Biomedical subjects

F Latif

Publications and source records attributed to F Latif.

At least 19 recordsLinked to original sources

PubMed1992

Chromosome 3p deletions in head and neck carcinomas: statistical ascertainment of allelic loss.

Loss of function of tumor suppressor genes is important in the origin and progression of common adult tumors. Loss of heterozygosity indicating allelic loss has been used to detect chromosomal regions that harbor these genes. Using over 20 restriction fragment length polymorphism markers spaced throughout the entire length of chromosome 3p, we have generated 3p allelotypes for 18-26 head and neck squamous cell carcinoma cell lines. We then estimated the average heterozygosity over 19 loci for a random sample drawn from natural populations to be 7.80 and that for the tumor lines to be 1.65, indicating a gross reduction of heterozygosity, presumably due to allelic loss. Further comparison of per locus heterozygosity in normal and tumor DNAs showed which loci contributed to the general loss of heterozygosity. We showed that the commonly deleted region of 3p probably lies telomeric to D3S3 (3p14) and centromeric to RAF1 (3p25). This large region includes several putative tumor suppressor genes involved in multiple common tumor types of lung, breast, kidney, ovary, and cervix. The data demonstrate that chromosome 3p allelic loss is a common event in head and neck cancers and suggest that chromosome 3p tumor suppressor genes contribute to the pathogenesis of these tumors.

Alleles↗

PubMed1992

Screening for von Hippel-Lindau disease by DNA polymorphism analysis.

OBJECTIVE: Von Hippel-Lindau (VHL) disease is a rare, inherited multisystem neoplastic disorder. There is no biochemical test available to distinguish VHL disease gene carriers from their healthy siblings. We evaluated DNA polymorphism analysis as a method for identifying disease gene carriers. DESIGN: Prospective comparison of the results of DNA analysis with a comprehensive clinical screening examination. SETTING: The Clinical Center of the National Institutes of Health. PATIENTS: Blood was collected from 182 members of 16 families with VHL disease. Forty-eight asymptomatic individuals, at risk of developing this hereditary illness (with an affected parent or sibling), were examined for occult disease at the Clinical Center of the National Institutes of Health and tested by DNA polymorphism analysis. RESULTS: DNA polymorphism analysis predicted nine disease gene carriers and 33 individuals with the wild-type (normal) allele among the 48 individuals at risk of developing VHL disease; the test was not informative in six individuals. All nine individuals predicted to carry the VHL gene had evidence of occult disease on clinical examination. There was no clinical evidence of VHL disease in 32 of 33 individuals predicted to carry the wild-type allele. CONCLUSIONS: DNA polymorphism analysis can identify individuals likely to carry the VHL disease gene among asymptomatic members of disease families. This technique serves to focus attention on those individuals who require periodic medical examination and may help to alleviate the morbidity and mortality associated with this disease.

DNA↗

PubMed1992

Distinct hypermethylation patterns occur at altered chromosome loci in human lung and colon cancer.

Regional increases in DNA methylation occur in normally unmethylated cytosine-rich areas in neoplastic cells. These changes could potentially alter chromatin structure to inactivate gene transcription or generate DNA instability. We now show that, in human lung and colon cancer DNA, hypermethylation of such a region consistently occurs on chromosome 17p in an area that is frequently reduced to homozygosity in both tumor types. Over the progression stages of colon neoplasia, this methylation change increases in extent and precedes the allelic losses on 17p that are characteristic of colon carcinomas. We also show on chromosome 3p that regional hypermethylation may nonrandomly accompany chromosome changes in human neoplasia. Increased methylation is consistent in small-cell lung carcinoma DNA at two 3p loci that are constantly reduced to homozygosity in this tumor, but it is not seen in colon cancer DNA, in which these loci are infrequently structurally altered.

Carcinoma↗

PubMed1992

Molecular and cellular characterization of human renal cell carcinoma cell lines.

Recent studies have suggested that a tumor suppressor gene located in the region 3p21-26 of chromosome 3 is essential to the genesis of sporadic renal cell carcinoma (RCC) and that other tumor suppressor genes located on other chromosomes may be involved with progression of this malignancy. The cellular heterogeneity of solid tumors complicates their analysis. In order to analyze a homogeneous population of tumor cells and identify genetic changes associated with histology in renal cortical tumors, we have established and characterized 35 RCC lines derived from tumor tissue from 31 patients with renal cell carcinomas. The overall success rate in establishing these cell lines from fresh or frozen specimens was 75% (18 of 24) and 35% (17 of 48), respectively. These lines differed in their morphology, growth rates, and tumorigenicity in athymic nude mice. Molecular characterization utilizing DNA fingerprinting and restriction fragment length polymorphism deletion analysis was performed to detect somatic mutations and loss of heterozygosity on the short arm of chromosome 3. Analysis revealed loss of heterozygosity on chromosome 3p in 25 cell lines derived from 28 informative nonpapillary forms of RCC (89%). Deletion-mapping analysis showed the retention of the distal locus, D3S18, in one of the RCC cell lines, which further localized the position of the putative tumor suppressor gene to the region proximal to D3S18. Although deletions on chromosome 3 have been recently suggested to be specific to the clear cell-type phenotype, our results revealed no correlation between loss of heterozygosity and clear or granular cell types.

Animals↗

PubMed1992

Molecular characterization of a large homozygous deletion in the small cell lung cancer cell line U2020: a strategy for cloning the putative tumor suppressor gene.

Homozygous deletions are instrumental in the detection and cloning of tumor suppressor genes. We report the isolation and characterization of 39 new single-copy probes saturating a submicroscopic homozygous deletion detected in the DNA of the small cell lung cancer (SCLC) cell line U2020. The probes were selected from a large collection, covering the entire length of chromosome 3 with an estimated average spacing of 100-150 kb. Based on the number of probes in the deletion and the probe density, the size of the U2020 submicroscopic deletion was estimated to be in the range of 4-7 megabases. Among the deleted loci, 17 showed conservation across species, probably representing potential coding gene sequences. By genetic and physical mapping of a large randomly chosen fraction of the deleted probes, we defined the location of the U2020 deletion within chromosome band 3p12. Our cloning strategy is based on narrowing the region of interest by eliminating probes that retain heterozygosity in SCLC samples, thus selecting for probes in the region of common loss.

Blotting, Southern↗

PubMed1992

A genetic linkage map of 96 loci on the short arm of human chromosome 3.

We constructed a genetic map of 96 loci on the short arm of human chromosome 3 (3p) in 59 families provided by the Centre d'Etude du Polymorphisme Humaine (CEPH). Twenty-nine continuously linked loci were placed on the map with likelihood support of at least 1000:1; one locus, D3S213, was placed on the map with likelihood support of 871:1; D3Z1, an alpha satellite centromeric repeat probe, was placed on the map with likelihood support of 159:1; 65 loci were assigned regional locations. The average heterozygosity of the uniquely ordered markers was 49%. The map extends from 3p26, the terminal band of 3p, to the centromere (from D3S211 to D3Z1). Multipoint linkage analysis indicated that the male, female, and sex-averaged maps extend for 102, 147, and 116 cM, respectively. The mean genetic distance between uniquely ordered loci on the sex-averaged map was 4.0 cM. Probe density was greatest for the region of 3p between D3F15S2e and the telomere. The sex-averaged map contained two intervals greater than 10 cM. Seventeen probes were localized by fluorescence in situ hybridization. The loci described in this report will be useful in building an integrated genetic and physical map of this chromosome.

Chromosome Mapping↗

PubMed1992

Presymptomatic diagnosis of von Hippel-Lindau disease with flanking DNA markers.

Von Hippel-Lindau (VHL) disease is a dominantly inherited cancer syndrome characterised by the development of retinal, cerebellar, and spinal haemangioblastomas, renal cell carcinoma, and phaeochromocytoma. The gene for VHL disease has been mapped to chromosome 3p25-p26 and flanking markers identified. We have investigated the usefulness of currently available DNA markers for the presymptomatic diagnosis of VHL disease. In the first part of this investigation, genetic linkage data from two previously published studies were updated and reanalysed to provide accurate estimates of sex specific recombination fractions and to confirm that there is no evidence of locus heterogeneity. In the second part of this study, 14 families containing 23 asymptomatic subjects at 50% prior risk of VHL disease were investigated with closely linked DNA markers (RAF1, D3S18, D3S732). Seventeen subjects were informative with one or more markers, six of whom were informative at markers flanking the VHL disease gene. By combining age related and DNA based risk information the carrier risk for 11 subjects was reduced to < 2%.

Adolescent↗

PubMed1991