Cytogenetic Features and Clinical Outcomes of Patients With Non-secretory Multiple Myeloma in the Era of Novel Agent Induction Therapy

BackgroundNon-secretory multiple myeloma (NSMM) is a rare subtype of multiple myeloma (MM) characterized by the absence of monoclonal protein in the serum and/or urine. We look at the clinical and cytogenetic features of NSMM in this study.Patients and MethodsThis study evaluates a cohort of 30 patients with newly diagnosed NSMM seen at the Mayo Clinic, Rochester, MN, between 2008 and 2018 and treated with novel agent induction therapies. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test.ResultsThese patients with NSMM appear to have a large disease burden at diagnosis with a median bone marrow plasma cell percentage of 70% and more than one-half of all patients having Multiple Myeloma International Staging System Stage III disease. There was a higher preponderance for t(11;14) primary cytogenetic abnormality in this NSMM cohort, accounting for more than 50% of the cohort. Finally, the overall survival of this cohort appears to be slightly worse than a matched-control group of newly diagnosed patients with MM with secretory disease.ConclusionsFuture multi-institution studies confirming these above findings on this rare entity are warranted.     

Benign salivary gland tumors: A cytogenetic study of 21 cases

Cytogenetic findings of 21 benign salivary gland tumors, including 14 pleomorphic adenomas, 5 Warthin's tumors, 1 myoepithelioma, and 1 cystadenoma, are reported. The present study confirms that pleomorphic adenomas characteristically have highly specific rearrangements involving only a few chromosome regions (3p21, 8q12 and 12q13–15) which suggests their specific role in the mixed tumors genesis. Warthin's tumors also show nonrandom numerical and structural alterations that were concurrent in one of the cases studied. To our knowledge no cytogenetic data are available in myoepitheliomas and cystadenomas. The former reveals a normal karyotype and the latter shows only clonal numerical alterations (gain of chromosomes 2 and 18). © 1995 Wiley-Liss, Inc.     

Loss of heterozygosity at 7p in Wilms' tumour development

Chromosome 7p alterations have been implicated in the development of Wilms' tumour (WT) by previous studies of tumour cytogenetics, and by our analysis of a constitutional translocation (t(1;7)(q42;p15)) in a child with WT and radial aplasia. We therefore used polymorphic microsatellite markers on 7p for a loss of heterozygosity (LOH) study, and found LOH in seven out of 77 informative WTs (9%). The common region of LOH was 7p15-7p22, which contains the region disrupted by the t(1;7) breakpoint. Four WTs with 7p LOH had other genetic changes; a germline WT1 mutation with 11p LOH, LOH at 11p, LOH at 16q, and loss of imprinting of IGF2. Analysis of three tumour-associated lesions from 7p LOH cases revealed a cystic nephroma-like area also having 7p LOH. However, a nephrogenic rest and a contralateral WT from the two other cases showed no 7p LOH. No particular clinical phenotype was associated with the WTs which showed 7p LOH. The frequency and pattern of 7p LOH demonstrated in our studies indicate the presence of a tumour suppressor gene at 7p involved in the development of Wilms' tumour.     

Congenital MLL-positive B-cell acute lymphoblastic leukemia (B-ALL) switched lineage at relapse to acute myelocytic leukemia (AML) with persistent t(4;11) and t(1;6) translocations and JH gene rearrangement

Congenital acute leukemia is a rare form of childhood leukemia, in which lineage conversion at relapse is very rarely reported. Here we describe a case of congenital B-cell acute lymphoblastic leukemia (B-ALL) with t(4;11) and t(1;6) translocations, which at relapse underwent a switch to monocytic lineage with persistence of the original cytogenetic translocations and clonal rearrangement of the JH gene. Similar to the other described cases of congenital acute leukemia with lineage conversion, our case had a MLL gene rearrangement and followed an aggressive clinical course.     

Application of interphase cytogenetics for the detection of t(11;14)(q13;q32) in mantle cell lymphomas

Background: The chromosomal translocation t(11;14)(q13;q32) is thehallmark of mantle cell lymphoma (MCL) in which it can be detectedcytogenetically in about 75% of cases. The t(11;14) translocationjuxtaposes the bcl-1 locus in chromosome band 11q13 next to the IgH locus inchromosome band 14q32 and, thus, leads to deregulation of the cell cycleregulatory protein cyclin D1, which is encoded by the CCND1 gene localizedat the telomeric border of the bcl-1-locus. MCL has the worst prognosis ofall low-grade non-Hodgkins lymphomas (NHL). In some instances, however,histopathologic differentiation between MCL and other low-grade B-cell NHLis difficult. Therefore, detection of the t(11;14) translocation is ofessential diagnostic value for the risk-adjusted management of patients withMCL. Unfortunately, chromosome analyses are frequently hampered by the lowyield and quality of tumor metaphases. As the 11q13 breakpoints arescattered over a region of more than 120 kb the application of moleculargenetic techniques is also limited.Patients and methods: We established an interphase fluorescence in situhybridization (FISH) approach for the detection of the t(11;14)translocation by use of a cosmid probe hybridizing to the IgH constantregion and a YAC spanning the bcl-1 region. Cells containing a t(11;14)translocation show a co-localisation of the signals for IgH and bcl-1. Eightcontrol samples and 15 MCL specimens were investigated.Results: According to our control studies, samples containing more than10% of cells with this signal constellation can be diagnosed ascarrying a clonal t(11;14) translocation. All eleven MCL found to carry thet(11;14) translocation by chromosome analysis were positive in our FISHassay. Additionally, two of four MCL lacking a clonal t(11;14) translocationby chromosome analysis were shown to carry this aberration in 14% and37% of interphase nuclei. Southern blot data indicate that our FISHassay reliably detects the t(11;14) translocation irrespective of thelocation of the breakpoints within the bcl-1 region.Conclusions: The described interphase FISH assay provides a reliable androutinely applicable tool for diagnosis of the t(11;14) translocation.     

11;19 Translocation in a congenital leukemia with two cell populations of lymphoblasts and monoblasts

This report describes a case of a female infant of congenital leukemia with a chromosomal translocation t(11;19) (q23;p13) which presented initially with lymphoid features and at relapse with monocytic ones. The clinical course and the results of sequential cytochemical, cytogenetic and immunological studies are considered to be consistent with the interpretation of leukemogenesis of the myelo-monocytoid progenitor cell which still retains the capability of exhibiting lymphoid features to a limited extent. Although leukemia with t(11;19) has been classified as ANLL, most commonly M5 of FAB classification, the patients with this chromosomal abnormality may have a mixed leukemia in which cells with lymphoid features and those with monocytic ones exist.     

Role of genetic polymorphisms in tumour angiogenesis

Angiogenesis plays a crucial role in the development, growth and spread of solid tumours. Pro- and anti-angiogenic factors are abnormally expressed in tumours, influencing tumour angiogenesis, growth and progression. Polymorphisms in genes encoding angiogenic factors or their receptors may alter protein expression and/or activity. This article reviews the literature to determine the possible role of angiogenesis-related polymorphisms in cancer. Further research studies in this potentially crucial area of tumour biology are proposed.     

Molecular Cytogenetics of t(12;21)(p13;q22)

The translocation t(12;21)(p13;q22) is a frequent nonrandom rearrangement of B-cell lineage childhood acute lymphoblastic leukemia (ALL) which fuses the TEL and AML1 genes, normally localized to 12p13 and 21q22, respectively. The crucial chimeric gene, TEL-AML1, is transcribed from the der(21) and encodes the 336 NH₂ aminoacids of TEL fused to the majority of the AML1 protein. The t(12;21) is very often associated with loss of the normal, untranslocated TEL allele. These various aspects are presented here.     

Phenotypic and genotypic characterization of 14 leukemia and lymphoma cell lines with 11q23 translocations

11q23 translocation is the most popular chromosomal abnormality in infant leukemia. In adults, it is often encountered in non-Hodgkin's lymphoma (NHL). In this study, we analyzed the phenotypic and genotypic characteristics of 9 acute leukemic cell lines with 11q23 translocations and one with deletion of the 11q23 locus, nine of which were established by researchers in this group, together with 4 NHL cell lines with 11q23 translocations. All lines were considered to belong to the B-cell lineage at different stages. All 10 leukemic lines showed clonal rearrangement of the immunoglobulin heavy chain (IgH) gene: two corresponded to the B-precursor stage (CD19⁺, cytoplasmic μ⁻), while the other 8 corresponded to the pre-B stage (cytoplasmic μ⁺). All 4 NHL lines showed rearrangements of both the IgH and Igκ genes with three expressing surface Ig; specifically, mature B-cell phenotype. As for myelocytic-monocytic markers, at least one out of 4 antigens examined were positive in 8 of the 10 leukemic cell lines, while only one of the 4 NHL lines was reactive. There were essentially no clear phenotypic or genotypic differences between t(4;11) and t(11;19) cell lines, supporting the view that both diseases have similar clinicopathological characteristics. These cell lines are also valuable for cloning genes at the chromosomal breakpoints.     

Additional chromosome 1q aberrations and der(16)t(1;16), correlation to the phenotypic expression and clinical behavior of the Ewing family of tumors

The cytogenetic hallmark of the Ewing family of tumors is t(11;22)(q24;q12) in its simple, complex or variant forms and/or its molecular equivalent EWS/FLI, EWS/ERG rearrangement. Additional secondary consistent chromosomal aberrations include the der(16)t(1;16) and, frequently, other chromosome 1q abnormalities leading to 1q overdosage. We studied whether these secondary cytogenetic changes are correlated to clinical features and phenotypic expression which may have a prognostic impact.Successful cytogenetic evaluation was performed in eight patients with a Ewing family tumor. In four of these, in addition to the primary aberration, chromosome 1q overdosage (including two with der(16)t(1;16)) was noted. Out of these four patients, two had metastatic disease at the time of evaluation, while in the other four, disease was localized. Morphologically, the tumors with the additional 1q aberration, revealed the pPNET subtype more frequently than the typical Ewing. They also expressed a higher degree of neural differentiation by neural marker immunocytochemistry, in comparison to tumors without the 1q aberration.Determination of the prognostic significance of this finding requires a longer follow-up with a larger group of patients.     

Preferential Occurrence of Breast Carcinomas with Loss of Chromosome 16q and der(16)t(1;16)/der(1;16) in Middle-aged Patients with Hyperplasia of Mammary Glands

Structural and numerical alterations of chromosome 16 are considered to be commonly involved in the genesis of breast cancer. To reveal etiological factors that predispose cells to these alterations, we examined the frequencies of chromosome 16 aneusomy, 16q loss and 1;16 fusion indicating der(16)t(1;16)/der(1;16) by multi-color fluorescence in situ hybridization in 46 tumors resected mostly from young (≤34 years old) or elderly (≥75 years old) women, and compared the results with those in a patient group representing a common age distribution of Japanese patients in whom chromosome 16 status in the tumor had already been studied. The correlation of these chromosome 16 alterations with age, hyperplasia in adjacent mammary glands, cancer history, and obesity indices was investigated in a total of 244 patients. In the present 46 tumors, the frequency of 16q loss and der(16)t(1;16) did not differ between 20 younger patients (30% and 15%) and 23 elderly patients (43% and 13%). However, the incidences of 16q loss and der(16)t(1;16) were low in comparison with the values of 64% and 38% in the 198 Japanese patients representing the common age distribution ( P < 0.001). In addition, 16q loss and der(16)t(1;16) were more frequent in tumors arising in hyperplastic mammary glands (68%, 44%) than in those without (52%, 24%) ( P < 0.01). Such correlations were not evident for 16cen aneusomy. Other etiological factors examined were not correlated with these chromosome 16 alterations. The 16q loss and der(16)t(1;16) formation were more frequently involved in the development of breast cancer in middle-aged patients than in young and elderly patients. High-level estrogens and/or sensitivity of mammary glandular cells to estrogens might induce breast cancers with structural changes of chromosome 16.     

A physical analysis of the Y chromosome shows no additional deletions, other than Gr/Gr, associated with testicular germ cell tumour

Testicular germ cell tumour (TGCT) is the most common malignancy in men aged 15-45 years. A small deletion on the Y chromosome known as 'gr/gr' was shown to be associated with a two-fold increased risk of TGCT, increasing to three-fold in cases with a family history of TGCT. Additional deletions of the Y chromosome, known as AZFa, AZFb and AZFc, are described in patients with infertility; however, complete deletions of these regions have not been identified in TGCT patients. We screened the Y chromosome in a series of TGCT cases to evaluate if additional deletions of Y were implicated in TGCT susceptibility. Single copy Y chromosome STS markers with an average inter-marker spacing of 128 kb were examined in constitutional DNA of 271 index TGCT patients. Three markers showed evidence of deletions, sY1291, indicative of 'gr/gr' (eight out of 271; 2.9%), Y-DAZ3 contained within 'gr/gr' (21 out of 271; 7.7%) and a single deletion of the marker G66152 was identified in one TGCT case. No other markers demonstrated deletions. While several regions of the Y chromosome are known to be deleted and associated with infertility, our study provides no evidence to suggest regions of Y deletion, other than 'gr/gr', are associated with susceptibility to TGCT in UK patients.     

Metachronous gastric MALT lymphoma and early gastric cancer: is residual lymphoma a risk factor for the development of gastric carcinoma?

BACKGROUND: Helicobacter pylori plays a major role in the pathogenesis of primary gastric MALT lymphoma (GML) and gastric carcinoma. The occurrence of these two diseases metachronously in a same patient is a rare event. PATIENTS AND METHODS: Gastric biopsies and gastrectomy resection specimens of four patients who developed GML and early gastric cancer (EGC) were analysed by morphology, immunohistochemistry and molecular biology. RESULTS: Four patients (three males and one female; mean age 48 years) were diagnosed with GML. Helicobacter pylori infection was observed in three cases. Two patients had localized disease (stages IE and IIE, respectively) and were treated with H. pylori eradication therapy followed by an alkylating agent for one patient. Two patients had disseminated disease (stage IV), and were treated with an alkylating agent. Three cases were t(11;18) positive. All patients achieved initially complete lymphoma remission. Long-term endoscopic surveillance detected an EGC at the same location as the lymphoma in all patients at a mean time of 9.5 years (range 2.5-17 years) after lymphoma diagnosis. Gastrectomy specimens showed residual GML in all cases. CONCLUSION: Prolonged residual GML could constitute an additional risk factor for the development of gastric carcinoma. Long-term endoscopic surveillance is mandatory in patients treated conservatively for gastric MALT lymphoma.     

脑源性神经营养因子在涎腺腺样囊性癌中的表达及意义

[目的]探讨脑源性神经营养因子（BDNF）与涎腺腺样囊性癌（SACC）的关系。[方法]采用免疫组织化学方法检测45例SACC切片中BDNF的表达,并统计分析BDNF与SACC组织学分型、临床分期、神经侵犯和远处转移之间的关系。[结果]BDNF在SACC中的阳性表达率为84.4%（38/45）,BDNF表达强度与SACC的组织学分型和神经侵犯无明显关系（P〉0.05）,而与临床分期、远处转移关系密切（P〈0.05）。[结论]SACC中存在BDNF异常表达,而且BDNF可能促进了SACC的发生发展。     

Importance of FISH combined with Morphology,Immunophenotype and Cytogenetic Analysis of Childhood/ Adult Acute Lymphoblastic Leukemia in Omani Patients

Genetic changes associated with acute lymphoblastic leukemia (ALL) provide very important diagnostic andprognostic information with a direct impact on patient management. Detection of chromosome abnormalities byconventional cytogenetics combined with fluorescence in situ hybridization (FISH) play a very significant rolein assessing risk stratification. Identification of specific chromosome abnormalities has led to the recognition ofgenetic subgroups based on reciprocal translocations, deletions and modal number in B or T-cell ALL. In the lasttwelve years 102 newly diagnosed childhood/adult ALL bone marrow samples were analysed for chromosomalabnormalities with conventional G-banding, and FISH (selected cases) using specific probes in our hospital.G-banded karyotype analysis found clonal numerical and/or structural chromosomal aberrations in 74.2% ofcases. Patients with pseudodiploidy represented the most frequent group (38.7%) followed by high hyperdiploidygroup (12.9%), low hyperdiploidy group (9.7%), hypodiploidy (<46) group (9.7%) and high hypertriploidygroup (3.2%). The highest observed numerical chromosomal alteration was high hyperdiploidy (12.9%) withabnormal karyotypes while abnormal 12p (7.5%) was the highest observed structural abnormality followed byt(12;21)(p13.3;q22) resulting in ETV6/RUNX1 fusion (5.4%) and t(9;22)(q34.1;q11.2) resulting in BCR/ABL1fusion (4.3%). Interestingly, we identified 16 cases with rare and complex structural aberrations. Application ofthe FISH technique produced major improvements in the sensitivity and accuracy of cytogenetic analysis withALL patients. In conclusion it confirmed heterogeneity of ALL by identifying various recurrent chromosomalaberrations along with non-specific rearrangements and their association with specific immunophenotypes. Thisstudy pool is representative of paediatric/adult ALL patients in Oman.     

Cytogenetic analysis of 298 newly diagnosed cases of acute lymphoblastic leukaemia in Tunisia

Genetic changes associated with Acute Lymphoblastic Leukaemia (ALL) provide diagnostic and prognostic information with a direct impact on patient management. We report the cytogenetic analysis of 298 Tunisian patients with ALL, including 183 children and 115 adults. Chromosome abnormalities have been detected in 68.2% of our patients associating clonal numerical and/or structural rearrangements. Some chromosomal abnormalities especially hyperdiploidy, 19p13 abnormalities, 8q24 translocations, 12p, 6q deletions and TCR rearrangements occur at a lower incidence compared to that reported in other populations. ALL cases (5.7%) had miscellaneous clonal abnormalities. We also found in our Tunisian series a higher incidence for T-lineage ALL more than usually described. Among structural chromosomal abnormalities, t(9;22)(q34;q11) resulting in the BCR/ABL fusion and the t(12;21)(p13;q22) resulting in the TEL/AML1 fusion were studied by FISH providing additional diagnostic and prognostic information. We conclude that although the incidence of our cytogenetic results are slightly different, their clinical significance is similar to that described in the literature.     

Mechanistic aspects of the cytotoxic activity of glufosfamide, a new tumour therapeutic agent

Beta-D-glucosyl-ifosfamide mustard (D 19575, glc-IPM, INN = glufosfamide) is a new agent for cancer chemotherapy. Its mode of action, which is only partly understood, was investigated at the DNA level. In the breast carcinoma cell line MCF7 glufosfamide inhibited both the synthesis of DNA and protein in a dose-dependent manner, as shown by the decreased incorporation of [3H-methyl]-thymidine into DNA and [14C]-methionine into protein of these cells. Treatment of MCF7 cells with 50 microM glufosfamide was sufficient to trigger poly(ADP-ribose) polymerase (PARP) activation, as revealed by immunofluorescence analysis. Both CHO-9 cells, which are O6-methylguanine-DNA methyltransferase (MGMT)-deficient, and an isogenic derivative, which has a high level of MGMT, showed the same cytotoxic response to beta-D-glc-IPM, indicating that the O6 position of guanine is not the critical target for cytotoxicity. By contrast, a sharp decrease in survival of cross-link repair deficient CL-V5 B cells was observed already at concentrations of 0.1 mM beta-D-glc-IPM, whereas the wild-type V79 cells showed a 90% reduction in survival only after treatment with 0.5 mM of this compound. The therapeutically inactive beta-L-enantiomer of glufosfamide also showed genotoxic effects in the same assays but at much higher doses. This was probably due to small amounts of ifosfamide mustard formed under the conditions of incubation. The results indicate that the DNA crosslinks are the most critical cytotoxic lesions induced by beta-D-glc-IPM.     

Translocation t(12;13)(p13.3;q12.2) is Not Restricted to Lymphoid Malignancies; Report of a Further Case with Hypereosinophilia

We report two cases of t(12;13)(p13;q12). One was found in a lymphoid disorder, as previously described, while the second was observed in a myeloproliferative syndrome with hypereosinophilia. As t(12;13) has already been described in association with hypereosinophilia in a case of acute lymphoblastic leukaemia, we suggest that the association of t(12;13) with hypereosinophilia is not random.