SEARCH · PubMed Health

Results for “structural genomics”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 523 records · Page 29Linked to original sources

PubMed2000

Genomic structure of the gene for mouse germ cell nuclear factor (GCNF).

BACKGROUND: The germ cell nuclear factor (GCNF, also known as retinoid acid receptor-related testis-associated receptor, neuronal cell nuclear receptor or NR6A1) is an orphan receptor in the nuclear receptor superfamily found in mammals, amphibians and fish. The mouse Gcnf gene is expressed in the placenta and the developing nervous system and germ cells, and responds to retinoic acid. RESULTS: We have defined the intron-exon structure of the mouse Gcnf gene and found that it contains 11 exons. Exons 1-4 encode the 75 amino acid amino-terminal domain and exon 4 also encodes the core DNA-binding domain. The carboxy-terminal extension is encoded by exon 5, exons 6 and 7 encode the hinge region, and exons 7-11 encode the putative ligand-binding domain. Unusually, the two zinc-finger motifs in the DNA-binding domain are encoded by separate exons. CONCLUSIONS: The protein-coding region of GCNF is contained in 11 exons. The genomic structure of this nuclear receptor gene will be useful for further studies.

Amino Acid Sequence↗

PubMed2000

Genomic structure of the gene for the human P1 protein (MCM3) and its exclusion as a candidate for autosomal recessive polycystic kidney disease.

The locus PKHD1 (polycystic kidney and hepatic disease 1) has been linked to all typical forms of the autosomal recessive polycystic kidney disease (ARPKD) and maps to chromosome 6p21.1-p12. We previously defined its genetic interval by the flanking markers D6S1714 and D6S1024. In our current work, we have fine-mapped the gene for the human P1 protein (MCM3), thought to be involved in the DNA replication process, to this critical region. We have also established its genomic structure. Mutation analyses using SSCP were performed in ARPKD patients' cDNA samples, leading to the exclusion of this gene as a candidate for this disorder. We also identified two intragenic polymorphisms that allowed families with critical recombination events to be evaluated. Although neither marker was informative in these individuals, they are the closest yet described for PKHD1 and may help to refine the candidate region.

Cell Cycle Proteins↗

PubMed2005

Genomic structure, alternative splicing and tissue expression of rFrp/sFRP-4, the rat frizzled related protein gene.

Secreted frizzled related proteins (sFRP) are regulators of Wnt signaling pathways that play central roles in developmental processes and oncogenesis. Various sFRP genes have been cloned from different tissues and implicated in diverse biological activities. rFrp, the rat homologue of sFRP-4, was initially identified as being upregulated in mutant p53-induced cellular transformation. Here, we report on the isolation of five novel splice variants, rFrp/sFRP-4 II, II, III, IVa and IVb. The complete rFrp/sFRP-4 genomic structure spans over 31 kb covering 9 exons. Except for the variant IVb, which was derived from IVa by alternative polyadenylation signal, variants I to IVa were alternatively spliced to different exons in the 3'end of mRNA and resulted in transcripts with truncated open reading frame. The deduced proteins of the variants had truncated C-termini, however, the two key functional protein domains, the cysteine-rich domain and the netrin-like domain of the isoforms, were not altered. In addition, different transcriptional initiation sites were found with variants II and IV, implying that these variants may be regulated differently from the rFrp/sFRP-4. RT-PCR analysis showed that these splice variants displayed different patterns of tissue-specific expression. Northern blot analysis revealed that the rFrp/sFRP-4 is most abundant in the ovary. Taken together, our findings suggest that alternative splicing of rFrp/sFRP-4 plays a role in regulating tissue-specific expression. The truncated C terminals of rFrp/sFRP-4 variants may confer structural specificity and hence exert different biological functions in different tissues. Characterization of these novel splice variants should help to elucidate the function of the sFRP family gene.

Alternative Splicing↗

PubMed2001

Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia.

Two overlapping and antiparallel genes on chromosome 1, Disrupted In Schizophrenia 1 and 2 (DISC1 and DISC2), are disrupted by a (1;11)(q42.1;q14.3) translocation which segregates with schizophrenia through at least four generations of a large Scottish family. Consequently, these genes are worthy of further investigation as candidate genes potentially involved in the aetiology of major psychiatric illness. We have constructed a contiguous clone map of PACs and cosmids extending across at least 400 kb of the chromosome 1 translocation breakpoint region and this has provided the basis for examination of the genomic structure of DISC1. The gene consists of thirteen exons, estimated to extend across at least 300 kb of DNA. The antisense gene DISC2 overlaps with exon 9. Exon 11 contains an alternative splice site that removes 66 nucleotides from the open reading frame. The final intron of DISC1 belongs to the rare AT-AC class of introns. We have also mapped marker DIS251 in close proximity to DISC1, localising the gene within a critical region identified by several independent studies. Information regarding the structure of the DISC1 gene will facilitate assessment of its involvement in the aetiology of major mental illness in psychotic individuals unrelated to carriers of the translocation.

Cell Line↗

PubMed2004

Conservation of the genomic structure and receptor-mediated signaling between human and rat IL-24.

IL-24/MDA-7 is a new member of the IL-10 family of cytokines, which signals through two heterodimeric receptor complexes (IL-20R1/IL-20R2 and IL-22R/IL-20R2). Previously, we identified a rat gene named mob-5, which encodes a secreted protein that shares a high degree of homology with human IL-24. Expression of mob-5 and its putative cell surface receptors was shown to be upregulated by oncogenic ras. Here we show that not only do rat mob-5 and human IL-24 share a strikingly similar genomic structure but also that the rat MOB-5 protein can bind to and signal through the human IL-24 receptors. Like human IL-24, binding of the rat MOB-5 protein to the human IL-24 receptors leads to activation of the JAK/STAT pathway, which in turn supports receptor-dependent survival and proliferation of Ba/F3 cells. Furthermore, using human colon cancer cell lines with somatic knockout of either the mutant or the wild-type k-ras allele, we demonstrate that the human IL-24 receptors also are upregulated by oncogenic ras. Taken together, these results provide strong experimental evidence that MOB-5 is indeed the rat homolog of human IL-24.

Amino Acid Sequence↗

PubMed1999

Refined physical mapping and genomic structure of the EXTL1 gene.

Recently, the EXTL1 gene, a member of the EXT tumor suppressor gene family, has been mapped to 1p36, a chromosome region which is frequently implicated in a wide variety of malignancies, including breast carcinoma, colorectal cancer and neuroblastoma. In this study, we show that the EXTL1 gene is located between the genetic markers D1S511 and D1S234 within 200 kb of the LAP18 gene on chromosome 1p36. 1, a region which has been proposed to harbor a tumor suppressor gene implicated in MYCN-amplified neuroblastomas. In addition, we determined the genomic structure of the EXTL1 gene, revealing that the EXTL1 coding sequence spans 11 exons within a 50-kb region.

Breast Neoplasms↗

PubMed2006

Genomic structure, promoter analysis and expression of the porcine (Sus scrofa) TLR4 gene.

Toll-like receptor 4 (TLR4) is essential for initiating the innate response to lipopolysaccharide (LPS) from Gram-negative bacteria by acting as a signal-transducing receptor. As the pig industry faces a unique array of related pathogens, it is anticipated that the genotype of swine TLR4 could be of crucial importance in future strategies aimed at improving genetic resistance to infectious diseases. In order to help in investigating TLR4 as a candidate disease-resistance gene in pigs, we established its genomic structure and produced sufficient flanking intronic sequences to enable simple PCR amplification of the coding portions of the gene. Expression in different porcine tissues was studied and showed splicing variations in mRNA sequences. The cDNA sequence for poTLR4 contains an open reading frame of 2526bp that codes for 841 aa, 98 and 568bp in the 5'- and 3'-UTRs, respectively. Overall, the general organization of porcine, human, murine, and avian TLR4 genes is quite similar: three exons with the third one very long. A high level of conservation of the size and the sequence, especially for the two last exons and particularly in the sequence corresponding to the LRRs and TIR domain, is observed between species. The important antimicrobial properties of these proteins may account for a conservative selection pressure on these TLR4 coding sequences. Several putative binding sites described in the human and murine promoter of TLR4 genes have been identified in the 5'-flanking region of poTLR4. Conversely, this region lacks a TATA box, consensus initiator sequences, or GC-rich regions. The basic sequence data gathered will allow the establishment of an inventory of naturally occurring variation in porcine TLR4, so that alleles can be tested for disease association studies.

Animals↗

PubMed1998

Characterisation of the mouse homologue of CD151 (PETA-3/SFA-1); genomic structure, chromosomal localisation and identification of 2 novel splice forms.

CD151 (PETA-3/SFA-1) is a member of the Transmembrane 4 Superfamily (TM4SF) of cell-surface proteins and, like other TM4SF members CD9 and CD63, is expressed by platelets, megakaryocytes and endothelial cells. The precise function of CD151 is unknown however complexes containing CD151 and beta1 integrins have been isolated from a number of cell systems and studies using anti-CD151 monoclonal antibodies have suggested a role in transmembrane signalling and cell adhesion. To further investigate the function of CD151 we have determined the genomic organisation of mouse CD151 (Cd151). Cd151 spans 4 kb and contains six coding region exons. Using 5' RACE and reverse transcriptase-polymerase chain reaction (RT-PCR) we have identified three 5' UTR splice variants which arise through alternate splicing of three exons. Splice variants were detected in a number of mouse tissues by RT-PCR. Analysis of the Cd151 genomic structure reveals a high degree of structural conservation with other TM4SF molecules supporting the theory that family members have arisen from gene duplication of a common ancestral gene. Cd151 maps to chromosome 7, in close linkage to the p gene (OCA2 in humans), and helps define a boundary in the human/mouse homology relationships.

Alternative Splicing↗

PubMed2000

Genomic structure of the human plasma prekallikrein gene, identification of allelic variants, and analysis in end-stage renal disease.

Kallikreins are serine proteases that catalyze the release of kinins and other vasoactive peptides. Previously, we have studied one tissue-specific (H. Yu et al., 1996, J. Am. Soc. Nephrol. 7: 2559-2564) and one plasma-specific (H. Yu et al., 1998, Hypertension 31: 906-911) human kallikrein gene in end-stage renal disease (ESRD). Short sequence repeat polymorphisms for the human plasma kallikrein gene (KLKB1; previously known as KLK3) on chromosome 4 were associated with ESRD in an African American study population. This study of KLKB1 in ESRD has been extended by determining the genomic structure of KLKB1 and searching for allelic variants that may be associated with ESRD. Exon-spanning PCR primer sets were identified by serial testing of primer pairs designed from KLKB1 cDNA sequence and DNA sequencing of PCR products. Like the rat plasma kallikrein gene and the closely related human factor XI gene, the human KLKB1 gene contains 15 exons and 14 introns. The longest intron, F, is almost 12 kb long. The total length of the gene is approximately 30 kb. Sequence of the 5'-proximal promoter region of KLKB1 was obtained by shotgun cloning of genomic fragments from a bacterial artificial clone containing the KLKB1 gene, followed by screening of the clones using exon 1-specific probes. Primers flanking the exons and 5'-proximal promoter region were used to screen for allelic variants in the genomic DNA from ESRD patients and controls using the single-strand conformation polymorphism technique. We identified 12 allelic variants in the 5'-proximal promoter and 7 exons. Of note were a common polymorphism (30% of the population) at position 521 of KLKB1 cDNA, which leads to the replacement of asparagine with a serine at position 124 in the heavy chain of the A2 domain of the protein. In addition, an A716C polymorphism in exon 7 resulting in the amino acid change H189P in the A3 domain of the heavy chain was observed in 5 patients belonging to 3 ESRD families. A third polymorphism in the coding sequence was a C699A shift that caused an amino acid change, H183Q. This allele was observed in 8 cases from 6 ESRD families but was not found in any control DNAs. Individually or combined, the allelic variants observed are not statistically associated with ESRD, though in several cases (e.g., H183Q) the small number of people in the population carrying these alleles limits our ability to statistically test for significant association with ESRD. Two new CA/GT repeat polymorphic markers, designated KLK3f and KLK3g, that have heterozygosities of 0.65 and 0.84, respectively, were identified within introns M and N. Analysis using the relative predispositional effect technique indicated that the frequencies of alleles 4 and 8 of KLK3f and allele 8 of KLK3g were significantly different between controls and ESRD cases. They accounted for 0.226, 0.096, and 0.313, respectively, in the probands of 166 ESRD families compared to 0.172, 0.066, and 0.244 in 139 healthy race-matched controls (allele P and total P < 0.05 for all three alleles). Therefore, although polymorphisms in the coding and 5'-proximal promoter of KLKB1 show no statistically significant association with ESRD in African Americans, there is still evidence for association of this part of chromosome 4 with ESRD. This observation suggests that other sequences within or near KLKB1, or another gene nearby, may contribute to ESRD susceptibility.

Alleles↗

PubMed2005

Fertility, segregation at a herbicide-resistance locus, and genome structure in BC hybrids from two important weedy Amaranthus species.

Field studies have established high potential for hybridization between two important and often coexisting weedy species, Amaranthus hybridus and Amaranthus tuberculatus. Prezygotic reproductive barriers between these species are believed to be limited to pollen competition and availability. A greenhouse study showed that a herbicide-resistance gene (ALS) from A. hybridus could be introgressed into an advanced A. tuberculatus background (BC2). However, evidence is lacking in support of such transfer in nature. Postzygotic reproductive barriers may minimize, if not preclude, natural introgression. Indeed, A. hybridus xA. tuberculatus hybrids are characterized by reduced fertility and even floral neuterism. The purpose of this study was to assess hybrid fertility in the BC1 generation and its relationship with genome structure and segregation at ALS. Fertility was assessed by measuring seed output and by pollen evaluation, and segregation at ALS was determined via a molecular marker system. The two parental species have the same ploidy (2n = 32) but differ in DNA content (2C) values, with A. tuberculatus chromosomes being on average 29% greater than those of A. hybridus. Given that most (98%) BC(1)s were homoploid, 2C values were used as indicators of relative genomic constitution. Fertility in the BC1 generation was greater than that of F1s, and 3% of BC1s had seed output similar to that of the parental species. Fertility in the BC1 did not correlate (in a strict way) with reconstitution of parental genomes. Hybrid sterility appeared to be controlled by relatively few loci. Heterozygosity at ALS was negatively correlated with fertility. Also, the A. tuberculatus ALS allele was not observed in the A. hybridus sexual condition, monoecism. Linkage of ALS to a locus associated (directly or via epistasis) with hybrid sterility may explain the fertility penalty observed with ALS introgression. Moreover, this linkage might explain why sequenced herbicide-resistance ALS alleles from sympatric A. tuberculatus and A. hybridus populations show independent evolution.

Amaranthaceae↗

PubMed1999

Characterization of the human talin (TLN) gene: genomic structure, chromosomal localization, and expression pattern.

Talin is a high-molecular-weight cytoskeletal protein, localized at cell-extracellular matrix associations known as focal contacts. In these regions, talin is thought to link integrin receptors to the actin cytoskeleton. Talin plays a key role in the assembly of actin filaments and in spreading and migration of various cell types. Talin proteins are found in a wide variety of organisms, from slime molds to humans. The human Talin (HGMW-approved symbol TLN) gene was previously mapped to chromosome 9p, but little was known of its sequence and genomic structure. To characterize human TLN further, we have isolated a single bacterial artificial chromosome clone, harboring the entire gene. The gene extends over more than 23 kb and consists of 57 exons. We have localized TLN to human chromosome band 9p13 by both fluorescence in situ hybridization and radiation hybrid mapping. Northern blot analysis detected TLN expression in various human tissues, including leukocytes, lung, placenta, liver, kidney, spleen, thymus, colon, skeletal muscle, and heart. Based on its chromosomal location, expression pattern, and protein function, we considered TLN as a candidate gene for cartilage-hair hypoplasia (CHH), an autosomal recessive metaphyseal chondrodysplasia, previously mapped to 9p13. We sequenced the entire TLN coding sequence in several CHH patients, but no functional mutations were detected.

Cartilage↗

PubMed1995

Determination of the genomic structures of two nonallelic preproinsulin genes in Xenopus laevis using the polymerase chain reaction.

We have previously cloned cDNAs that correspond to two different nonallelic preproinsulin genes in the amphibian, Xenopus laevis (Shuldiner et al., 1989, J. Biol. Chem. 264, 9428-9432). The coding regions of the two genes are very similar (i.e., 93% amino acid identity). While both preproinsulin genes are expressed coordinately in the adult pancreas, they are differentially expressed in prepancreatic embryos during neurulation (Shuldiner et al., 1991, Proc. Natl. Acad. Sci. USA 88, 7679-7683). We now report the use of the polymerase chain reaction (PCR) to investigate the genomic structures of both Xenopus preproinsulin genes. First, the nucleotide sequence of a portion of the 5' untranslated region that was lacking in our cDNA clones was obtained using rapid amplification of cDNA ends (5' RACE). Then, oligonucleotide primers were designed that flanked putative exon-intron splice boundaries, and intronic sequences in each of the two nonallelic genes were amplified. We determined that both Xenopus preproinsulin genes contain two introns, one interrupting the 5' untranslated region, and the second interrupting the region encoding the C-peptide. The introns are similar in position, but of greater length than those reported in most other species. Interestingly, dideoxy sequence analysis of the PCR-amplified introns revealed that the exon-intron splice junctions are well conserved between the two nonallelic genes, but internal to these junctions, the respective introns diverge significantly from each other. Thus, ample time has elapsed since the duplication of these two genes for marked divergence to occur within the introns suggesting that these regions are not important for expression in the adult pancreas. From these studies, we predict that elucidation of the sequences of the 5' flanking regions of the two nonallelic preproinsulin genes will reveal conserved regions that will be important for coordinate expression, as well as less conserved regions that will either be unimportant for coordinate expression (i.e., pancreatic expression) or important for differential expression (i.e., prepancreatic expression).

Animals↗

PubMed1992

Genomic structure and expression of the human fau gene: encoding the ribosomal protein S30 fused to a ubiquitin-like protein.

The fau gene is the cellular homolog of the fox sequence in the Finkel-Biskis-Reilly Murine Sarcoma Virus (FBR-MuSV). This virus acquired the fau sequence in its reversed transcriptional orientation. Human and mouse fau cDNA's were identified and both encode a new protein of 133 AA. We show that fau (for FBR-MuSV associated ubiquitiously expressed gene) becomes expressed in all different tissues tested as a 600 bp messenger and we report the genomic structure of the human fau gene. The gene consists of five exons and four introns and the 5' untranslated region displays characteristic features for a housekeeping gene. Fau encodes the ribosomal protein S30 fused to a Ubiquitin-like protein.

Amino Acid Sequence↗

PubMed2001

Genomic structure of the sandworm, Perinereis vancaurica tetradentata, troponin C.

Troponin C (TnC) superfamily genes essentially possess five introns, the positions of all but the fourth being highly conserved. The fourth intron is frequently absent from protostomian invertebrate genes, such as calmodulin or TnC. We previously proposed that the common ancestor of TnC superfamily genes never possessed an intron corresponding to today's fourth introns, and that members of the superfamily independently gained a fourth intron in the evolutionary pathway of each lineage. In the present study, we isolated the TnC cDNA from the sandworm, Perinereis vancaurica tetradentata and determined its genomic structure. Sandworm TnC appears to exist as a single copy gene consisting of six exons and five introns. The positions of the first, second, third and fifth introns are identical to other TnCs, but that of the fourth intron is unique. This is in good agreement with the above-mentioned scheme, i.e. the gain of the fourth intron of sandworm TnC might have occurred within the annelid lineage after annelida/mollusca divergence.

Amino Acid Sequence↗

PubMed1998

Genomic structure of the spermatid-specific hsp70 homolog gene located in the class III region of the major histocompatibility complex of mouse and man.

The Hsc70t gene is a Hsp70 homolog gene expressed constitutively in spermatids in mice. This gene is linked to two heat-inducible Hsp70 genes, Hsp70.1 and Hsp70.3, located in the MHC class III region. The syntenic region of human chromosome 6 contains the HSPA1B, HSPA1A, and HSPA1L genes. Here, we have isolated a HSPA1L cDNA clone from human testicular cells. The HSPA1L gene contained an intron 13 bp upstream of the initiating ATG. A similar genomic structure was found in the Hsc70t gene. The transcription initiation site of the Hsc70t gene was located at ca. 600 bp upstream of the heat-inducible Hsp70.3 gene, linked head-to-head. Sequence alignment of the mouse and human genes revealed that the human HSPA1L and HSPA1A genes were orthologous to the mouse Hsc70t and Hsp70.3 genes, respectively. Conserved sequence stretches observed in the 5' flanking region and the first exon of the spermatid-specific Hsp70 gene may be involved in regulation of the specific gene expression.

Animals↗

PubMed1988

Drosophila basement membrane procollagen alpha 1(IV). II. Complete cDNA sequence, genomic structure, and general implications for supramolecular assemblies.

A Drosophila melanogaster gene for a basement membrane procollagen chain was recently identified from the sequence homology of the carboxyl (NC1) end of the polypeptide that it encodes with the corresponding domain of human and murine collagens IV (Blumberg, B., MacKrell, A. J., Olson, P. F., Kurkinen, M., Monson, J. M., Natzle, J. E., and Fessler, J. H. (1987) J. Biol. Chem. 262, 5947-5950). This gene is at chromosome location 25C. Here we report the complete 6-kilobase cDNA sequence coding for a chain of 1775 amino acids, as well as the genomic structure. The gene is composed of nine relatively large exons separated by eight relatively small introns. This organization is different from the multiple small exons separated by large introns reported for mouse and human type IV collagens (Kurkinen, M., Bernard, M. P., Barlow, D. P., and Chow, L. T. (1985) Nature 317, 177-179. Sakurai, Y., Sullivan, M., and Yamada, Y. (1986) J. Biol. Chem. 261, 6654-6657. Soininen, R., Tikka, L., Chow, L., Pihlajaniemi, T., Kurkinen, M., Prockop, D. J., Boyd, C. D., and Tryggvason, K. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 1568-1572). Drosophila and human alpha 1(IV) procollagen chains share not only polypeptide domains near their amino and carboxyl ends for making specialized, intermolecular junctional complexes, but also 11 of 21 sites of imperfections of the collagen triple helix. However, neither the number nor the nature of the amino acids in these imperfections appear to have been conserved. These imperfections of the helical sequence may be important for the supramolecular assembly of basement membrane collagen. The 9 cysteine residues of the Drosophila collagen thread domain are arranged as several variations of a motif found in vertebrate collagens IV only near their amino ends, in their "7 S" junctional domains. The relative positions of these cysteine residues provide numerous opportunities for disulfide bonding between molecules in both parallel and antiparallel arrays. There is a pseudorepeat of one-third of the thread length, and there are numerous possibilities for disulfide-linked microfibrils and networks. We propose that collagen microfibrils, stabilized by disulfide segment junctions, are a versatile ancestral form from which specialized collagen fibers and networks arose.

Amino Acid Sequence↗

PubMed2001

Gene for the human transmembrane-type protein tyrosine phosphatase H (PTPRH): genomic structure, fine-mapping and its exclusion as a candidate for Peutz-Jeghers syndrome.

Mutations in the serine/threonine kinase STK11 lead to Peutz-Jeghers syndrome (PJS) in a subset of affected individuals. Significant evidence for linkage to a second potential PJS disease locus on 19q13.4 has previously been described in one PJS family (PJS07). In the current study, we investigated this second locus for PJS gene candidates. We mapped the main candidate gene in this region, the gene for the transmembrane-type protein tyrosine phosphatase H (PTPRH), within 15 kb telomeric to the marker D19S880. We determined its genomic structure, and performed mutation analysis of all exons and the exon-intron junctions of the PTPRH gene in the PJS07 family. No disease causing mutation was identified in PTPRH in affected individuals, suggesting the existence of an as yet not identified gene on 19q13.4 as a second PJS gene.

Chromosomes, Human, Pair 19↗

PubMed2002

Quantitative expansion of structural genomic alterations in the spectrum of neuroendocrine lung carcinomas.

The pathogenesis and interrelationships of neuroendocrine lung carcinomas are not well understood. Tissue macro-arrays prepared from surgical resection specimens from 35 patients with typical carcinoid (TC), six with atypical carcinoid (AC), 13 with large cell neuroendocrine carcinoma (LCNEC), and 15 with small cell lung carcinoma (SCLC) were investigated by fluorescence in situ hybridization (FISH) and immunohistochemistry. Hybridizations with locus-specific DNA probes demonstrated a high incidence of deletion for the tumour suppressor genes p53 and retinoblastoma (Rb), and for the oncogene cyclin D1, comparable in all carcinoma types. Similarly, an increase of DNA copy number for the Her-2/neu and c-myc oncogenes was noted in all neoplasms. A more detailed quantitative analysis of the results, however, demonstrated increasing numbers of cells harbouring these genomic alterations, from low-grade TC to highly malignant SCLC, with the exception of cyclin D1 deletion. Mutations of the p53 and Rb genes, as assayed by immunohistochemical studies, were observed at high incidence in high-grade carcinomas, compared with a low incidence in the low-grade carcinomas. Conversely, in all carcinoma types, neither membrane-bound Her-2/neu nor nuclear cyclin D1 was detected. It is concluded that structural genomic alterations are frequent in neuroendocrine lung carcinomas and that their occurrence may be underestimated by immunohistochemical studies alone. The quantitative expansion of the Rb, p53, c-myc, and Her-2/neu alterations towards high-grade carcinomas suggests common pathogenetic mechanisms in the spectrum of these neoplasms.

Adult↗