Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer. (1/1281)

The evolution of alterations on chromosome 9, including the putative tumor suppressor genes mapped to the 9p21-22 region (the MTS genes), was studied in relation to the progression of human urinary bladder neoplasia by using whole organ superimposed histologic and genetic mapping in cystectomy specimens and was verified in urinary bladder tumors of various pathogenetic subsets with longterm follow-up. The applicability of chromosome 9 allelic losses as non-invasive markers of urothelial neoplasia was tested on voided urine and/or bladder washings of patients with urinary bladder cancer. Although sequential multiple hits in the MTS locus were documented in the development of intraurothelial precursor lesions, the MTS genes do not seem to represent a major target for p21-23 deletions in bladder cancer. Two additional tumor suppressor genes involved in bladder neoplasia located distally and proximally to the MTS locus within p22-23 and p11-13 regions respectively were identified. Several distinct putative tumor suppressor gene loci within the q12-13, q21-22, and q34 regions were identified on the q arm. In particular, the pericentromeric q12-13 area may contain the critical tumor suppressor gene or genes for the development of early urothelial neoplasia. Allelic losses of chromosome 9 were associated with expansion of the abnormal urothelial clone which frequently involved large areas of urinary bladder mucosa. These losses could be found in a high proportion of urothelial tumors and in voided urine or bladder washing samples of nearly all patients with urinary bladder carcinoma.  (+info)

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer. (2/1281)

Recent studies have shown that patients whose bladder cancer exhibit overexpression of RB protein as measured by immunohistochemical analysis do equally poorly as those with loss of RB function. We hypothesized that loss of p16 protein function could be related to RB overexpression, since p16 can induce transcriptional downregulation of RB and its loss may lead to aberrant RB regulation. Conversely, loss of RB function has been associated with high p16 protein expression in several other tumor types. In the present study RB negative bladder tumors also exhibited strong nuclear p16 staining while each tumor with strong, homogeneous RB nuclear staining were p16 negative, supporting our hypothesis. To expand on these immunohistochemical studies additional cases were selected in which the status of the p16 encoding gene had been determined at the molecular level. Absent p16 and high RB protein expression was found in the tumors having loss of heterozygosity within 9p21 and a structural change (mutation or deletion) of the remaining p16 encoding gene allele, confirming the staining results. These results strongly support the hypothesis that the RB nuclear overexpression recently associated with poor prognosis in bladder cancer is also associated with loss of p16 function and implies that loss of p16 function could be equally deleterious as RB loss in bladder and likely other cancers.  (+info)

Diaphyseal medullary stenosis with malignant fibrous histiocytoma: a hereditary bone dysplasia/cancer syndrome maps to 9p21-22. (3/1281)

Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is an autosomal dominant bone dysplasia/cancer syndrome of unknown etiology. This rare hereditary cancer syndrome is characterized by bone infarctions, cortical growth abnormalities, pathological fractures, and eventual painful debilitation. Notably, 35% of individuals with DMS develop MFH, a highly malignant bone sarcoma. A genome scan for the DMS-MFH gene locus in three unrelated families with DMS-MFH linked the syndrome to a region of approximately 3 cM on chromosome 9p21-22, with a maximal two-point LOD score of 5.49 (marker D9S171 at recombination fraction [theta].05). Interestingly, this region had previously been shown to be the site of chromosomal abnormalities in several other malignancies and contains a number of genes whose protein products are involved in growth regulation. Identification of this rare familial sarcoma-causing gene would be expected to simultaneously define the cause of the more common nonfamilial, or sporadic, form of MFH-a tumor that constitutes approximately 6% of all bone cancers and is the most frequently occurring adult soft-tissue sarcoma.  (+info)

Identification and characterization of a homozygous deletion found in ovarian ascites by representational difference analysis. (4/1281)

We have performed representational difference analysis (RDA) on DNA from tumor cells and normal fibroblasts isolated from the ascites of a patient with ovarian cancer. Five of six products of the RDA were homozygously deleted from the tumor DNA. One of these products has been characterized and identifies a homozygous deletion of approximately 6.9 Mb at chromosome 9p21 in the original ovarian tumor material. This deletion encompasses CDKN2A (p16), CDKN2B (p15), and IFN-alpha. PCR analysis of other tumor cell lines using the novel STS based on the RDA product has shown it to lie between IFN-alpha and p16, and to identify the distal extent of a homozygous deletion in another ovarian cancer cell line. These data provide further evidence for a tumor suppressor locus distinct from, but mapping close to, p16 on 9p21. Cytogenetic analysis using comparative genomic hybridization (CGH) performed on the same primary tumor confirmed a loss of material from chromosome 9p. However, the CGH technique had neither the resolution nor the sensitivity to define a subregion of homozygous loss.  (+info)

Frequent genetic alterations in simple urothelial hyperplasias of the bladder in patients with papillary urothelial carcinoma. (5/1281)

In order to understand the origin of bladder cancer, very early urothelial lesions must be investigated in addition to more advanced tumors. Tissue from 31 biopsies of 12 patients with urothelial hyperplasias and simultaneous or consecutive superficial papillary tumors were used to microdissect urothelium from 15- microm sections of biopsies. The biopsies were obtained with the recently developed highly sensitive diagnostic method of 5-aminolevulinic acid-induced fluorescence endoscopy (AFE). Besides flat and papillary urothelial neoplasms, the method of photodynamic diagnostics also detects simple urothelial hyperplasias as fluorescent positive lesions. In addition, 12 fluorescence-positive biopsies showing histologically normal urothelium were investigated. Fluorescence in situ hybridization was done using a dual color staining technique of biotinylated centromeric probes of chromosomes 9 and 17 and digoxigenin-labeled gene-specific P1 probes for chromosomes 9q22 (FACC), 9p21(p16/CDKI2), and 17p13(p53). Ten of 14 hyperplasias (70%) showed deletions of chromosome 9. In 7 out of 8 patients with genetic alterations in the hyperplasias the genetic change was also present in the papillary tumor. Six out of 12 samples of microdissected normal urothelium also showed genetic alterations on chromosome 9. Microdissection of urothelial lesions, obtained during AFE, has led to the first unequivocal documentation of genetic changes in urothelial lesions diagnosed as normal in histopathology. Thus, this technical approach is important to provide insight into the earliest molecular alterations in bladder carcinogenesis.  (+info)

Retinitis pigmentosa and progressive sensorineural hearing loss caused by a C12258A mutation in the mitochondrial MTTS2 gene. (6/1281)

Family ZMK is a large Irish kindred that segregates progressive sensorineural hearing loss and retinitis pigmentosa. The symptoms in the family are almost identical to those observed in Usher syndrome type III. Unlike that in Usher syndrome type III, the inheritance pattern in this family is compatible with dominant, X-linked dominant, or maternal inheritance. Prior linkage studies had resulted in exclusion of most candidate loci and >90% of the genome. A tentative location for a causative nuclear gene had been established on 9q; however, it is notable that no markers were found at zero recombination with respect to the disease gene. The marked variability in symptoms, together with the observation of subclinical muscle abnormalities in a single muscle biopsy, stimulated sequencing of the entire mtDNA in affected and unaffected individuals. This revealed a number of previously reported polymorphisms and/or silent substitutions. However, a C-->A transversion at position 12258 in the gene encoding the second mitochondrial serine tRNA, MTTS2, was heteroplasmic and was found in family members only. This sequence change was not present in 270 normal individuals from the same ethnic background. The consensus C at this position is highly conserved and is present in species as divergent from Homo sapiens as vulture and platypus. The mutation probably disrupts the amino acid-acceptor stem of the tRNA molecule, affecting aminoacylation of the tRNA and thereby reducing the efficiency and accuracy of mitochondrial translation. In summary, the data presented provide substantial evidence that the C12258A mtDNA mutation is causative of the disease phenotype in family ZMK.  (+info)

Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31. (7/1281)

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and by Ashkenazi Jewish ancestry. We previously had mapped the defective gene (DYS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this interval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, might represent independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families with FD and for carriers, on the basis of close flanking markers and the capacity to identify >98% of FD chromosomes by their haplotype.  (+info)

Molecular cytogenetic detection of 9q34 breakpoints associated with nail patella syndrome. (8/1281)

The nail patella syndrome (NPS1) is an autosomal dominant disorder characterised by dysplasia of the finger nails and skeletal abnormalities. NPS1 has been mapped to 9q34, to a 1 cM interval between D9S315 and the adenylate kinase gene (AK1). We have mapped the breakpoints within the candidate NPS1 region in two unrelated patients with balanced translocations. One patient [46,XY,t(1;9)(q32.1;q34)] was detected during a systematic survey of old cytogenetic files in Denmark and southern Sweden. The other patient [46,XY,t(9;17)(q34.1;q25)] was reported previously. D9S315 and AK1 were used to isolate YACs, from which endclones were used to isolate PACs. Two overlapping PAC clones span the 9q34 breakpoints in both patients, suggesting that NPS1 is caused by haploinsufficiency due to truncation or otherwise inactivation of a gene at or in the vicinity of the breakpoints.  (+info)

• 1
• 2
• 3
• 4
• 5
• 6
• 7
• 8
• 9
• 10