PubMed Health⌕ Search

Biomedical subjects

D Horsman

Publications and source records attributed to D Horsman.

At least 19 recordsLinked to original sources
PubMed2004

Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Several studies have reported that the risk of breast cancer decreases with increasing duration of breast-feeding. Whether breast-feeding is associated with a reduced risk of hereditary breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations is currently unknown. METHODS: We conducted a case-control study of women with deleterious mutations in either the BRCA1 or the BRCA2 gene. Study participants, drawn from an international cohort, were matched on the basis of BRCA mutation (BRCA1 [n = 685] or BRCA2 [n = 280]), year of birth (+/-2 years), and country of residence. The study involved 965 case subjects diagnosed with breast cancer and 965 control subjects who had no history of breast or ovarian cancer. Information on pregnancies and breast-feeding practices was derived from a questionnaire administered to the women during the course of genetic counseling. Conditional logistic regression analyses were used to estimate odds ratios (ORs) for the risk of breast cancer. All statistical tests were two-sided. RESULTS: Among women with BRCA1 mutations, the mean total duration of breast-feeding was statistically significantly shorter for case subjects than for control subjects (6.0 versus 8.7 months, respectively; mean difference = 2.7 months, 95% confidence interval [CI] = 1.4 to 4.0; P<.001). The total duration of breast-feeding was associated with a reduced risk of breast cancer (for each month of breast-feeding, OR = 0.98, 95% CI = 0.97 to 0.99; P(trend)<.001). Women with BRCA1 mutations who breast-fed for more than 1 year were less likely to have breast cancer than those who never breast-fed (OR = 0.55, 95% CI = 0.38 to 0.80; P =.001), although no such association was seen for BRCA2 (OR = 0.95, 95% CI = 0.56 to 1.59; P =.83). CONCLUSIONS: Women with deleterious BRCA1 mutations who breast-fed for a cumulative total of more than 1 year had a statistically significantly reduced risk of breast cancer.

Adult↗
PubMed2001

Identification of four novel dinucleotide repeat polymorphisms in the IL-2 and IL-2beta receptor genes.

Two polymorphic regions have been described within the IL-2 and IL-2 receptor beta genes comprising 15 and 8 alleles, respectively. Whether these polymorphisms have biologic importance is unknown, although they have been variably identified in associated with certain chronic disease states. We report here the detection of four new alleles designated IL-2 A* (122 bp), IL-2R-2 (169 bp), IL-2R 0 (165 bp), and IL-2R 9 (147 bp) in patients with rheumatoid arthritis and normal controls from the Pacific Northwest. The number of alleles now recognized at these loci within the IL-2 and IL-2Rbeta genes increases to 16 and 12, respectively.

Alleles↗
PubMed2000

Association between dinucleotide repeat in non-coding region of interferon-gamma gene and susceptibility to, and severity of, rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis ranges from a mild, non-deforming arthropathy with little long-term disability to severe, incapacitating, deforming arthritis which may be refractory to conventional disease-modifying agents. Epidemiological studies show an important genetic influence in rheumatoid arthritis, and MHC region genes and cytokine genes within and outside this region have been considered as candidates. We did a case-control study to test whether polymorphisms in the interferon-gamma gene are associated with severity of rheumatoid arthritis. METHODS: Interferon gamma dinucleotide repeat polymorphisms were examined with quantitative genescan technology, and HLA-DR alleles were identified by PCR and restriction-fragment-length polymorphism analysis. We studied 60 patients with severe rheumatoid arthritis, 39 with mild disease, and 65 normal controls. FINDINGS: Susceptibility to, and severity of, rheumatoid arthritis were related to a microsatellite polymorphism within the first intron of the interferon-gamma gene. A 126 bp allele was seen in 44 (73%) of 60 patients with severe rheumatoid arthritis, compared with eight (21%) of 39 with mild disease (odds ratio 10.66 [95% CI 4.1-24.9]), and with eight (12%) of 65 normal controls (19.59 [7.7-49.9]). Conversely, a 122 bp allele at the same locus was found in four (7%) patients with severe disease compared with 25 (64%) of those with mild disease (0.04 [0.01-0.1]) and with 52 (80%) of controls (0.018 [0.005-0.06]). INTERPRETATION: This association may be valuable for understanding the mechanism of disease progression, for predicting the course of the disease, and for guiding therapy.

Adult↗
PubMed2000

Identification of four novel dinucleotide repeat polymorphisms in the TNF-alpha and TNF-beta genes.

Five polymorphic regions (a to e) have been recognized within the TNF gene region. These polymorphisms appear to be of biological importance as individual alleles have been associated with higher production of TNF and/or an increased risk of rheumatoid arthritis or diabetes mellitus. We report here the detection of four new alleles designated a14 (122 bp), b8 (131 bp), b9 (132 bp), and d0 (122 bp) in patients with rheumatoid arthritis and normal controls from the Pacific Northwest. This increases to 39 the number of alleles now recognized at these loci.

Arthritis, Rheumatoid↗
PubMed2000

Involvement of the X chromosome in non-Hodgkin lymphoma.

Gain of an X chromosome is observed as a secondary, acquired karyotypic alteration in a significant proportion of malignant lymphomas. To determine the potential involvement of X-linked genes in neoplastic development, we have analyzed the inactivation status of the supernumerary X chromosome in lymphomas in both male and female patients. In males, neither methylation of FMR1 nor expression of XIST was detected, demonstrating that the duplicated chromosome was not subject to inactivation. In females, both expressed polymorphisms and polymorphisms associated with methylation differences between the active and inactive X chromosome were analyzed to determine whether the duplicated chromosome was active or inactive. To facilitate this analysis, allele-specific PCR primers were designed for detection of previously described polymorphisms in the IDSX and G6PD genes. The female lymphomas were shown to be clonal in origin, and duplication of either the active (5 cases) or inactive (4 cases) X chromosome was observed. Correlations between clinical status and the inactivation status of the X chromosome involved in the duplication were not observed in our relatively small sample, although 4/4 informative cases with a t(14;18) showed duplication of the active X chromosome. In the course of these studies, we detected hypermethylation of the androgen receptor (AR) locus in an extremely high proportion of both male (7/9) and female (9/10) samples. These results are discussed with respect to whether sex chromosome aneuploidies in tumors are involved in, or simply the result of, the neoplastic process. Genes Chromosomes Cancer 28:246-257, 2000.

Adult↗
PubMed1999

Small noncleaved, non-Burkitt's (Burkit-Like) lymphoma: cytogenetics predict outcome and reflect clinical presentation.

PURPOSE: To correlate cytogenetic abnormalities with clinical presentation and outcome in Burkitt-like, small noncleaved non-Burkitt's lymphoma (SNC-NB). PATIENTS AND METHODS: Thirty-nine patients with SNC-NB lymphoma and a clonal karyotype were evaluated between January 1989 and January 1996. All were from British Columbia, Canada, underwent uniform clinical staging, and were treated on investigational protocols by a small group of clinicians. RESULTS: Three groups of patients were identified by clonal karyotype on cytogenetic analysis: (1) those with a c-myc translocation (n = 11); (2) those with dual translocation of c-myc and bcl-2 (n = 13); and (3) those with other cytogenetic abnormalities (n = 15). The c-myc group was younger, presented with earlier stage de nova disease, and had a better clinical prognostic factor profile. The dual-translocation and other groups were older and presented in advanced stage with poorer prognostic features, and a larger proportion of the dual-translocation group patients had transformed from previously diagnosed follicular lymphoma. The median overall survival (OS) time for all patients was 5 months. The median OS time for the dual-translocation group was only 2.5 months, as compared with 7 months and 8 months for the c-myc and other group, respectively (P < .001). There were no survivors beyond 7 months among the dual-translocation group, as opposed to 32% and 25% 2-year OS rates in the c-myc and other group. CONCLUSION: SNC-NB lymphoma is a clinically and cytogenetically heterogenous disease. Dual translocation of c-myc and bcl-2 is characterized by a rapid clinical course and extremely poor outcome. This latter entity may represent the most clinically aggressive lymphoma thus far characterized and warrants intensive investigational treatment where feasible.

Adolescent↗
PubMed1999

Cytogenetic and cytologic features of chondroid lipoma of soft tissue.

The cytologic and cytogenetic findings of chondroid lipoma, a rare benign tumor of soft tissue, have not been described. This report details the morphologic features of a fine-needle aspiration biopsy specimen and describes a novel cytogenetic finding. The main cytologic features consisted of clustered, variably mature, multivacuolated, hibernoma-like cells enmeshed in a capillary plexus, with a background of chondromyxoid material. Cytogenetic analysis revealed a balanced translocation t (11, 16)(q13;p12-13) distinct from the known translocation involving 16p11 in myxoid and round-cell liposarcoma. The 11q13 breakpoint was previously noted in hibernomas, raising the possibility of a common genetic deregulation.

Biopsy, Needle↗
PubMed1998

Clinicopathological analysis of follicular lymphoma with a polyploid karyotype.

The prognostic significance of specific cytogenetic abnormalities in follicular lymphoma (FL) is an area of ongoing research. A small percentage of FL are characterized by a polyploid karyotype. Several studies have analyzed ploidy level to determine its role as an independent prognostic factor in non-Hodgkins lymphoma, with equivocal results, mostly using DNA flow cytometry to ascertain ploidy status. We have performed cytogenetic analyses on 180 cases of FL with a t(14;18) diagnosed between 1980 and 1995. Cases were divided into a polyploid group (20 cases) and a non-polyploid group (160 cases), polyploidy defined as a modal chromosome number of 58 or greater. Each group included examples of the 3 subtypes of FL, [Working Formulation]: 1) follicular small cleaved cell (FSC), 2) follicular mixed, small and large cell (FM), and 3) follicular large cell (FLC). The median follow-up time was 38.5 months. The histological subclassification of the polyploid group revealed much less FSC (30% vs 66%, p < 0.004) and much more FLC (25% vs 4%, p < 0.003) than the non-polyploid group, implying histological progression may occur in parallel with the development of polyploidy. Recognized clinical prognostic factors were evenly distributed between the two groups and no survival difference was detected. We show that polyploidy as determined by classical cytogenetics is present in different frequencies across the subtypes of FL with a t(14;18), but is not an independent prognostic factor for survival in FL.

Cohort Studies↗
PubMed1997

Immunolocalization of the ICE/Ced-3-family protease, CPP32 (Caspase-3), in non-Hodgkin's lymphomas, chronic lymphocytic leukemias, and reactive lymph nodes.

Immunohistochemical analysis of the apoptosis-effector protease CPP32 (Caspase-3) in normal lymph nodes, tonsils, and nodes affected with reactive hyperplasia (n = 22) showed strong immunoreactivity in the apoptosis-prone germinal center B-lymphocytes of secondary follicles, but little or no reactivity in the surrounding long-lived mantle zone lymphocytes. Immunoblot analysis of fluorescence-activated cell sorted germinal center and mantle zone B cells supported the immunohistochemical results. In 22 of 27 (81%) follicular small cleaved cell non-Hodgkin's B-cell lymphomas, the CPP32-immunopositive germinal center lymphocytes were replaced by CPP32-negative tumor cells. In contrast, the large cell component of follicular mixed cells (FMs) and follicular large cell lymphomas (FLCLs) was strongly CPP32 immunopositive in 12 of 17 (71%) and in 8 of 14 (57%) cases, respectively, whereas the residual small-cleaved cells were poorly stained for CPP32 in all FLCLs and in 12 of 17 (71%) FMs, suggesting that an upregulation of CPP32 immunoreactivity occurred during progression. Similarly, cytosolic immunostaining for CPP32 was present in 10 of 12 (83%) diffuse large cell lymphomas (DLCLs) and 2 of 3 diffuse mixed B-cell lymphomas (DMs). Immunopositivity for CPP32 was also found in the majority of other types of non-Hodgkin's lymphomas studied. Plasmacytomas were CPP32 immunonegative in 4 of 12 (33%) cases, in contrast to normal plasma cells, which uniformly contained intense CPP32 immunoreactivity, implying downregulation of CPP32 in a subset of these malignancies. All 12 peripheral blood B-cell chronic lymphocyte leukemia specimens examined were CPP32 immunopositive, whereas 3 of 3 small lymphocytic lymphomas were CPP32 negative, suggesting that CPP32 expression may vary depending on the tissue compartment in which these neoplastic B cells reside. The results show dynamic regulation of CPP32 expression in normal and malignant lymphocytes.

Animals↗
PubMed1996

Localization by chromosome microdissection of a recurrent breakpoint region on chromosome 6 in human B-cell lymphoma.

Deletion of the long arm of chromosome 6 (6q) is one of the most common chromosomal alterations in human B-cell lymphomas. Conventional cytogenetic banding analysis and loss-of-heterozygosity (LOH) studies have detected several common regions of deletion ranging across the entire long arm (6q), with no defined recurrent breakpoint yet identified. We describe here a strategy combining chromosome microdissection and fluorescence in situ hybridization (Micro-FISH) to determine a minimal region of deletion along chromosome 6. Seven clinical cases and one cell line of follicular lymphoma containing a t(14;18) and one case of diffuse lymphoma, also with a t(14;18), were used for this study. All nine cases had previously defined abnormalities of chromosome 6 determined by cytogenetic analysis. The results of chromosome dissection were unexpected and in contrast to the suggestion of disparate breakpoints by conventional chromosome banding. Specifically, Micro-FISH analysis provided evidence for a common breakpoint at 6q11 in seven of nine cases. After Micro-FISH analysis, all of the presumed simple deletions of chromosome 6 were carefully reanalyzed and shown to actually represent either nonreciprocal translocations (three cases), interstitial deletions (five cases), or isochromosome (one case). The recurrent proximal breakpoint (6q11) was detected in seven of nine cases, with the minimal region of deletion encompassing 6q11 to 6q21. By analogy to other tumor systems, the identification of recurring breakpoints within 6q11 may suggest that a gene(s) important to the genesis or progression of follicular lymphoma can be localized to this band region.

Chromosome Aberrations↗
PubMed1996

The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein.

The recurrent translocation t(8;16)(p11;p13) is a cytogenetic hallmark for the M4/M5 subtype of acute myeloid leukaemia. Here we identify the breakpoint-associated genes. Positional cloning on chromosome 16 implicates the CREB-binding protein (CBP), a transcriptional adaptor/coactivator protein. At the chromosome 8 breakpoint we identify a novel gene, MOZ, which encodes a 2,004-amino-acid protein characterized by two C4HC3 zinc fingers and a single C2HC zinc finger in conjunction with a putative acetyltransferase signature. In-frame MOZ-CBP fusion transcripts combine the MOZ finger motifs and putative acetyltransferase domain with a largely intact CBP. We suggest that MOZ may represent a chromatin-associated acetyltransferase, and raise the possibility that a dominant MOZ-CBP fusion protein could mediate leukaemogenesis via aberrant chromatin acetylation.

Acetyltransferases↗
PubMed1995

Evidence of cumulative gene losses with progression of premalignant epithelial lesions to carcinoma of the bronchus.

Human bronchial carcinoma is thought to develop through progressive stages from basal cell hyperplasia to squamous metaplasia, dysplasia, carcinoma in situ, and finally invasive cancer. In this study, we used tissue microdissection to examine loss of heterozygosity of chromosomes 3p21, 5q21, and 9p21 at each stage of the epithelial progression to invasive cancers. Forty-eight premalignant/malignant bronchial sites were biopsied from 13 patients (including 9 subjects without cancer) using fluorescence bronchoscopy. Eighteen sites with moderate/severe dysplasia in 6 patients were subjected to bronchoscopic and molecular follow-up during a 3-month to 2-year period. Seven separate cases of advanced non-small cell bronchial cancers were also analyzed. From the baseline biopsies, the prevalence of 3p and 9p deletions increased significantly from no deletion in the hyperplasia/metaplasia samples (n = 9) to 37 and 31% of the informative cases, respectively, in the dysplasia samples (n = 29), to 100 and 83%, respectively, for the carcinomas in situ (n = 6), and 100% in the invasive cancers (n = 11). Chromosome 5q deletion was significantly more frequent in invasive cancers (70% of the informative cases) as compared to carcinoma in situ (40%), dysplasias (33%), and hyperplasia/metaplasia samples (11%). The number of chromosome alterations also increased significantly from the lowest to the highest grade lesions, showing evidence of accumulation of genetic damage from one group to another. The molecular follow-up analysis showed that the same genomic alteration can persist in a given dysplastic bronchial area for several months or years, and that the persistence or the regression of the molecular abnormality is well correlated with the evolution of the disease on follow-up. Our results suggest that molecular analysis of bronchial biopsies obtained by fluorescence bronchoscopy may be a very useful means to study the natural history of preinvasive bronchial lesions and the outcome of interventions, such as with chemopreventive treatment.

Aged↗
PubMed1995

Lymphocytosis of large granular lymphocytes in patients with Hodgkin's disease.

Clonal disorders of large granular lymphocytes (LGL) of either CD3- (NK cell) or CD 3+ (T-cell) phenotype have been described. B-cell malignancies such as hairy cell leukemia and non-Hodgkin's lymphoma have been observed in association with the T-cell type of LGL leukemia. Here we report the occurrence of LGL lymphocytosis in four patients with Hodgkin's disease. Immunophenotyping studies showed that these LGL were CD 3- in three patients and CD3+ in the other. LGL were polyclonally expanded in both patients in whom clonality could be assessed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Cytogenetic findings in seven lacrimal gland neoplasms.

We have undertaken cytogenetic investigation of seven benign and malignant lacrimal gland neoplasms. This study showed recurrent chromosomal abnormalities involving chromosomes 3, 8, 9, and 12. These features are similar to those found in benign and malignant salivary gland tumors, which suggests possible common mechanisms involved in the neoplastic proliferation of these histologically related tumors.

Adenocarcinoma↗
PubMed1994

Complex karyotypic alterations in an endometrial stromal sarcoma.

Cytogenetic investigation of a low-grade endometrial stromal sarcoma (ESS) revealed structural rearrangements of chromosomes 3, 6, and 7. The karyotypic findings in the few cases of ESS reported reveal recurrent involvement of both homologues of chromosome 7, with less consistent changes affecting chromosomes 6 and 17. The cytogenetic and histologic features of these uterine stromal tumors require further study.

Adult↗
PubMed1992

Structural rearrangement of the Y chromosome in a case of acute myeloid leukemia M2.

Involvement of the Y chromosome in numerical changes associated with acute nonlymphocytic leukemia is quite common, whereas acquired structural rearrangements of the Y chromosome are much rarer, there being only four such cases documented in the literature [1]. We identified a case of acute myeloid leukemia (AML M2) with rearrangements of chromosomes 1, 10, and Y; at remission, all analyzed metaphases were normal, confirming the acquired nature of the Y chromosome abnormality.

Adult↗
PubMed1992

t(11;18)(q21;q21.1): a recurring translocation in lymphomas of mucosa-associated lymphoid tissue (MALT)?

A distinct subtype of extranodal malignant lymphoma derived from mucosa-associated lymphoid tissues (MALT) has recently been defined. We have detected an acquired t(11;18)(q21;q21.1) in a patient with a MALT lymphoma of the stomach. This translocation has previously been described in two other patients with extranodal lymphoma. The BCL2 oncogene, which is located at band 18q21.3 and is activated by the t(14;18)(q32;q21) in follicular lymphoma, was not rearranged in this case. This newly identified t(11;18) may be a recurring translocation specifically associated with MALT lymphomas. Genes located at the breakpoint sites of chromosome 11 and/or chromosome 18 may be crucial to the pathogenesis of this type of malignant lymphoma.

Base Sequence↗