomerase activity results in increased telomere length that eventually reaches a plateau, accompanied by the generation of telomere length heterogeneity and the accumulation of extrachromosomal telomeric repeat DNA, principally in the form of telomeric circles (t-circles). Telomeric DNA was observed in promyelocytic leukemia bodies, but no intertelomeric copying or telomere exchange events were identified, and there was no increase in telomere dysfunction-induced foci. These data indicate that human cells possess a mechanism to negatively regulate telomere length by trimming telomeric DNA from the chromosome ends, most likely by t-loop resolution to form t-circles. Additionally, these results indicate that some phenotypic characteristics attributed to alternative lengthening of telomeres (ALT) result from increased mean telomere length, rather than from the ALT mechanism itself.

Diagn Mol Pathol, 18, 119- 124

Nuclear FISH. Automation, analysis, and interpretation.

G.B. C{\^o}t{\'e}

Automated fluorescent in situ hybridization scanners are more rapid and accurate than people and are becoming more popular. However, the methods used by these machines to score and interpret fluorescent in situ hybridization signals in nuclei are still those used by human observers. A new approach is presented to make the software classify the fluorescent patterns in additional relevant categories, thus avoiding the rejection of relevant information and consequent bias. The statistical interpretation of the fluorescent pattern distributions is carried out with a maximum likelihood estimation of the most likely proportions of various cell lines in the sample, and thus determines the diagnosis and the level of mosaicism in a single step. This approach is faster and more accurate than those used by human observers. It requires the scanning of fewer nuclei, less efforts for validation, and it makes the interpretation of results much simpler.

PLoS One, 4, 0- 0

Human telomere length correlates to the size of the associated chromosome arm.

J.L. Wise, R.J. Crout, D.W. McNeil, R.J. Weyant, M.L.Marazita, S.L. Wenger

The majority of human telomere length studies have focused on the overall length of telomeres within a cell. In fact, very few studies have examined telomere length for individual chromosome arms. The objective of this study was to examine the relationship between chromosome arm size and the relative length of the associated telomere. Quantitative Fluorescence In Situ Hybridization (Q-FISH) was used to measure the relative telomere length of each chromosome arm in metaphases from cultured lymphocytes of 17 individuals. A statistically significant positive correlation (r = 0.6) was found between telomere length and the size of the associated chromosome arm, which was estimated based on megabase pair measurements from

Mol Cytogenet, 2, 16

Molecular cytogenetic characterisation of a mosaic add(12)(p13.3)with an inv dup(3)(q26.31 --> qter) detected in an autistic boy.

Isabel M Carreira, Joana B Melo, Carlos Rodrigues, Liesbeth Backx, Joris Vermeesch, Anja Weise, Nadezda Kosyakova, Guiomar Oliveira, Eunice Matoso

ABSTRACT: BACKGROUND: Inverted duplications (inv dup) of a terminal chromosome region are a particular subset of rearrangements that often results in partial tetrasomy or partial trisomy when accompanied by a deleted chromosome. Associated mosaicism could be the consequence of a post-zygotic event or could result from the correction of a trisomic conception. Tetrasomies of distal segments of the chromosome 3q are rare genetic events and their phenotypic manifestations are diverse. To our knowledge, there are only 12 cases reported with partial 3q tetrasomy. Generally, individuals with this genomic imbalance present mild to severe developmental delay, facial dysmorphisms and skin pigmentary disorders. RESULTS: We present the results of the molecular cytogenetic characterization of an unbalanced mosaic karyotype consisting of mos 46,XY,add(12)(p13.3) [56]/46,XY [44] in a previously described 11 years old autistic boy, re-evaluated at adult age. The employment of fluorescence in situ hybridization (FISH) and multicolor banding (MCB) techniques identified the extra material on 12p to be derived from chromosome 3, defining the additional material on 12p as an inv dup(3)(qter --> q26.3::q26.3 --> qter). Subsequently, array-based comparative genomic hybridization (aCGH) confirmed the breakpoint at 3q26.31, defining the extra material with a length of 24.92 Mb to be between 174.37 and 199.29 Mb. CONCLUSION: This is the thirteenth reported case of inversion-duplication 3q, being the first one described as an inv dup translocated onto a non-homologous chromosome. The mosaic terminal inv dup(3q) observed could be the result of two proposed alternative mechanisms. The most striking feature of this case is the autistic behavior of the proband, a characteristic not shared by any other patient with tetrasomy for 3q26.31 --> 3qter. The present work further illustrates the advantages of the use of an integrative cytogenetic strategy, composed both by conventional and molecular techniques, on providing powerful information for an accurate diagnosis. This report also highlights a chromosome region potentially involved in autistic disorders.

Mol Cytogenet, 2, 15

Application of molecular cytogenetic techniques to clarify apparentlybalanced complex chromosomal rearrangements in two patients withan abnormal phenotype: case report.

de Vree, Paula Jp, Marleen Eh Simon, van Dooren, Marieke F, Gerda Ht Stoevelaar, Jos{\'e} Tw Hilkmann, Michel A Rongen, Gido Cm Huijbregts, Annemieke Jmh Verkerk, Pino J Poddighe

ABSTRACT: BACKGROUND: Complex chromosomal rearrangements (CCR) are rare cytogenetic findings that are difficult to karyotype by conventional cytogenetic analysis partially because of the relative low resolution of this technique. High resolution genotyping is necessary in order to identify cryptic imbalances, for instance near the multiple breakpoints, to explain the abnormal phenotype in these patients. We applied several molecular techniques to elucidate the complexity of the CCRs of two adult patients with abnormal phenotypes. RESULTS: Multicolour fluorescence in situ hybridization (M-FISH) showed that in patient 1 the chromosomes 1, 10, 15 and 18 were involved in the rearrangement whereas for patient 2 the chromosomes 5, 9, 11 and 13 were involved. A 250 k Nsp1 SNP-array analysis uncovered a deletion in chromosome region 10p13 for patient 1, harbouring 17 genes, while patient 2 showed no pathogenic gains or losses. Additional FISH analysis with locus specific BAC-probes was performed, leading to the identification of cryptic interstitial structural rearrangements in both patients. CONCLUSION: Application of M-FISH and SNP-array analysis to apparently balanced CCRs is useful to delineate the complex chromosomal rearrangement in detail. However, it does not always identify cryptic imbalances as an explanation for the abnormal phenotype in patients with a CCR.

Molecular Cytogenetics, 2, 0- 0

Automated detection of residual cells after sex-mismatched stem-cell transplantation - evidence for presence of disease-marker negative residual cells.

J. Erlecke, I. Hartmann, M. Hoffmann, T. Kroll, H. Starke, A. Heller, A. Gloria, H.G. Sayer, T. Johannes, U. Claussen, T. Liehr, I.F. Loncarevic

A new chimerism analysis based on automated interphase fluorescence in situ hybridization (FISH) evaluation was established to detect residual cells after allogene sex-mismatched bone marrow or blood stem-cell transplantation.Cells of 58 patients were characterized as disease-associated due to presence of a bcr/abl-gene-fusion or a trisomy 8 and/or a simultaneous hybridization of gonosome-specific centromeric probes. The automatic slide scanning platform Metafer with its module MetaCyte was used to analyse 3,000 cells per sample. RESULTS: Overall 454 assays of 58 patients were analyzed. 13 of 58 patients showed residual recipient cells at one stage of more than 4% and 12 of 58 showed residual recipient cells less than 4%, respectively. As to be expected, patients of the latter group were associated with a higher survival rate (48 vs. 34 month). In only two of seven patients with disease-marker positive residual cells between 0.1-1.3% a relapse was observed. Besides, disease-marker negative residual cells were found in two patients without relapse at a rate of 2.8% and 3.3%, respectively. CONCLUSION: The definite origin and meaning of disease-marker negative residual cells is still unclear. Overall, with the presented automatic chimerism analysis of interphase FISH slides, a sensitive method for detection of disease-marker positive residual cells is on hand.

J Transl Med, 7, 46

Human fallopian tube: a new source of multipotent adult mesenchymalstem cells discarded in surgical procedures.

Tatiana Jazedje, Paulo M Perin, Carlos E Czeresnia, Mariangela Maluf, Silvio Halpern, Mariane Secco, Daniela F Bueno, Natassia M Vieira, Eder Zucconi, Mayana Zatz

BACKGROUND: The possibility of using stem cells for regenerative medicine has opened a new field of investigation. The search for sources to obtain multipotent stem cells from discarded tissues or through non-invasive procedures is of great interest. It has been shown that mesenchymal stem cells (MSCs) obtained from umbilical cords, dental pulp and adipose tissue, which are all biological discards, are able to differentiate into muscle, fat, bone and cartilage cell lineages. The aim of this study was to isolate, expand, characterize and assess the differentiation potential of MSCs from human fallopian tubes (hFTs). METHODS: Lineages of hFTs were expanded, had their karyotype analyzed, were characterized by flow cytometry and underwent in vitro adipogenic, chondrogenic, osteogenic, and myogenic differentiation. RESULTS: Here we show for the first time that hFTs, which are discarded after some gynecological procedures, are a rich additional source of MSCs, which we designated as human tube MSCs (htMSCs). CONCLUSION: Human tube MSCs can be easily isolated, expanded in vitro, present a mesenchymal profile and are able to differentiate into muscle, fat, cartilage and bone in vitro.

Cancer Genet. Cytogenet., 193, 44- 53

Gene amplification in myeloid leukemias elucidated by fluorescence in situ hybridization.

K.C. Rayeroux, L.J. Campbell

Gene amplification in hematologic malignancies is uncommon. When karyotyping leukemia cells, gene amplification is generally seen as double-minute (dmin) chromosomes and homogeneously staining regions (hsr). One of the more commonly amplified regions is MYC at 8q24.21, but amplification of MLL at 11q23 and regions on 9p, 19q, and elsewhere on 11q have been reported. Increased copy number of these genes has been associated with poor prognosis. Over an 11-year period, we identified 31 cases of possible gene amplification, 27 of which had enough sample material for further investigations. A total of 17 cases had dmin only, 13 cases had hsr only, and 1 case had both dmin and hsr in the karyotype. Fluorescence in situ hybridization (FISH) analysis identified amplification of MYC in 12 cases, all on dmin, and amplification of MLL in eight cases, all on hsr. Regions other than MYC and MLL were amplified in eight cases and, using multicolor FISH and multicolor banding, we identified a number of novel regions of amplification: 13q11 approximately q12.1, 15q26.1 approximately q26.3, and 17q12. We also identified one case where two different chromosomal regions were simultaneously amplified in the same cell line.

Mod Pathol, 22(1), 79-86

t(11;18)(q21;q21) in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue in stomach: a study of 48 cases

G Wang, A Auerbach, M Wei, N Dow, TS Barry, L Hodge, D Schaffer, LH Sobin, NS Aguilera

Gastric extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MZL-MALT) is speculated to be immune mediated and is notable for responding to treatment by Helicobacter pylori eradication. However, the gastric MZL-MALT with t(11;18)(q21;q21) has been shown to be resistant to treatment by H. pylori eradication. We studied the molecular, immunohistochemical, and histological aspects of 48 cases of gastric MZL-MALT and used a reverse transcription real-time PCR assay to assess the presence of a t(11;18)(q21;q21) in formalin-fixed, paraffin-embedded tissue. Florescence in situ hybridization for t(11:18)(q21;q21) was used to confirm the real-time PCR results. Three distinct morphological subtypes were recognized: monocytoid, small lymphocytic, and plasmacytoid. Morphology, immunophenotype, and immunoglobulin heavy chain (IgH) gene rearrangement were correlated with the results of the t(11:18)(q21;q21) assay. Of the 48 analyzed cases, 15 (31%) were positive for t(11;18)(q21;q21) and 33 (69%) were monoclonal for IgH gene rearrangement. Of the 15, 13 (87%) cases with t(11;18)(q21;q21) translocation showed IgH gene rearrangement by PCR. Of the 33 t(11;18)(q21;q21)-negative cases tested, 20 cases (61%) showed IgH gene rearrangement. The 15 t(11;18)(q21;q21) translocation-positive cases had either monocytoid (12 of 15) or small lymphocytic morphology (3 of 15). Aberrant expression of CD43 was observed in 8 of 15 (53%) t(11;18)(q21;q21)-positive cases and 21 of 31 (68%) t(11;18)(q21;q21)-negative cases. Our data show that t(11;18)(q21;q21)-positive MZL-MALTs frequently show monocytoid morphology, less often small lymphocytic morphology, and not purely plasmacytoid morphology. Identification of a t(11;18)(q21;q21) by reverse transcription real-time PCR is highly specific for MZL-MALT and helps in the diagnosis of MZL-MALT. Studying the correlation between this translocation and morphological features may increase our understanding of the role of this translocation in the pathogenesis and the clinical behavior of gastric MZL-MALT.

Nat Genet, 41(5), 619-24

Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate

BS Carver, J Tran, A Gopalan, Z Chen, S Shaikh, A Carracedo, A Alimonti, C Nardella, S Varmeh, PT Scardino, C Cordon-Cardo, W Gerald, PP Pandolfi

Chromosomal translocations involving the ERG locus are frequent events in human prostate cancer pathogenesis; however, the biological role of aberrant ERG expression is controversial. Here we show that aberrant expression of ERG is a progression event in prostate tumorigenesis. We find that prostate cancer specimens containing the TMPRSS2-ERG rearrangement are significantly enriched for loss of the tumor suppressor PTEN. In concordance with these findings, transgenic overexpression of ERG in mouse prostate tissue promotes marked acceleration and progression of high-grade prostatic intraepithelial neoplasia (HGPIN) to prostatic adenocarcinoma in a Pten heterozygous background. In vitro overexpression of ERG promotes cell migration, a property necessary for tumorigenesis, without affecting proliferation. ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression. Thus, ERG has a distinct role in prostate cancer progression and cooperates with PTEN haploinsufficiency to promote progression of HGPIN to invasive adenocarcinoma.

Cancer Genet Cytogenet, 188, 1- 25

Cancer-causing karyotypes: chromosomal equilibria between destabilizing aneuploidy and stabilizing selection for oncogenic function.

L. Li, A.A. McCormack, J.M. Nicholson, A. Fabarius, R. Hehlmann, R.K. Sachs, P.H. Duesberg

The chromosomes of cancer cells are unstable, because of aneuploidy. Despite chromosomal instability, however, cancer karyotypes are individual and quasi-stable, as is evident especially from clonal chromosome copy numbers and marker chromosomes. This paradox would be resolved if the karyotypes in cancers represent chromosomal equilibria between destabilizing aneuploidy and stabilizing selection for oncogenic function. To test this hypothesis, we analyzed the initial and long-term karyotypes of seven clones of newly transformed human epithelial, mammary, and muscle cells. Approximately 1 in 100,000 such cells generates transformed clones at 2-3 months after introduction of retrovirus-activated cellular genes or the tumor virus SV40. These frequencies are too low for direct transformation, so we postulated that virus-activated genes initiate transformation indirectly, via specific karyotypes. Using multicolor fluorescence in situ hybridization with chromosome-specific DNA probes, we found individual clonal karyotypes that were stable for at least 34 cell generations-within limits, as follows. Depending on the karyotype, average clonal chromosome numbers were stable within +/- 3%, and chromosome-specific copy numbers were stable in 70-100% cells. At any one time, however, relative to clonal means, per-cell chromosome numbers varied +/-18% and chromosome-specific copy numbers varied +/-1 in 0-30% of cells; unstable nonclonal markers were found within karyotype-specific quotas of <1% to 20% of the total chromosome number. For two clones, karyotypic ploidies also varied. With these rates of variation, the karyotypes of transformed clones would randomize in a few generations unless selection occurs. We conclude that individual aneuploid karyotypes initiate and maintain cancers, much like new species. These cancer-causing karyotypes are in flexible equilibrium between destabilizing aneuploidy and stabilizing selection for transforming function. Karyotypes as a whole, rather than specific mutations, explain the individuality, fluidity, and phenotypic complexity of cancers.

Mol Cytogenet, 2, 7

Unbalanced chromosome 1 abnormalities leading to partial trisomy1q in four infants with Down syndrome and acute megakaryocytic leukemia.

Maria Luiza Macedo Silva, do Socorro Pombo-de-Oliveira, Maria, Susana C Raimondi, Hasmik Mkrtchyan, Eliana Abdelhay, de Figueiredo, Amanda Faria, de Souza, Mariana Tavares, Daniela Ribeiro Ney Garcia, de Ventura, Eliane Maria Soares, de Sousa, Adriana Martins, Thomas Liehr

ABSTRACT: BACKGROUND: Children with Down syndrome (DS) have an increased risk of childhood acute leukemia, especially acute megakaryoblastic leukemia (AMKL) also called acute myeloid leukemia (AML) type M7. Here four yet unreported infants with such malignancies are reported. RESULTS: An unbalanced translocation involving chromosome 1 was identified by GTG banding in all cases. These were characterized in more detail by molecular cytogenetic approaches. Additional molecular analysis revealed in three of the four cases mutations in exon 2 of the GATA binding protein 1 (globin transcription factor 1), located in Xp11.23. CONCLUSION: Our results corroborate that abnormalities of chromosome 1 are common in DS-associated AMKL. Whether this chromosomal region contains gene(s) involved in hematopoietic malignant transformation remains to be determined.

Diabetes, 57(11), 2950--2957
November, 2008

Lymphocytes of type 2 diabetic women carry a high load of stablechromosomal aberrations: a novel risk factor for disease-relatedearly death.

Bernhard O. Boehm, Peter M{\"o}ller, Josef H{\"o}gel, Bernhard R. Winkelmann, Wilfried Renner, Silke Rosinger, Ursula Seelhorst, Britta Wellnitz, Winfried M{\"a}rz, Julia Melzner, Silke Br{\"u}derlein

OBJECTIVE—Diabetes is associated with an increased risk of death in women. Oxidative stress due to chronic hyperglycemia leads to the generation of reactive oxygen species and loss of chromosomal integrity. To clarify whether diabetes is a premature aging syndrome, we determined telomere erosion dynamics and occurrence of structural chromosomal aberrations in women of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study. RESEARCH DESIGN AND METHODS—Telomere lengths and karyotypes were examined in peripheral blood mononuclear cells. Regarding these parameters, surviving and deceased type 2 diabetic women of the LURIC study were compared with nondiabetic LURIC women with or without coronary heart disease and with healthy female control subjects. RESULTS—Significantly enhanced telomere attrition was seen in all LURIC subjects compared with healthy control subjects. Although the average telomere-length loss is equivalent to well >10 years of healthy aging, telomere erosion was not associated with outcome within the LURIC cohort. However, strikingly high numbers of stable chromosomal aberrations were found in type 2 diabetic women but not in LURIC disease control subjects or in healthy individuals. Furthermore, within the younger age- groups, deceased type 2 diabetes patients had significantly more marker chromosomes than the surviving type 2 diabetic patients. CONCLUSIONS—All women at high risk for cardiovascular death have accelerated telomere erosion, not caused by type 2 diabetes per se but likely linked to other risk factors, including dyslipidemia. By contrast, the occurrence of marker chromosomes is associated with type 2 diabetes and is a novel risk factor for type 2 diabetes–related early death. Type 2 diabetes is characterized by increased morbidity and all-cause mortality (1,2). The combination of excess caloric intake and reduced physical activity leading to obesity, dyslipidemia, and hypertension increases the risk for diabetes and coronary heart disease (CHD). Recent data show that among diabetic men, the mortality rate has decreased significantly, whereas in diabetic women, no such trend was found (3). The all-cause mortality rate difference between diabetic and nondiabetic women is considerable. Therefore, the combination of diabetes with multiple risk factors identifies women at particularly high risk (2,4). The relative risk for morbidity and mortality in women with diabetes is increased compared with nondiabetic control subjects (2,5). Diabetes may therefore be regarded as a premature aging syndrome in which the overall metabolic shift leads to genotoxic stress that results in loss of chromosomal integrity (rev. in 6). Oxidative stress plays a crucial role in the pathogenesis of type 2 diabetes and in diabetes-associated complications. The generation of reactive oxygen species (ROS) is a common downstream mechanism whereby multiple by-products of glucose and (pro)inflammatory molecules exert adverse effects (7–11). DNA damage and telomere attrition can serve as markers of these processes and, consequently, mirror the pace of biological aging (rev. in 12–14). Hypothesizing along these lines, we studied telomere erosion dynamics and/or the occurrence of structural chromosomal aberrations in women with type 2 diabetes who were participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) prospective cohort study (15). Life expectancy within the LURIC female cohort falls short by ∼10 years compared with the general female population in Germany. Telomeric erosion was much further advanced in all LURIC women, irrespective of type 2 diabetes, compared with age-matched control subjects, the difference amounting to >10 life-years. We further found a strikingly enhanced number of structural chromosomal aberrations in the peripheral lymphocytes of women with type 2 diabetes that was diabetes specific and, within the younger age-groups, associated with mortality.

Korean J Lab Med, 28(4), 262--266
August, 2008

Tetrasomy 8 in a patient with acute monoblastic leukemia.

Juwon Kim, Tae Sung Park, Jaewoo Song, Kyung-A. Lee, Sang-Guk Lee, June-Won Cheong, Jong Rak Choi

Trisomy 8 is one of the most frequent numerical chromosomal abnormalities observed in hematological malignancies, whereas tetrasomy 8 is a clonal aberration seen mainly in myeloid disorders such as acute myelod leukemia (AML) and myelodysplastic syndromes. In contrast to trisomy 8, tetrasomy 8 is a rare chromosomal aberration, in that only 17 reported AML cases with isolated tetrasomy 8 have been documented. Interestingly, the majority of reported cases were associated with monocytic-lineage leukemias. According to recent reports, tetrasomy 8 is regarded as a poor prognostic factor, and most patients having this abnormality relapsed and died within 1 yr. Here, we report a patient with acute monoblastic leukemia having tetrasomy 8 and a very aggressive disease course.

Nat Genet, 40(7), 806--7; author reply
July, 2008

ESR1 gene amplification in breast cancer: a common phenomenon?

Lindsay A. Brown, Jeremy Hoog, Suet-Feung Chin, Yu Tao, Abd Alnaser Zayed, Koei Chin, Andrew E. Teschendorff, John F. Quackenbush, John C. Marioni, Samuel Leung, Charles M. Perou, Torsten O. Neilsen, Matthew Ellis, Joe W. Gray, Philip S. Bernard, David G. Huntsman, Carlos Caldas

Blood, 111(8), 4329--4337
April, 2008

High EVI1 levels predict adverse outcome in acute myeloid leukemia:prevalence of EVI1 overexpression and chromosome 3q26 abnormalitiesunderestimated.

Sanne Lugthart, van Drunen, Ellen, van Norden, Yvette, van Hoven, Antoinette, Claudia A J Erpelinck, Peter J M Valk, H. Berna Beverloo, Bob L{\"o}wenberg, Ruud Delwel

Inappropriate expression of EVI1 (ecotropic virus integration-1), in particular splice form EVI1-1D, through chromosome 3q26 lesions or other mechanisms has been implicated in the development of high-risk acute myeloid leukemia (AML). To validate the clinical relevance of EVI1-1D, as well as of the other EVI1 splice forms and the related MDS1/EVI1 (ME) gene, real-time quantitative polymerase chain reaction was performed in 534 untreated adults with de novo AML. EVI1-1D was highly expressed in 6\% of cases (n = 32), whereas 7.8\% were EVI1(+) (n = 41) when all splice variants were taken into account. High EVI1 predicted a distinctly worse event-free survival (HR = 1.9; P = .002) and disease-free survival (HR = 2.1, P = .006) following multivariate analysis. Importantly, we distinguished a subset of EVI1(+) cases that lacked expression of ME (EVI1(+)ME(-); n = 17) from cases that were ME(+) (EVI1(+)ME(+); n = 24). The atypical EVI1(+)ME(-) expression pattern exhibited cytogenetically detectable chromosomal 3q26 breakpoints in 8 cases. Fluorescence in situ hybridization revealed 7 more EVI1(+)ME(-) cases that carried cryptic 3q26 breakpoints, which were not found in the EVI1(+)ME(+) group. EVI1(+)ME(-) expression predicts an extremely poor prognosis distinguishable from the general EVI1(+) AML patients (overall survival [OS]: P