The FHIT Gene, Spanning the Chromosome 3p14.2 Fragile Site and Renal Carcinoma–Associated t(3;8) Breakpoint, Is Abnormal in Digestive Tract Cancers

AbstractA 200–300 kb region of chromosome 3p14.2, including the fragile site locus FRA3B, is homozygously deleted in multiple tumor-derived cell lines. Exon amplification from cosmids covering this deleted region allowed identification of the human FHIT gene, a member of the histidine triad gene family, which encodes a protein with 69% similarity to an S. pombe enzyme, diadenosine 5′, 5′′′ P1, P4-tetraphosphate asymmetrical hydrolase. The FHIT locus is composed of ten exons distributed over at least 500 kb, with three 5′ untranslated exons centromeric to the renal carcinoma–associated 3p14.2 breakpoint, the remaining exons telomeric to this translocation breakpoint, and exon 5 within the homozygously deleted fragile region. Aberrant transcripts of the FHIT locus were found in ∼50% of esophageal, stomach, and colon carcinomas

Cloning and characterization of loci surrounding the familial renal cell carcinoma t(3;8) translocation break point

A major goal of gene mapping is to identify candidate oncogenes and tumor suppressor genes, that might play an important role in the pathogenesis of cancer. In the present study we mapped several important genes, using somatic cell hybrid panels and fluorescence in situ hybridization (FISH) methodologies. We further investigated the role of such genes in tumor specific chromosomal translocations. We mapped a novel member of the receptor tyrosine phosphatase gene family, protein tyrosine phosphatase gamma (PTPRG), to the short arm of chromosome 3, region 3p14.2. This chromosome region harbors two important cytogenetic markers: (a) the t(3;8) constitutional translocation breakpoint, associated with familial renal cell carcinoma (RCC), and (b) the most common aphidicolin induced fragile site in the human genome, FRA3B. Because the chromosome location and enzymatic properties of the PTPRG gene suggested a candidate tumor suppressor gene, we undertook a detailed study of the gene structure in normal cells, t(3;8) carrier cells and kidney tumors. We determined that the gene consisted of 30 exons distributed over 780 kb and tested for PTPRG mutations in 28 tumor DNAs from clear cell RCCs and no mutations were detected any tumor specimen. In parallel, we cloned the t(3;8) breakpoint, characterized homozygous deletions in tumor derived cell lines of epithelial origin, that lie within the fragile site, FRA3B. Also, we narrowed a potential tumor suppressor locus to 500 kb flanking the t(3;8) break. This region includes the FRA3B and the transcriptional regulatory region of PTPRG gene

Emergence of pristinamycin resistance in India

Quinupristin and dalfopristin combination has been advocated as a drug of choice for multi-drug resistant (MDR) gram-positive cocci (GPC). We are reporting two cases of neonatal septicemia, caused by the methicillin resistant Staphylococcus aureus (MRSA), showing primary in vitro pristinamycin resistance. The Minimum inhibitory concentrations (MIC) for pristinamycin in these two cases were 30 µg and 25 µg, respectively. Universal advocacy of pristinamycin for the therapy of MDR GPC infections should be re-evaluated

Chromosome locations of genes encoding human signal transduction adapter proteins, Nck (NCK), Shc (SHC1), and Grb2 (GRB2).

Abnormalities due to chromosomal aberration or point mutation in gene products of growth factor receptors or in ras gene products, which lie on the same signaling pathway, can cause disease in animals and humans. Thus, it can be important to determine chromosomal map positions of genes encoding "adapter" proteins, which are involved in transducing signals from receptor tyrosine kinases to downstream signal recipients such as ras, because adaptor protein genes could also, logically, serve as targets of mutation, rearrangement, or other aberration in disease. Therefore, DNAs from panels of rodent-human hybrids carrying defined complements of human chromosomes were assayed for the presence of the cognate genes for NCK, SHC, and GRB2, three SH2 or SH2/SH3 (Src homology 2 and 3) domain-containing adapter proteins. Additionally, NCK and SHC genes were more narrowly localized by chromosomal in situ hybridization. The NCK locus is at chromosome region 3q21, a region involved in neoplasia-associated changes; the SHC cognate locus, SHC1, is at 1q21, and the GRB2 locus is at 17q22-qter telomeric to the HOXB and NGFR loci. Both SHC1 and GRB2 are in chromosome regions that may be duplicated in some tumor types