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PubMed1994

p53 gene mutations in breast cancers in midwestern US women: null as well as missense-type mutations are associated with poor prognosis.

We determined the pattern of mutations in exons 2-11 and adjacent intronic regions in breast cancers from Midwestern US white women. Twenty-one mutations were detected in 53 tumors (39.6%). Comparisons of the pattern of mutations within exons 5-9 showed that the frequency of missense mutations (44%) was lower in breast cancers of US Midwestern women than in most tumor types including breast cancers in other populations. Compared to breast cancers reported in a Scottish population, US women had a high frequency of G:C-->T:A transversions (P = 0.046). These findings suggest that environmental or endogenous factors contribute to p53 mutagenesis in mammary tissue to different extents among different populations. With a median follow-up of 19 months, the presence of a mutation was associated with shorter time to disease recurrence (P = 0.05) and shorter survival (P = 0.003). Putative dominant negative missense-type mutations (missense and in-frame microdeletions; P = 0.001) and null mutations (hemizygous nonsense and frameshift mutations; P = 0.007) were equally ominous. Thus, tumors with missense p53 mutations resulting in over-expression of a dysfunctional but otherwise intact protein have a clinical outcome similar to tumors with null mutations resulting in a truncated or garbled protein.

Adult↗
PubMedDate not supplied

[Nucleotide sequence of the E1B area and the adjacent 3'-terminal segment of the E1A oncogene from monkey adenovirus SA7 (C8)].

The SA7 (C8) simian adenovirus was sequenced from the 1478th to 3194th nucleotide. The region includes the 3'-terminal part of E1A and the major part of the E1B coding region. The sequence obtained was compared with the structure of SA7 (P) DNA previously determined in the region 1-2338, and many differences were found which are nucleotide substitutions, microdeletions and microinsertions. Among point substitutions the most frequent was the C-->T transition in CG pairs known as hot spots of mutations. Differences of our sequence from the previously published one was also revealed.

Adenovirus E1A Proteins↗
PubMed1993

[High-resolution cytogenetic study of a patient with Prader-Willi syndrome].

We investigated a patient with Prader-Willi syndrome by using the high-resolution banding technique. His clinical findings were also examined in some detail. The patient had interstitial deletion of 15q, with breakpoints at 15q11.2 and 15q13. However, he had a normal karyotype at about 400 bands per haploid-set. During the course of this study, it was realized that a small deletion in the proximal 15q could be easily overlooked when a mitotic spread of about 400-bands or less per haploid-set was used. It is suggested that the high-resolution banding technique is of great importance in identifying microdeletions and other microaberrations of chromosomes.

Child↗
PubMed1994

Mutation and overexpression of the p53 tumor suppressor gene frequently occurs in uterine and ovarian sarcomas.

OBJECTIVE: To determine the frequency of mutation and overexpression of the p53 tumor suppressor gene in female genital tract sarcomas. METHODS: Immunostaining for p53 was performed in frozen sections of 46 ovarian and uterine sarcomas. Single-stranded conformation polymorphism analysis of exons 4-9 of the p53 gene was performed in 33 sarcomas. We performed DNA sequencing of the p53 gene in 22 cases in which we found p53 protein overexpression and/or shifted bands on single-stranded conformation polymorphism analysis. RESULTS: Overexpression of p53 was seen in 27 of 46 sarcomas (59%), including 26 of 41 (63%) mixed mesodermal tumors, one of four (25%) leiomyosarcomas, and zero of one endometrial stromal sarcoma. Among the 33 sarcomas subjected to molecular analysis, 21 demonstrated mutations in the p53 gene (64%). Eighteen cancers had a single mutation, whereas three cases showed two mutations in the p53 gene. There was one mutation in exon 4, seven mutations in exon 5, three mutations in exon 6, six mutations in exon 7, six mutations in exon 8, and one mutation in exon 9. With the exception of one microdeletion, which predicted a truncated protein product, all of the mutations were missense point mutations. All but one of the point mutations resulted in changes in the predicted amino acid sequence. There were 18 transition mutations (75%), five transversions (21%), and one deletion (4%). CONCLUSIONS: Mutation of the p53 tumor suppressor gene, with resultant overexpression of p53 protein, frequently occurs in ovarian and uterine sarcomas. Because most of the mutations are transitions, p53 mutations in these cancers likely arise from spontaneous errors in DNA synthesis and repair rather than from exposure to carcinogens.

Adult↗
PubMed1994

Growth suppression of normal mammary epithelial cells by wild-type p53.

p53 mutations are frequent in human breast cancer. In order to understand the role of p53 in the context of the accumulation of mutations in breast cancer, a model of non transformed mammary cells was sought. The HC11 cells are immortalized, non transformed rodent mammary epithelial cells which synthesize milk proteins following stimulation with lactogenic hormones. p53 protein was readily detected in HC11 protein extracts with the PAb421 antibody. Two mutations were identified in the p53 cDNA from HC11 cells: a missense mutation at codon 138, substituting Trp for Cys, and a microdeletion, codon 123 to 130, of exon 5. The latter results from an intronic mutation of the splice acceptor site at the intron 4/exon 5 junction. The mutations affect separate p53 alleles, and no wt allele was found. Wt p53 was introduced into HC11 cells by means of a retroviral vector, under the control of a Cd(++)-inducible promoter. In the presence of CdSO4 a dramatic growth inhibition was observed. A temperature-sensitive mutant p53 gene was also transfected into HC11 cells. This resulted in a marked inhibition of cells growth at 32 degrees C, when the p53 is in the wt conformation, while no effect was observed at 37 degrees C, when the mutant conformation is predominant. wt p53-mediated inhibition of monolayer growth does not involve induction of programmed cell death and does not activate de novo synthesis of differentiation-specific milk proteins. We conclude that mutations in the p53 gene likely played a role in their immortalization. The HC11 cells provide a model for assessing the cooperative action of other mutations in mammary tumorigenesis.

Alleles↗
PubMed1994

Immunohistochemical and genetic characterization of the M Cagliari alpha-1-antitrypsin molecule (M-like alpha-1-antitrypsin deficiency).

BACKGROUND: Genetic alpha-1-antitrypsin (AAT) deficiency may be due to defective secretion, intracellular degradation, or lack of synthesis. Defective secretion results in hepatocytic storage and liver disease. These two events occur only with the common deficiency variant, Z AAT, and with a few rare deficiency variants, called M-like. Hepatocytic storage of AAT (either Z or M-like) can be demonstrated in tissue sections by specific immunostaining with a polyclonal anti-AAT antibody, that recognizes all variants of AAT. A monoclonal antibody capable of selectively and exclusively reacting with Z AAT has been generated and successfully used in both serum and tissue studies. EXPERIMENTAL DESIGN: To determine whether a new M-like variant, M Cagliari, carries a mutation different from Z AAT, we have compared antigenic properties and DNA sequences of the two variants. Liver tissue sections from PiZ and PiM Cagliari patients were stained with both polyclonal anti-AAT and monoclonal anti-Z AAT antibodies. DNAs were polymerase chain reaction-amplified with AAT-specific primers and sequenced. RESULTS: Liver tissue sections from PiZ livers were positively stained with either the polyclonal or the monoclonal antibody. The PiM Cagliari liver sections reacted with the polyclonal antibody, but not with the monoclonal anti-Z AAT, thus indicating a difference in antigenicity from Z AAT. Accordingly, DNA analysis ruled out a Z mutation and revealed a microdeletion in exon II, identical with M Malton. CONCLUSIONS: A simple immunohistochemical assay based upon the application of both polyclonal and monoclonal antibodies represents a reliable test to distinguish Z and nonZ AAT deficiencies, thus assisting in the selection of cases worthy of more time-consuming analyses such as DNA sequencing. The same approach may be used for the characterization of as yet undefined PiM cases with AAT liver storage.

Adult↗
PubMed1994

The rates and patterns of deletions in the human factor IX gene.

Deletions are commonly observed in genes with either segments of highly homologous sequences or excessive gene length. However, in the factor IX gene and in most genes, deletions (of > or = 21 bp) are uncommon. We have analyzed DNA from 290 families with hemophilia B (203 independent mutations) and have found 12 deletions > 20 bp. Eleven of these are > 2 kb (range > 3-163 kb), and one is 1.1 kb. The junctions of the four deletions that are completely contained within the factor IX gene have been determined. A novel mutation occurred in patient HB128: the data suggest that a 26.8-kb deletion occurred between two segments of alternating purines and pyrimidines and that a 2.3-kb sense strand segment derived from the deleted region was inserted. For our sample of 203 independent mutations, we estimate the "baseline" rates of deletional mutation per base pair per generation as a function of size. The rate for large (> 2 kb) deletions is exceedingly low. For every mutational event in which a given base is at the junction of a large deletion, there are an estimated 58 microdeletions (< 20 bp) and 985 single-base substitutions at that base. Analysis of the nine reported deletion junctions in the factor IX gene literature reveals that (i) five are associated with inversions, orphan sequences, or sense strand insertions; (ii) four are simple deletions that display an excess of short direct repeats at their junctions; (iii) there is no dramatic clustering of junctions within the gene; and (iv) with the exception of alternating purines and pyrimidines, deletion junctions are not preferentially associated with repetitive DNA.

Base Sequence↗
PubMed1993

Rubinstein-Taybi syndrome caused by submicroscopic deletions within 16p13.3.

The Rubinstein-Taybi syndrome (RTS) is a well-defined complex of congenital malformations characterized by facial abnormalities, broad thumbs and big toes, and mental retardation. The breakpoint of two distinct reciprocal translocations occurring in patients with a clinical diagnosis of RTS was located to the same interval on chromosome 16, between the cosmids N2 and RT1, in band 16p13.3. By using two-color fluorescence in situ hybridization, the signal from RT1 was found to be missing from one chromosome 16 in 6 of 24 patients with RTS. The parents of five of these patients did not show a deletion of RT1, indicating a de novo rearrangement. RTS is caused by submicroscopic interstitial deletions within 16p13.3 in approximately 25% of the patients. The detection of microdeletions will allow the objective conformation of the clinical diagnosis in new patients and provides an excellent tool for the isolation of the gene causally related to the syndrome.

Chromosome Deletion↗
PubMed1995

DiGeorge syndrome and partial monosomy 10p: case report and review.

DiGeorge syndrome (DGS) is predominantly caused by partial monosomy 22q11, but a subset of patients with DGS show deletions of 10p or other chromosomal abnormalities. The authors describe a 20 months old girl with DGS and a monosomy 10p bringing the number of DGS patients with this chromosomal abnormality to nine. She has a monosomy 10p13-pter and a trisomy 10q26-qter due to a meiotic recombination of a maternal inversion (10) (p13q26). The proposita's phenotype demonstrates typical features of the del (10p) syndrome which include mental retardation, abnormally shaped skull, hypertelorism, low nasal bridge, micrognathia, dysmorphic low set ears, short neck, foot abnormalities, and cardiac defect. The diagnosis of DGS was made unequivocally within the first weeks of life because of the typical features-cardiac defect, hypoplastic thymus, T-cell defect, hypocalcemia, and hypoparathyroidism. The common DGS mutation-microdeletion 22q11-was excluded by FISH analysis, and the breakpoints on chromosome 10 were mapped between D10S189 and D10S191 on the short arm and proximal to D10S25 on the long arm.

Chromosome Deletion↗
PubMed1996

[3 children with velocardiofacial (Shprintzen) syndrome].

In three children, girls of 3, 8, and 12 years old, who attended or had attended public health care facilities, velocardiofacial syndrome was diagnosed. The most important symptoms are cleft palate, cardiac anomalies, characteristic facies (almond-shaped eyes, wide nose, small ears) and learning problems. The syndrome has an autosomal dominant inheritance pattern with a very variable expression. Using fluorescence in situ hybridisation, microdeletions of the long arm of chromosome 22 have been identified in 70% of the patients (22qII). Velocardiofacial syndrome should be considered in any child with cleft palate, velopharyngeal insufficiency and/or hypernasal speech, and notably in children with nasal regurgitation of food in the first year of life, poor growth, developmental problems, facial dysmorphism and/or conotruncal cardiac anomalies.

Abnormalities, Multiple↗
PubMed1996

Deletions and rearrangements inactivate the p16INK4 gene in human glioma cells.

Structural alterations in the p16INK4 gene were examined in early passage human glioma cell lines and related to the expression of p16 transcripts and protein. Using the Southern blot approach, we observed both homozygous and hemizygous deletions, as well as rearrangements of the p16 and p15 genes in 5 of the 7 cell lines (71%). Two cell lines, MGR3 and HBT28, revealed hemizygous deletion of the p16 and p15 genes combined with indistinguishable rearrangements of the remaining p15-p16 locus that resulted in loss of exon 2 sequences for p15 and p16, but retention of p16 exon 1; neither of these cell lines expressed p16 mRNA. Data for a third cell line, MGR2, indicated a similar, but unique rearrangement involving the p15 and p16 genes. MGR2, which retained a single wild-type p15-p16 locus, showed expression of p16 transcript, but not of p16 protein as indicated by Western blot analysis. All the glioma cell lines expressed similar levels of the retinoblastoma protein and no amplification of the cyclin-dependent kinase 4 gene. These results demonstrate that human glioma cells contain p16 gene microdeletions and rearrangements that contribute to inactivation of the cell cycle regulatory protein.

Blotting, Southern↗
PubMed1996

Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients.

Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (i) FISH analysis, (ii)PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (iii) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS.

Abnormalities, Multiple↗
PubMed1996

Biallelic alterations of both ETV6 and CDKN1B genes in a t(12;21) childhood acute lymphoblastic leukemia case.

Recently, a new recurrent t(12;21)(pl3;q22) has been identified in a B-cell lineage childhood acute lymphoblastic leukemia (ALL). The translocation results in a fusion of two known genes, ETV6/TEL (12p13) and AML1 (21q22), previously shown to be involved in the pathogenesis of myeloid disorders. We report results of cytogenetic fluorescence in situ hybridization and molecular studies of a B-cell childhood common ALL with a cryptic 12;21 translocation. Aberrations identified in this case involve both chromosomes 12 and include not only the ETV6-AML1 gene fusion and two different microdeletions of ETV6 but also the hemizygous loss of CDKN1B, D12S119, and KRAS2 loci and a putative rearrangement of the second CDKN1B allele as a result of an inv(12)(p13q24). Moreover, it was shown that the AML1-ETV6 reciprocal chimeric transcript was not present in the malignant cells, and hence may not play a major role in leukemogenesis. In addition, the putative loss of wild-type function of CDKN1B and ETV6 could indicate a synergistic effect of both genes in the pathogenesis of this leukemia case.

Adolescent↗
PubMed1996

Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study.

The major cause of hyperphenylalaninemia is mutations in the gene encoding phenylalanine hydroxylase (PAH). The known mutations have been identified primarily in European patients. The purpose of this study was to determine the spectrum of mutations responsible for PAH deficiency in the United States. One hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were subjects for clinical and molecular investigations. PAH gene mutations associated with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 of 294 independent mutant chromosomes, a diagnostic efficiency of 95%. The spectrum is composed of 71 different mutations, including 47 missense mutations, 11 splice mutations, 5 nonsense mutations, and 8 microdeletions. Sixteen previously unreported mutations were identified. Among the novel mutations, five were found in patients with MHP, and the remainder were found in patients with PKU. The most common mutations were R408W, IVS12nt1g-->a, and Y414C, accounting for 18.7%, 7.8%, and 5.4% of the mutant chromosomes, respectively. Thirteen mutations had relative frequencies of 1%-5%, and 55 mutations each had frequencies < or = 1%. The mutational spectrum corresponded to that observed for the European ancestry of the U.S. population. To evaluate the extent of allelic variation at the PAH locus within the United States in comparison with other populations, we used allele frequencies to calculate the homozygosity for 11 populations where >90% ascertainment of mutations has been obtained. The United States was shown to contain one of the most heterogeneous populations, with homozygosity values similar to Sicily and ethnically mixed sample populations in Europe. The extent of allelic heterogeneity must be a major determining factor in the choice of mutation-detection methodology for molecular diagnosis in PAH deficiency.

Alleles↗
PubMed1996

[High incidence of p53 mutations in primary and metastatic head and neck tumors. Frequent protein overexpression in normal epithelium].

Mutation of the p53 tumor suppressor gene is the most commonly observed gene alteration in human cancers. In order to identify new prognostic factors and tumor aggressiveness in squamous cell head and neck carcinomas, we analyzed 50 node metastases and 28 primary tumors including 13 matched specimens for p53 alterations. Mutations were found in 54 (69%) tumors, 76% of which were missense, 9% were nonsense and 15% were microdeletions or microinsertions. Twenty-five mutations were transitions mostly G-->A (40%) and 20 were transversions mostly G-->T (25%) thus confirming the role of tobacco carcinogens in the induction of these mutations. For eight patients mutations were observed in matched primary tumors and metastases, indicating clonal dissemination of tumor cells in most of these carcinomas. Furthermore the incidence of mutations was not different in primary tumors and node metastases indicating that this gene alteration was not related to the metastatic dissemination. No correlation was found between mutation and clinical parameters, the 8-year survival rates were not different (log rank test: P = 0.49) in patients with and without mutation. There was a good correlation between p53 mutation and protein overexpression (Fisher's exact test: P < 10(-4). Interestingly, immunostaining was also observed in basal cells from normal mucosa and in early lesions adjacent to the primary tumor in 11/15 specimens irrespective of the presence of mutation in the corresponding tumors. p53 protein overexpression may therefore constitute a biomarker for early stages of carcinogenesis of the head and neck epithelium.

Carcinoma, Squamous Cell↗
PubMed1996

[A literature review of Norrie disease].

Norrie disease is a rare genetic disorder characterized by bilateral congenital blindness. The salient clinical feature early in life is a dense, white, vascularized mass behind each lens due to maldeveloped retina. Cataracts and corneal opacities are developed in young childhood, followed by bulbar atrophies. Histopathologic examination suggests primary vitreoretinal dysplasia because of developmental arrest of the retina in the middle embryonic stage. Occasional patients show psychomotor retardation or progressive hearing loss as part of a multisystem disorder. The disease is transmitted by an X-linked recessive form of inheritance, with sons of female carriers having a 50% risk for expressing the disease. In recent years, a candidate gene for Norrie disease has been isolated and characterized, which encompasses 27 kilobases and consists of three exons interspersed by two introns. Microdeletions and a variety of point mutations in the disease gene were identified in Norrie patients, although the genotype-phenotype correlation remains to be defined, and molecular diagnosis is now available for Norrie disease. The encoded protein has homology to a protein domain involving mucins and TGF beta, which may play an essential role in targeting of retinal/neural connections.

Blindness↗
PubMedDate not supplied

[Which genetic tests in infertile men?].

Genetic investigations of idiopathic male infertilities should be systematic and should include a familial inquiry, a careful physical examination looking for one of the many genetic syndromes with male sterility and the karyotype. Moreover the search of a microdeletion in Yq AZF region should be undertaken as soon as it is possible; The licity of ICSI in genetic male infertility is discussed depending on the autosomal recessive or Yq linked genetic origin.

Fertilization in Vitro↗
PubMedDate not supplied

Current applications of molecular cytogenetic technologies.

This review discusses select current applications of fluorescent in situ hybridization (FISH) which may be of utility for the average clinical cytogenetic laboratory. Owing to the large number of men and women affected, the applications chosen to illustrate the use of FISH technology in cancer focus on two diseases: breast cancer and prostate cancer. The applicability of FISH to detect common aneuploidies, such as trisomy 21, trisomy 18, trisomy 13 and the sex chromosome aneuploidies in prenatal diagnosis, is discussed, as well as FISH for the detection of microdeletions and microduplications. Quality assurance/quality control issues and standards and guidelines relating to laboratory practices in molecular cytogenetic testing are reviewed.

Breast Neoplasms↗