Frequent deletion of hSNF5/INI1, a component of the SWI/SNF complex, in chronic myeloid leukemia.
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During routine two-fusion fluorescence in situ hybridization analysis of patients with blast crisis of chronic myeloid leukemia (CML), we observed that yeast artificial chromosome 29GD7, which is distal to BCR at 22q11, failed to hybridize to the 9q+ derivative chromosome in 3 of 11 (27%) cases. This deleted region is close to hSNF5/INI1 (SMARCB1), a gene that encodes a widely expressed component of the SWI/SNF chromatin remodeling complex and that suffers biallelic mutations in malignant rhabdoid tumors. To determine whether hSNF5/INI1 was also deleted in patients with CML, we performed fluorescence in situ hybridization analysis with a specific cosmid probe. Deletion of hSNF5/INI1 on the 9q+ chromosome was found in 9 of 25 (36%) cases in blast crisis (lymphoid, n = 3; myeloid, n = 6). For the three of these nine patients for whom material was available prior to transformation, deletions were also seen in chronic phase, indicating that they are early events. Analysis of an additional 21 patients in chronic phase revealed heterozygous loss of hSNF5/INI1 in 5 (24%) cases. Of the 14 patients who had hSNF5/INI1 deletions, 7 showed a mosaic pattern of hybridization in which only a proportion of CML cells that harbored both the t(9;22) derivative chromosomes had a deletion, indicating that loss of hSNF5/INI1 was acquired during the course of the disease. Single-strand conformation polymorphism analysis of all nine hSNF5/INI1 exons and splice junctions failed to reveal any mutations for 31 patients in transformation, including 8 who had deletions, although two polymorphisms were identified. We conclude that deletions of hSNF5/INI1 are frequent in patients with CML. Such deletions may be associated with reduced levels of hSNF5/INI1 expression, which could contribute to leukemogenesis by altering chromatin-mediated transcriptional control. Alternatively, the deletions could target another unidentified gene at 22q11 that plays a role in the pathogenesis of CML. (+info)
Two regions of deletion in 9p23-24 in sporadic breast cancer.
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Allelic deletions of 9p including band 21-22 are common in various types of human carcinomas including breast cancer. Our previous cytogenetic studies had identified constitutional chromosomal changes in 9p23-24 in patients of a male-breast-cancer family and 9p23-24 alterations in a cell line established from a sporadic female breast cancer. To find out whether this genomic region is involved more frequently in alterations in sporadic breast cancers, we have surveyed 80 microdissected tumor samples for both loss of heterozygosity (LOH) and homozygous deletion at 22 microsatellite loci spanning 9p22 to 9p24 using fluorescent multiplex PCR. LOH at one or more loci was observed in 32 (40%) of these tumors. Homozygous deletion was detected in four cases. Eleven tumors had LOH at all of the informative loci analyzed, whereas 21 tumors showed partial-terminal or interstitial allelic loss of 9p. Deletion mapping identified two common regions of deletion: (a) 4 cM including D9S281 to D9S286; and (b) 1 cM including D9S1808 to D9S268. (+info)
CDKN2A gene inactivation in epithelial sporadic ovarian cancer.
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The tumour suppressor gene CDKN2A, located on chromosome 9p21, encodes the cell cycle regulatory protein p16. Inactivation of the CDKN2A gene could lead to uncontrolled cell growth. In order to determine the role of CDKN2A in the development of sporadic ovarian cancer, loss of heterozygosity at 9p21-22, homozygous deletion, mutation and methylation status of the CDKN2A gene as well as CDKN2A expression were examined in a panel of serous papillary ovarian cancer. The frequency of loss of heterozygosity (LOH) for one or more informative markers at 9p21-22 was 65% (15/23). The most common deleted region was located between interferon (IFN)-alpha and D9S171. Homozygous deletions and mutations of the CDKN2A gene were not found. There was no evidence of methylation in exon 1, but methylation in exon 2 of CDKN2A gene was found in 26% (6/23). Absence of CDKN2A gene expression was shown in 27% (6/22) at mRNA level and 21% (4/19) at protein level. These data suggest that the CDKN2A gene is involved in the tumorigenesis of ovarian cancer, but the mechanisms of CDKN2A gene inactivation in serous papillary ovarian cancer remains unclear. (+info)
Loss of heterozygosity in epithelial cells obtained by bronchial brushing: clinical utility in lung cancer.
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To determine whether loss of heterozygosity (LOH) could be a useful diagnostic test for lung cancer, we evaluated LOH in cells obtained from bronchial brushings. Cells from radiographically normal and abnormal lungs were obtained from 55 patients undergoing diagnostic bronchoscopy. Among 38 patients with lung cancer, LOH was present in at least one chromosomal locus in 79%, whereas cytology was positive for malignant cells in 37%. LOH was not restricted to the airway containing the tumor; fifty-three percent of the cancer patients had LOH in the contralateral lung, as did 59% of patients without lung cancer. There was an association between the extent of LOH and proximity to the cancer. The LOH score, which combined measures of fractional allelic loss and percentage of cells with allelic loss, was greater in subjects with positive cytology and on the side of the tumor. A LOH score >10 was positive in 58% of tumor-bearing lungs, in 13% of the contralateral lungs in cancer patients, and in no patients without cancer. Our results suggest that extensive and widespread allelic loss, as indicated by a high LOH score, may be diagnostic of lung cancer. Additional studies will be needed to clarify the clinical potential of using bronchial epithelial cell LOH as a biomarker and diagnostic test for lung cancer. (+info)
Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: A report from the Children's Cancer Group.
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Cytogenetic abnormalities of chromosome arm 9p occur frequently in children with acute lymphoblastic leukemia (ALL). We analyzed 201 such cases (11%) in 1,839 children with newly diagnosed ALL treated between 1989 and 1995 on risk-adjusted protocols of the Children's Cancer Group (CCG). The majority of patients (131; 65%) with a 9p abnormality were classified as higher risk. Nearly all patients had complex karyotypes; most cases had deletions of 9p, add/der(9p), a dicentric involving chromosome arm 9p, and/or balanced translocations and inversions involving 9p. Event-free survival (EFS) estimates at 6 years for patients with and without a 9p aberration were 61% (standard deviation [SD] = 5%) and 76% (SD = 2%; P <.0001). In addition, patients with a 9p abnormality had an increased cumulative incidence of both marrow (P =.04) and central nervous system (P =.0001) relapses. Overall survival also was significantly worse for patients with an abnormal 9p (P <.0001). These effects were most pronounced in standard-risk patients (age 1 to 9 years with white blood cell count <50,000/microL): 6-year EFS of 61% (SD = 9%) versus 80% (SD = 2%; P <.0001). Also, a 9p aberration was an adverse risk factor for B-lineage, but not T-lineage patients. The effect of 9p status on EFS was attenuated, but maintained in a multivariate analysis of EFS after adjustment for Philadelphia chromosome status, age, white blood cell (WBC) count, sex, race, and ploidy group (P =.01). Thus, abnormalities of chromosome arm 9p identify a subgroup of standard-risk patients with increased risk of treatment failure. (+info)
Joint multipoint linkage analysis of multivariate qualitative and quantitative traits. I. Likelihood formulation and simulation results.
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We describe a variance-components method for multipoint linkage analysis that allows joint consideration of a discrete trait and a correlated continuous biological marker (e.g., a disease precursor or associated risk factor) in pedigrees of arbitrary size and complexity. The continuous trait is assumed to be multivariate normally distributed within pedigrees, and the discrete trait is modeled by a threshold process acting on an underlying multivariate normal liability distribution. The liability is allowed to be correlated with the quantitative trait, and the liability and quantitative phenotype may each include covariate effects. Bivariate discrete-continuous observations will be common, but the method easily accommodates qualitative and quantitative phenotypes that are themselves multivariate. Formal likelihood-based tests are described for coincident linkage (i.e., linkage of the traits to distinct quantitative-trait loci [QTLs] that happen to be linked) and pleiotropy (i.e., the same QTL influences both discrete-trait status and the correlated continuous phenotype). The properties of the method are demonstrated by use of simulated data from Genetic Analysis Workshop 10. In a companion paper, the method is applied to data from the Collaborative Study on the Genetics of Alcoholism, in a bivariate linkage analysis of alcoholism diagnoses and P300 amplitude of event-related brain potentials. (+info)
Significant differences in the frequency of transcriptional units, types and numbers of repetitive elements, GC content, and the number of CpG islands between a 1010-kb G-band genomic segment on chromosome 9q31.3 and a 1200-kb R-band genomic segment on chromosome 3p21.3.
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We determined the nucleotide sequence of the entire 1,010,525-bp insert contained in CEPH YAC clone 867e8. This human genomic segment was derived from chromosome 9q31.3 and corresponds to a G-band region. We compared this segment, in terms of structure, with a previously characterized 1,201,033-bp sequence in CEPH YAC936c1 that had come from a portion of human chromosome 3p21.3 corresponding to an R-band region. The two segments were significantly different with respect to the frequency of transcriptional units, the types and numbers of repetitive elements present, their GC content, and the number of CpG islands. Alu elements, GC content, and CpG islands all showed positive correlations with the abundance of exons, but the distribution of LINE1s did not. These observations might reflect an influence of the first three of these features on the functions or expression of genes in the respective regions. In addition to a novel gene (F36) lying at the centromeric end of the 9q segment, we found a cluster of placenta-specific genes within a small section (about 400 kb) on the telomeric side of YAC867e8. This cluster consisted of four apparently unrelated ESTs and two genes, pregnancy-associated plasma protein-A (PAPP-A) and a novel gene (tentatively named EST-YD1). Our characterization of the two chromosomal regions provided evidence that genes are not evenly distributed throughout the human genome, and that gene richness is correlated with the GC content and with the frequency of either Alu elements or CpG islands. (+info)
Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa).
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Almost 70% of urinary bladder neoplasms present as low-grade papillary noninvasive tumors (stage pTa). To determine which genomic alterations can occur in pTa tumors of different grades and to evaluate the prognostic significance of chromosomal imbalances, we analyzed 113 pTa tumors (40 grade 1, 55 grade 2, 18 grade 3) by comparative genomic hybridization. pTaG1 (1.9 +/- 2.0) and pTaG2 (3.1 +/- 2.9) tumors had only few genomic alterations with 9q- (44%), 9p- (36%), and -Y (21%) being most prevalent. Neither the total number of aberrations nor any individual alteration was linked to the risk of recurrence in 95 pTaG1/G2 tumors with clinical follow-up information. pTaG3 tumors were characterized by a high number of alterations (7.7 +/- 4.5; P < 0.0001 for G3 versus G2). Several chromosomal imbalances that have previously been reported to be typical for invasive bladder neoplasms were significantly more frequent in pTaG3 than in pTaG2 tumors, including 2q-, 5p+, 5q-, 6q-, 8p-, 10q-, 18q-, and 20q+. A malfunction of genes at these loci may contribute to the development of high-grade urothelial neoplasias. However, there is no evidence for a direct role of these alterations for development of invasive tumor growth. (+info)