Specific Karyotypic Abnormalities Research Articles

Clinical Characteristics of Acute Myeloid Leukemia Patients with RUNX1 Gene Mutation

To investigate the incidence of Runt-related transcription factor 1 (RUNX1) gene and its associated gene mutations in patients with acute myeloid leukemia (AML), and analyze its clinical characteristics and prognosis. The genomic DNA-PCR method was used to detect the exon of RUNX1 gene, and the gene mutations were analyzed by genetic sequencing. NPM1, DNMT3A, FLT3-ITD, IDH1/2, K/N-RAS, CEPBA, TET2, and WT1 co-mutations were also detected. Patients were followed up to determine efficacy and prognosis. Among 171 patients, the RUNX1 gene mutation was detected in 17 cases, and the mutation rate was 9.9%. The type of RUNX1 gene mutation was 9 missense mutations, 4 frameshift mutations, and 4 nonsense mutations. The peripheral blood leukocyte count of the patients in mutation group was 3 (1-101) ×109/L, which was significantly lower than those in the non-mutation group [26 (1-298)×109/L] (P=0.002), while the platelet count was 79 (22-166)×109/L, which was higher than 50 (8-351)×109/L in the non-mutation group (P=0.010), and the proportion of bone marrow blasts of the patients in the mutation group was 37 (0-72)%, which was lower than 53 (0-98)% in the non-mutation group (P=0.020). The RUNX1 mutation rate in M0 type was 55.6%, and in M4 type was 13.6%, which was significantly higher than other FAB subtypes (P=0.003). There was no significant difference in age, sex, hemoglobin concentration, and counts of peripheral blood mononuclear cells (P>0.05). The prognosis of cytogenetics in the patients in the middle and high-risk groups was 88.1% and 89.7%, which were significantly higher than that in the low-risk group, and the difference showed statistically significant (P=0.018). There was no significantly relationship between RUNX1 and specific karyotype abnormalities, including Trisomy 8, Del (7q), t (8; 21), and Inv (16) (P>0.05). There was a significant relationship between RUNX1 gene mutation and IDH1/2, N/K-RAS gene mutation (P<0.01). The complete response rate (CR) of the patients with chemotherapy in the RUNX1 mutation group(37.5%) was significantly lower than 79.4% in the non-mutated group (P=0.001). The overall survival (OS) of the patients in RUNX1 gene mutation group was lower than that in non-mutation group (P<0.05). AML patients with RUNX1 gene mutation shows unique clinical and biological characteristics, RUNX1 mutation can be regarded as a molecular marker of poor prognosis in AML patients.

Loss of TRIM62 expression is an independent adverse prognostic factor in acute myeloid leukemia.

Tripartite motif (TRIM)-62 is a putative tumor suppressor gene whose role in leukemia is unknown. We evaluated the effect of TRIM62 protein expression in patients with acute myeloid leukemia (AML). We used reverse-phase protein array methodology to determine TRIM62 levels in leukemia-enriched protein samples from 511 patients newly diagnosed with AML. TRIM62 levels in AML cells were significantly lower than in normal CD34-positive cells, suggesting that TRIM62 loss might be involved in leukemogenesis, but was not associated with specific karyotypic abnormalities or Nucleophosmin (NPM1), Fms-like Tyrosine Kinase-3 (FLT3), or rat sarcoma viral oncogene (RAS) mutational status. Low TRIM62 levels were associated with shorter complete remission duration and significantly shorter event-free and overall survival rates, particularly among patients with intermediate-risk cytogenetics. In that AML subgroup, age and TRIM62 levels were the most powerful independent prognostic factors for survival. TRIM62 protein levels further refined the risk associated with NPM1 and FLT3 mutational status. TRIM62 loss was associated with altered expression of proteins involved in leukemia stem cell homeostasis (β-catenin and Notch), cell motility, and adhesion (integrin-β3, ras-related C3 botulinum toxin substrate [RAC], and fibronectin), hypoxia (Hypoxia-inducible factor 1-alpha [HIF1α], egl-9 family hypoxia-inducible factor 1 [Egln1], and glucose-regulated protein, 78 kDa [GRP78]), and apoptosis (B-cell lymphoma-extra large (BclXL) and caspase 9). Low TRIM62 levels, consistent with a tumor suppressor role, represent an independent adverse prognostic factor in AML.

Clinical and genetic predictors of prognosis in myelodysplastic syndromes.

Myelodysplastic syndromes are a collection of clonal hematopoietic disorders with a wide range of clinical manifestations and eventual outcomes. Accurate prediction of a patient's prognosis is useful to define the risk posed by the disease and which treatment options are most appropriate. Several models have been created to help predict the prognosis for patients with myelodysplastic syndromes. The International Prognostic Scoring System (IPSS) has been the standard tool used to risk stratify MDS patients since its publication in 1997. Other models have since been created to improve upon the IPSS, including the recent Revised International Prognostic Scoring System. Most models include the presence or severity of peripheral blood cytopenias, the proportion of bone marrow blasts, and specific karyotype abnormalities. Other factors including age, performance status, co-morbidities, transfusion dependence, and molecular biomarkers can further refine the prediction of prognosis in some models. Novel, disease specific biomarkers with prognostic value in myelodysplastic syndromes including cell surface markers, gene expression profiles, and high resolution copy number analyses have been proposed but not yet adopted clinically. Somatic abnormalities in recurrently mutated genes are the most informative prognostic biomarkers not currently considered by clinical risk models. Mutations in specific genes have independent prognostic significance and, unlike cytogenetic abnormalities, are present in the majority of myelodysplastic syndrome cases. However, mutational information can be complex and there are challenges to its clinical implementation. Despite these limitations, DNA sequencing can refine the prediction of prognosis for myelodysplastic syndrome patients and has become increasingly available in the clinic where it will help improve the care of patients with myelodysplastic syndromes.

Influence of Prognostic Factors on OverallSurvival in Myelodysplastic Syndromes.

Background:Accurate prediction of a patient's prognosis is useful to define the risk posed by the disease. Age, gender, peripheral blood cytopenia, proportion of bone marrow (BM) blasts, performance status, comorbidities, transfusion dependence, specific karyotype abnormalities and molecular biomarkers can refine the prediction of prognosis in MDS.Aim:to assess the influence of the some prognostic factors like age, gender, cytopenia, BM blast percentage, transfusion dependence, ferritin, hemoglobin (Hb), lactate dehydrogenase (LDH), albumin and specific karyotype abnormalities in myelodysplastic syndromes on overall survival (OS).Patients and methods:we retrospectively analyzed the cohort of 108 patients diagnosed between 1.1.2011 and 31.12.2013 at the University Clinic of Hematology, Ss Cyril and Methodius University, Skopje, Macedonia. They were evaluated for clinical and hematologic features at diagnosis and at leukemic transformation.Results:in the study group 62 were man and 46 women. Male to female ratio was 1.35 to 1. The differences in OS between men and women were significant (p = .03015). The mean age at diagnosis was 66,6 years. According to the age OS was 16,4 months. FAB subtypes influenced OS significantly (p = .03015). OS inversely correlated with BM blast percentage (p= .02327). Cytopenia had no impact on OS (p=.33755). Hb as a whole and groups with different levels of Hb had no influence on OS (p = .12142) and (p= .07535), respectively. The group with ferritin <500 µg/L had better OS (p=.04720). Transfusion dependence, LDH and albumin had no impact on OS. Leukemic transformation was noticed in 10 (9,3%) patients. Mortality was 36,1%.Conclusion:gender, FAB subtypes, BM blast percentage and the serum levels of ferritin had an influence on OS, while age, hemoglobin level, transfusion dependence, LDH and albumin had no impact on OS.

Clear Cell Renal Cell Carcinoma: Multiphasic Multidetector CT Imaging Features Help Predict Genetic Karyotypes

To determine whether imaging characteristics at multiphasic multidetector computed tomography (CT) correlate with common karyotypic abnormalities in patients with clear cell renal cell carcinomas (ccRCCs). Institutional review board approval was obtained, and informed consent was waived for this HIPAA-compliant retrospective study. From January 2000 through September 2007, the prenephrectomy multiphasic (corticomedullary, nephrographic, and excretory phases), multidetector helical CT images of 58 histologically proved and karyotyped ccRCCs were reviewed by two readers with experience in abdominal imaging. Imaging features assessed included degree of attenuation, contour, and presence of calcifications and neovascularity. These features were independently correlated with specific karyotypic abnormalities on the resected specimens. Degree of attenuation data were analyzed with logistic regression for significance (P < .05), and morphologic characteristics were analyzed with odds ratios for assessing their diagnostic power. On unenhanced scans, 7% (two of 28) of ccRCCs with the loss of chromosome 3p were calcified, whereas 37% (11 of 30) of lesions without this anomaly were calcified (odds ratio, 0.13). During the corticomedullary phase, ccRCCs with the loss of chromosome Y enhanced more than those without this anomaly (130.0 vs 102.5 HU, P = .04), and ccRCCs with trisomy 7 enhanced less than those without this anomaly (105.8 vs 139.3 HU, P = .04). During the excretory phase, ccRCCs with trisomy 5 enhanced more than those without this anomaly (115.5 vs 83.4 HU, P = .03). The genetic makeup of ccRCCs affects their imaging features at multidetector CT examinations. Multidetector CT imaging characteristics may help suggest differences at the cytogenetic level among ccRCCs.

Unraveling the Molecular Pathophysiology of Myelodysplastic Syndromes

Somatically acquired genetic abnormalities lead to the salient features that define myelodysplastic syndromes (MDS): clonal hematopoiesis, aberrant differentiation, peripheral cytopenias, and risk of progression to acute myeloid leukemia. Although specific karyotypic abnormalities have been linked to MDS for decades, more recent findings have demonstrated the importance of mutations within individual genes, focal alterations that are not apparent by standard cytogenetics, and aberrant epigenetic regulation of gene expression. The spectrum of genetic abnormalities in MDS implicates a wide range of molecular mechanisms in the pathogenesis of these disorders, including activation of tyrosine kinase signaling, genomic instability, impaired differentiation, altered ribosome function, and changes in the bone marrow microenvironment. Specific alterations present in individual patients with MDS may explain much of the heterogeneity in clinical phenotype associated with this disease and can predict prognosis and response to therapy. Elucidation of the full complement of genetic causes of MDS promises profound insight into the biology of the disease, improved classification and prognostic scoring schemes, and the potential for novel targeted therapies with molecular predictors of response.

Targeted treatment of chronic myeloid leukemia: role of imatinib.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by clonal expansion of pleuripotent hematopoetic stem cells. The incidence of CML is 1 to 2 cases per 100,000 people per year; in the Western Hemisphere, CML accounts for 15% of leukemias in adults. Discovery of the specific karyotypic abnormality of the Philadelphia (Ph) chromosome in the pathogenesis of CML has led to a better understanding of the disease and hence to an advancement of targeted therapeutics. Availability of imatinib as an accepted targeted therapy in newly diagnosed patients has changed the treatment paradigm in CML. The majority of CML patients in chronic phase achieve excellent and durable responses with standard-dose imatinib. Mechanisms of primary and secondary resistance to imatinib in CML have been extensively studied and newer tyrosine kinase inhibitors are now being evaluated for clinical use. It is important that at any time the CML treatment and response remain optimal and thus patients on imatinib require continuous monitoring for early detection of resistance. This review will discuss the treatment and guidelines for monitoring CML patients in the imatinib era.

Desmoplastic small round cell tumors: cytologic, histologic, and immunohistochemical features.

Desmoplastic small round cell tumor (DSRCT) is a recently recognized clinicopathologic entity that has a predilection for adolescent males and usually affects the abdominal cavity. Due to its uncommon nature, many pathologists lack experience with this tumor. The literature regarding DSRCT is reviewed with special attention to its histologic and cytologic diagnosis. Morphologic features of DSRCT and its immunohistochemical and cytogenetic profile are summarized and differential diagnosis with other small round cell tumors is discussed. As observed by both histologic and cytologic examinations, small round blue cells and fibrosclerotic stroma are the striking morphologic features of DSRCT. The typical immunohistochemical profile is characterized by coexpression of epithelial, mesenchymal, myogenic, and neural markers. Cytogenetically, this tumor harbors a specific karyotypic abnormality, namely t(11;22)(p13;q12). These features distinguish DSRCT from other members of the family of small round cell tumors.

Desmoplastic Small Round Cell Tumors: Cytologic, Histologic, and Immunohistochemical Features

Desmoplastic small round cell tumor (DSRCT) is a recently recognized clinicopathologic entity that has a predilection for adolescent males and usually affects the abdominal cavity. Due to its uncommon nature, many pathologists lack experience with this tumor. The literature regarding DSRCT is reviewed with special attention to its histologic and cytologic diagnosis. Morphologic features of DSRCT and its immunohistochemical and cytogenetic profile are summarized and differential diagnosis with other small round cell tumors is discussed. As observed by both histologic and cytologic examinations, small round blue cells and fibrosclerotic stroma are the striking morphologic features of DSRCT. The typical immunohistochemical profile is characterized by coexpression of epithelial, mesenchymal, myogenic, and neural markers. Cytogenetically, this tumor harbors a specific karyotypic abnormality, namely t(11;22)(p13;q12). These features distinguish DSRCT from other members of the family of small round cell tumors.

Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of T-lymphocytes, and human T-cell lymphotropic virus type-I (HTLV-I) is etiologically considered as the causative virus of ATLL. The karyotypes of ATLL are very complex in both number and structure, although no specific karyotype abnormalities have been identified. HTLV-I is thought to integrate its provirus into random sites in host chromosomal DNA and induces chromosomal instability. The BUB gene is a component of the mitotic checkpoint in budding yeast. Recently, human homologues of the BUB were identified and mutant alleles of hBUB1 and hBUBR1 were detected in two colorectal tumor cell lines, which showed microsatellite instability (MIN). In vitro, BUB proteins form a complex of monomers. These proteins interact with the human MAD1 gene product, a target of the HTLV-1 tax oncogene. We examined the role of checkpoint gene in the chromosomal abnormalities of ATLL by investigating mutations of hBUB1 and hBUBR1, and MIN of replication errors of BAX, insulin-like growth factor, and transforming growth factor β type II. We analyzed ten cases with ATLL and eight B-cell lymphomas (five diffuse large cell lymphomas, three follicular lymphomas). Complex chromosomal abnormalities were detected in ATLL, while B-cell lymphomas showed only simple or minimal chromosomal abnormalities. Significant mutations/deletion of hBUB1 or hBUBR1 were detected in four of ten cases with ATLL, including two heterozygous point mutations, one homozygous point mutation, and one with a 47 bp deletion. In contrast, only one of eight B-cell lymphomas showed nonsense mutation of hBUBR1. None of the ATLL and B-cell lymphomas showed MIN. In the multistage process of leukemogenesis of ATLL, our findings indicate that mutations of mitotic checkpoint genes may play an important role in the induction of complex chromosomal abnormalities.

Increase therapy-related leukemia secondary to breast cancer.

Therapy-related leukemia associated with chemotherapy, particularly alkylating agents and topoisomerase II inhibitors, are being reported with increasing frequency in the literature mainly after breast cancer. We also observed an increasing number of such leukemias in the data base of the specialized registry of hematological malignancies of the Côte d'Or department. Between 1980 and 1998, 156 AML and RAEB-t were registered in women in Côte d'Or. Among them, 12 occurred in women with breast cancer history (7.7%). Analysis by period of time shows a significant increase in the proportion of therapy-related leukemia secondary to breast cancer (P < 0.02). Chemotherapy including topoisomerase II inhibitors was used in 10 cases in which mitoxantrone was used in eight cases. In these eight cases, leukemia had clinical and biological characteristics usually described with topoisomerase II inhibitors but 44% were promyelocytic sub-type with the t(15;17) specific karyotypic abnormality. These data on a well-defined population demonstrate the increased proportion of therapy-related leukemia secondary to breast cancer, probably due to the use of mitoxantrone.

Use of FISH Analysis for Diagnosis of Renal Cell Carcinoma Subtypes

Cytogenetic and molecular genetic techniques have been used in demonstrating the chromosomal abnormalities which characterize specific subtypes of renal cell carcinoma (RCC). The aim of this study was to determine the efficiency of fluorescent in situ hybridization (FISH) technique in characterizing various subtypes of RCC based on the presence of specific chromosome abnormalities found in each RCC subtype. FISH was performed on touch imprint smears from eight renal cell carcinomas histologically confirmed by established criteria. In four tumors with histologic features of chromophobe renal cell carcinoma (ChRCC), interphase FISH was performed using centromeric probes for chromosomes 1, 2, 6, 10, 12, 17 and 21. All four ChRCC tumors showed one FISH signal corresponding to one copy number for each of these chromosomes. Two papillary RCCs included in this study showed trisomy 7 and 17, and loss of chromosome Y, using the corresponding chromosome centromeric probes. Similarly, we tested two clear cell RCCs for chromosome 3 short arm deletion with DNA probe 3p21.3. Both tumors showed loss of 3p21.3 signal. We conclude that interphase FISH performed on touch imprint smears is a relatively simple, rapid and reliable method for detecting chromosome abnormalities which are specific for various subtypes of RCC.

A Large Proportion of Patients With a Diagnosis of Essential Thrombocythemia Do Not Have a Clonal Disorder and May Be at Lower Risk of Thrombotic Complications

AbstractEssential thrombocythemia (ET) is traditionally considered to be a clonal disorder. No specific karyotypic abnormalities have been described, but the demonstration of clonality using X-chromosome inactivation patterns (XCIPs) has been used to differentiate ET from a non-clonal reactive thrombocytosis. However, these assays may be difficult to interpret, and contradictory results have been reported. We have studied 46 females with a diagnosis of ET according to the Polycythemia Vera Study Group (PVSG) criteria. XCIP results in 23 patients (50%) were uninterpretable due to either constitutive or possible acquired age-related skewing. Monoclonal myelopoiesis could be definitively shown in only 10 patients. Thirteen patients had polyclonal myelopoiesis, and in 8, it was possible to exclude clonal restriction to the megakaryocytic lineage. Furthermore, there was no evidence of clonal progenitors in purified CD34+CD33− and CD34+CD33+ subpopulations from bone marrow of 2 of these 13 patients. There was no difference between patients with monoclonal and polyclonal myelopoiesis with respect to age or platelet count at diagnosis, duration of follow-up, incidence of hepatosplenomegaly, or hemorrhagic complications. However, polyclonal patients were less likely to have experienced thrombotic events (P = .039). These results suggest that ET is a heterogeneous disorder, and the clinical significance of clonality status warrants investigation in a larger study.

A Large Proportion of Patients With a Diagnosis of Essential Thrombocythemia Do Not Have a Clonal Disorder and May Be at Lower Risk of Thrombotic Complications

Essential thrombocythemia (ET) is traditionally considered to be a clonal disorder. No specific karyotypic abnormalities have been described, but the demonstration of clonality using X-chromosome inactivation patterns (XCIPs) has been used to differentiate ET from a non-clonal reactive thrombocytosis. However, these assays may be difficult to interpret, and contradictory results have been reported. We have studied 46 females with a diagnosis of ET according to the Polycythemia Vera Study Group (PVSG) criteria. XCIP results in 23 patients (50%) were uninterpretable due to either constitutive or possible acquired age-related skewing. Monoclonal myelopoiesis could be definitively shown in only 10 patients. Thirteen patients had polyclonal myelopoiesis, and in 8, it was possible to exclude clonal restriction to the megakaryocytic lineage. Furthermore, there was no evidence of clonal progenitors in purified CD34+CD33− and CD34+CD33+ subpopulations from bone marrow of 2 of these 13 patients. There was no difference between patients with monoclonal and polyclonal myelopoiesis with respect to age or platelet count at diagnosis, duration of follow-up, incidence of hepatosplenomegaly, or hemorrhagic complications. However, polyclonal patients were less likely to have experienced thrombotic events (P = .039). These results suggest that ET is a heterogeneous disorder, and the clinical significance of clonality status warrants investigation in a larger study.

Random integration of HTLV-I provirus; increasing chromosomal instability

Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of mature helper (CD4) T-lymphocytes. Human T-cell lymphotropic virus type-I (HTLV-I) is etiologically considered to cause ATLL. It has been suggested that HTLV-I integrates its provirus into random sites in host chromosomal DNA after infection. Clonal integration has been observed in patients with ATLL, including smoldering, chronic and acute leukemia states. Almost all cases with ATLL demonstrate clonal chromosome abnormalities, with karyotypes being very complicated in both number and structure. However, there are no specific karyotype abnormalities in ATLL. In order to examine the role of HTLV-I in the pathogenesis of ATLL, we investigated whether or not HTLV-I randomly integrates and whether the integration site in the human genome is associated with any chromosomal abnormality. We analyzed 18 cases with ATLL, which included 15 cases with acute states, two cases with chronic states and one case with a smoldering state. In four of the 18 cases, the HTLV-I provirus integrated into the 9th chromosome, while in three cases, it integrated into the 1st or 10th chromosome. However, the integrated site in the chromosome varied in each case and the random integration was considered to be true. All 15 cases with acute ATLL had complicated chromosomal abnormalities and two cases with chronic and smoldering ATLL showed simple abnormal karyotypes, while one case with chronic ATLL showed a normal karyotype. In 15 of the 18 cases, the chromosomes with HTLV-I integration showed abnormalities. In particular, in two cases with simple chromosome abnormalities, HTLV-I integrated into the abnormal chromosome, but not into the normal chromosome. The HTLV-I proviral integration thus seems to be associated with chromosome abnormalities. In the multistage leukemogenesis of ATLL, these findings indicate that HTLV-I integration might play an important role in the induction of chromosomal instability.

BCNU-resistant human glioma cells with over-representation of chromosomes 7 and 22 demonstrate increased copy number and expression of platelet-derived growth factor genes.

We used standard karyotypic analyses of first-division cells to identify a subpopulation of cells in primary malignant gliomas with over-representation of chromosomes 7 and 22. These cells are a minor subpopulation in the primary tumor but become the dominant population after treatment in vitro of the cells with the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The selection for a cell with this specific karyotypic abnormality suggests that these chromosomes contain genes important to the growth of BCNU-resistant cells. Southern blot hybridization analyses demonstrate an increased copy number of the genes encoding platelet-derived growth factor (PDGF) A-chain and B-chain, which have been mapped to chromosomes 7 and 22, respectively. Reverse transcription followed by polymerase chain reaction (RT-PCR) analysis demonstrates increased expression of these genes. In addition, these cells secrete a mitogenic factor that stimulates 3H-thymidine uptake in NIH 3T3 cells. This factor is sensitive to anti-PDGF antibodies and beta-mercaptoethanol, but not to anti-EGF antibodies. These data suggest that autocrine and/or paracrine mechanisms occur in human malignant gliomas, and that over-expression of PDGF may play a role in the growth of BCNU-resistant cells in these tumors.

Trisomy 4 and de novo acute myelomonocytic leukemia in a Kuwaiti patient

Trisomy 4 is a rare but specific karyotypic abnormality associated with primary and secondary acute myeloblastic leukemia (AML). We report such an occurrence in a Kuwaiti patient with de novo acute myelomonocytic leukemia and its disappearance on achievement of complete remission.

Cardiac histologic pathology characteristic of trisomies 13 and 21

To identify fetal histologic features characteristic of specific chromosomal anomalies, we reviewed histologic slides of 415 cases, including therapeutic and spontaneous abortuses, stillbirths, and perinatal deaths. These included 126 cases (30%) with karyotypically confirmed trisomy 21 and 23 cases (5.5%) with trisomy 13. Two histologic abnormalities of the fetal heart were identified that correlated with specific karyotypic abnormalities: (1) a discrete central papillary muscle calcification was present in 14 of 85 (16%) cases with trisomy 21, in seven of 18 (39%) cases with trisomy 13, and in six of 255 (2%) controls ( P < .001); and (2) a focal ventricular epicardial lymphocytic infiltrate was present in 22 of 93 (24%) cases with trisomy 21 versus nine of 284 (3%) controls ( P < .001). When both histologic abnormalities coexisted, trisomy 21 was present in five of six cases (83%). Neither histologic finding was significantly associated with fetal or maternal infection or congenital heart defects. In a restricted prospective study of the hearts of fetuses with trisomy 21, papillary muscle calcification was demonstrated by specimen radiographs in four of six (67%) cases; one case was studied by specimen ultrasonogram, which identified a papillary muscle echodensity. We conclude that (1) a focal ventricular epicardial lymphocytic infiltrate is characteristic of trisomy 21, (2) papillary muscle microcalcifications are characteristic of trisomies 13 and 21, and (3) further studies are needed to determine whether papillary muscle calcification might be useful in antenatal ultrasonographic screening for chromosomal anomalies.

Familial aggregation of nasopharyngeal carcinoma and other malignancies. A clinicopathologic description.

Nasopharyngeal carcinoma (NPC) occurred in five members in three generations of a white American family of Scandinavian descent. Six other family members had malignancies including malignant melanoma, malignant lymphoma, squamous cell carcinoma of the tongue, adenocarcinoma of the colon, and asynchronous bilateral in situ and invasive ductal carcinomas of the breast. There was also a history of autoimmune disorders and exposure to smoke, fumes, and chemicals in some family members. Regression analysis revealed a significant covariate risk for exposure to smoking, alcohol ingestion, dust, salted or spicy foods, and poorly ventilated conditions. According to segregation analysis, the susceptibility to nasopharyngeal carcinoma and other malignancies in this family was transmitted as an autosomal codominant characteristic. A specific histocompatibility antigen (HLA) haplotype of A1-B37-DR6 was associated with a predisposition for NPC, but no linkage was identified. Laboratory studies in selected family members did not reveal significantly elevated levels of Epstein-Barr virus antibodies or serum carcinoembryonic antigen. No specific karyotypic abnormalities were identified with peripheral blood chromosome analysis. This family was an example of apparent autosomal codominant susceptibility to NPC and other malignancies. The relationship of malignancy to the HLA haplotype of A1-B37-DR6, autoimmune disorders, and cytogenetic abnormalities was intriguing but not defined clearly.

Plasma cell karyotype in multiple myeloma

Karyotypic abnormalities were studied in multiple myeloma and were correlated with clinical features. Among 115 evaluable patients, 46% had an abnormal karyotype. Trisomy 3, 5, 9, and 15 and monosomy 13 and 16 were the most common clonal abnormalities. Translocations described previously in other B cell malignancies occurred in nine patients, including four with t(8;14)(q24;q32) translocations. The association of all t(8;14) abnormalities with IgA protein type suggested a pathogenetic relationship between a specific karyotypic abnormality and myeloma protein type. Hypodiploidy occurred mainly in patients with only Bence Jones protein, was associated with resistance to therapy, and justified the early consideration of investigational therapies.