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At least 253 records · Page 14Linked to original sources
PubMed1990

DNA fingerprinting of 7,12-dimethylbenz[a]anthracene-induced and spontaneous CD-1 mouse liver tumors.

Determining to what degree chemicals and environmental agents contribute to the development of cancer would be materially enhanced by the ability to distinguish chemically induced tumors from those that arise spontaneously. Using DNA fingerprinting as an assay, we investigated whether somatic DNA rearrangements are more frequent in chemically induced mouse liver tumors than they are in spontaneous mouse liver tumors. Tumors were induced by a single i.p. injection of 12-day old male Crl:CD-1(ICR)BR (CD-1) mice with 20 nmol/g 7,12-dimethylbenz[a]-anthracene and were harvested 9 to 12 months after injection. Spontaneous tumors were obtained from 94- to 98-week old male CD-1 mice. We detected 8 rearrangements in 14 7,12-dimethylbenz[a]anthracene-induced tumors, which corresponds to a high rearrangement frequency of about 2% (of the minisatellite bands examined). Furthermore, 6 of these rearrangements included complete band losses which must have occurred early in tumor development. However, only 2 band changes were observed in 15 spontaneous tumors, and both changes were intensity shifts which may represent rearrangements that occurred later during tumor progression. Histological examination showed that the higher frequency of rearrangements in 7,12-dimethylbenz[a]anthracene-induced tumors versus spontaneous tumors was not related to differences in the degree of tumor progression or malignancy. Our results suggest that DNA fingerprinting may be a valuable assay for differentiating certain chemically induced tumors from spontaneous tumors.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1989

Localization of HeLa cell tumor-suppressor gene to the long arm of chromosome II.

Cytogenetic and molecular genetic analyses of human intraspecific HeLa x fibroblast hybrids have provided evidence for the presence of a tumor-suppressor gene(s) on chromosome 11 of normal cells. In the present study, we have carried out extensive RFLP analysis of various nontumorigenic and tumorigenic hybrids with at least 50 different chromosome 11-specific probes to determine the precise location of this tumor-suppressor gene(s). Two different hybrid systems, (1) microcell hybrids derived by the transfer of a normal chromosome 11 into a tumorigenic HeLa-derived hybrid cell and (2) somatic cell hybrids derived by the fusion of the HeLa (D98OR) cells to a retinoblastoma (Y79) cell line, were particularly informative. The analysis showed that all but one of the nontumorigenic hybrid cell lines contained a complete copy of the normal chromosome 11. This variant hybrid contained a segment of the long arm but had lost the entire short arm of the chromosome. The tumorigenic microcell and somatic cell hybrids had retained the short arm of the chromosome but had lost at least the q13-23 region of the chromosome. Thus, these results showed a perfect correlation between the presence of the long arm of chromosome 11 and the suppression of the tumorigenic phenotype. We conclude therefore that the gene(s) involved in the suppression of the HeLa cell tumors is localized to the long arm (q arm) of chromosome 11.

Cell Line↗
PubMed1979

Analysis of human cancer DNA for DNA sequences of human adenovirus type 4.

We investigated whether human adenovirus type 4 (Ad4) might cause cancer in humans. Cell culture and animal model studies indicated that Ad4-induced human tumors should contain Ad4 DNA sequences. Thus Ad4 DNA was labeled in vitro (sp act, approximately 10(7) 3H counts/min/microgram) and hybridized in liquid phase with DNA extracted from human tumors. No viral sequences were detected in 31 squamous cell carcinomas of the lung, 5 adenocarcinomas of the lung, 4 oat cell carcinomas of the lung, 4 carcinomas of the stomach, 10 carcinomas of the colon, 3 carcinomas of the kidney, 3 carcinomas of the breast, 2 carcinomas of the ovary, and 6 Hodgkin's lymphomas. Reconstruction experiments with added Ad4 DNA indicated that the probe detected about 1 copy of 5% of the Ad4 genome per tumor cell. Therefore, these data were strong evidence (but did not prove) that none of these particular tumors were induced by Ad4.

Adenoviruses, Human↗
PubMed1995

Allelic loss of sequences from the long arm of chromosome 10 and replication errors in endometrial cancers.

Thirty-seven endometrial cancers were subjected to an allelotype analysis in an attempt to identify chromosomal regions that are lost in a significant portion of tumors and to identify tumors characterized by replication errors. Thirty-nine highly polymorphic microsatellite markers representing all chromosomal arms, excluding the X and the short arms of the acrocentrics, were examined. An average of 20 informative cases were evaluated for each marker. Genetic alterations were detected in 30 of the 37 tumors. Replication errors were identified in 8 tumor specimens. Loss of heterozygosity was observed for loci on all chromosomes examined with the exception of chromosomes 4 and 20. The two most frequent sites of loss were at the marker loci examined on 10q (40%) and 17p (29%). Six additional simple sequence repeat markers from 10q were genotyped in an effort to refine the region of 10q loss. The chromosome 10 markers used in these studies were physically mapped with the use of a panel of somatic hybrids that retain defined portions of chromosome 10. The observed patterns of loss of sequences on 10q suggest a role for a tumor suppressor gene in the 10q23-26 region in the development or progression of endometrial cancers.

Alleles↗
PubMed1995

Frequent microsatellite alterations on chromosome 3p in esophageal squamous cell carcinoma.

By the microsatellite assay, two types of genetic alterations, loss of heterozygosity (LOH) and replication error (RER), were examined using 7 dinucleotide repeat markers [D3S1317 (3p26); CI3-1169 (3p25); CI3-946 (3p25); D3S1255 (3p24.2-25); CI3-771 (3p21.3); CI3-1413 (3p14.1-14.3); and CI3-373 (3p13)] on the short arm of chromosome 3p as well as 3 markers [D2S123 (2p15-16), IFNA (9p22), and D16S408 (16q12.1-13)] on other chromosomes in 35 patients with esophageal squamous cell carcinoma. On 3p, LOH was detected in 34% (12 of 35) and RER was detected in 60% (21 of 35) at single or multiple loci. RER occurred at a similar frequency in all stages and did not correlate with clinicopathological characteristics. On the other hand, LOH at the 3p25 locus was more frequently detected in carcinomas with lymph node metastasis than in those without it (P < 0.05). The incidences of microsatellite alterations were low on the chromosomes other than 3p, except at D2S123, where the incidence of RER was 20%. These findings suggest that RER on 3p is an early event and that a tumor suppressor gene which is involved in the progression of esophageal squamous cell carcinoma may exist near the 3p25 locus.

Base Sequence↗
PubMed1996

Ubiquitous somatic alterations at microsatellite alleles occur infrequently in Barrett's-associated esophageal adenocarcinoma.

Microsatellite alterations have been documented in a subset of sporadic tumors, including those of the colon, lung, bladder, stomach, and esophagus. This study documented the frequency of microsatellite alterations at 139 loci, comprising predominantly dinucleotide and tetranucleotide repeat units, in 17 cases of primary esophageal adenocarcinoma arising against a background of Barrett's metaplasia. Each tumor demonstrated alterations in at least one locus studied. Widespread microsatellite alterations, occurring at 45.3% (58 of 128) of loci tested, were detected in a single case. The remaining 16 tumors exhibited low levels of microsatellite instability, ranging from 0.8% (1 of 128) to 8.1% (10 of 123) of loci tested. The single case with ubiquitous somatic alterations showed no significant difference in the incidence of novel alleles at di- and tetranucleotide repeat loci. The 16 cases showing a low level of microsatellite alterations demonstrated a 3.3-fold higher incidence of novel alleles at tetranucleotide repeat loci compared to dinucleotide repeat loci. These data suggest that ubiquitous somatic alterations at microsatellite loci, considered a phenotypic expression of defective mismatch repair, occur infrequently in Barrett's-associated adenocarcinoma. However, the majority of these tumors demonstrate a low level of microsatellite alterations, perhaps reflecting the inherent instability of these markers.

Adenocarcinoma↗
PubMed1996

Uteri of women with endometrial carcinoma contain a histopathological spectrum of monoclonal putative precancers, some with microsatellite instability.

We have tested the hypothesis that endometrial precancers persist in uteri of patients with endometrial carcinoma and are monoclonal. Twenty-two hysterectomies with both well-differentiated endometrial adenocarcinoma and adjacent (normal or abnormal) noncancerous endometrium underwent successful clonal analysis using a PCR assay for nonrandom X chromosome inactivation. Monoclonal lesions included endometrial carcinoma, endometrial polyps, and atypical endometrial hyperplasias, whereas normal and anovulatory endometrium were polyclonal. Comparison of the specific X chromosome copy preferentially inactivated by the matched monoclonal cancers and associated monoclonal lesions allowed us to exclude polyps, but not endometrial hyperplasias, as potential precancers. The repetitive genetic marker (HUMARA) for X inactivation was altered in some cancers, permitting identification of microsatellite instability (RER+). Two patients with RER+ cancers also had adjacent RER+ hyperplasias. The seven monoclonal and two RER+ hyperplasias had focal or diffuse cytological atypia, a feature previously associated with risk for endometrial cancer. We conclude that: (a) putative endometrial precancers and cancers share a monoclonal growth pattern; (b) cancers with microsatellite instability may acquire this feature as precancers; and (c) monoclonal endometrial precancers have the morphology of hyperplasias, which vary in the extent of cytological atypia and degree of architectural complexity.

Adenocarcinoma↗
PubMed1997

Microsatellite instability is uncommon in uterine serous carcinoma.

Thirty-four uterine serous carcinomas, a type of endometrial carcinoma with aggressive behavior and a high frequency (90%) of p53 gene mutations, were analyzed for microsatellite instability (MI). Genomic DNA isolated from paired normal and tumor tissue was analyzed at eight microsatellite loci (D2S119, D2S123, D2S147, D10S197, D13S175, D18S58, D18S69, and ATn) located on four different chromosomes. All 34 tumors failed to meet the criteria for MI, defined as an alteration in the size of at least two of the microsatellite loci in tumor DNA when compared with normal DNA. Only three tumors demonstrated a shift in the size of a single microsatellite locus. Previously we reported MI in 20% of uterine endometrioid carcinomas, the most common type of endometrial carcinoma. The observed difference in the MI frequency between endometrioid and serous carcinoma is statistically significant (P = 0.003). Our data demonstrate that MI is uncommon in uterine serous carcinoma and support that different pathogenetic mechanisms are involved in the development of the two most common types of endometrial carcinoma.

Aged↗
PubMed1998

Allelic deletion in 11p15 is a common occurrence in esophageal and gastric adenocarcinoma.

BACKGROUND: Esophageal adenocarcinoma and gastric adenocarcinoma have distinct epidemiologic characteristics, but they are morphologically identical and sometimes clinically indistinguishable. Recent work in molecular oncology suggests that cancer types have distinct molecular genetic profiles that may explain their biologic differences. Gastric adenocarcinoma has previously been shown to have a relatively high rate of deletion in chromosome 11. To determine whether similar genetic loci are involved in esophageal adenocarcinoma, we assayed for genetic loss in chromosome 11 in samples of these cancers. METHODS: Dissection of neoplastic and nonneoplastic tissue was performed under direct microscopic visualization from histologic sections of 15 gastric adenocarcinomas and 15 esophageal adenocarcinomas. After DNA extraction, polymerase chain amplification products of a series of polymorphic microsatellite markers on chromosome 11 were analyzed by polyacrylamide gel electrophoresis. Tumor specific chromosomal deletion was signaled by the loss of microsatellite alleles. RESULTS: A panel of 3 polymorphic markers in 11p15 revealed overall incidences of loss of heterozygosity (LOH) of 53.3% in esophageal adenocarcinomas and 61.5% in gastric adenocarcinomas. A panel of 3 polymorphic markers in 11q22-23.3 revealed overall incidences of LOH of 14.3% in esophageal adenocarcinomas and 31% in gastric adenocarcinomas. Diffuse microsatellite instability, which was consistent with a replication error phenotype, was found in 2 of 15 (13.3%) gastric adenocarcinomas but was not deleted in esophageal adenocarcinomas. CONCLUSIONS: Esophageal and gastric adenocarcinoma have a similar significant incidence of genetic loss in 11p15. This is suggestive of the presence of a tumor suppressor gene that may be inactivated in both tumor types.

Adenocarcinoma↗
PubMed1986

Putative reverse transcriptase intermediates of human hepatitis B virus in primary liver carcinomas.

Nucleocapsid-pol fusion proteins have been detected by serological screening hepatocellular carcinoma tissues that contain hepatitis B virus (HBV) DNA. The existence of these fusion proteins suggests that HBV may synthesize its reverse transcriptase in a fashion analogous to the way that retroviruses synthesize and process a precursor. The accumulation of HBV reverse transcriptase intermediates in tumorous tissues and not in other tissues may be related to the absence of viral core particles and possibly contributes to tumor development.

Animals↗
PubMed1999

Tallimustine lesions in cellular DNA are AT sequence-specific but not region-specific.

Tallimustine (FCE 24517) is an AT-specific alkylating antitumor derivative of distamycin. This study examined levels of tallimustine lesions in intracellular DNA, their sequence- and region-specificity, and the long-range distribution of the drug binding motif. Tallimustine adducts in DNA converted to strand breaks by heating allowed the quantitation of drug lesions. In bulk DNA of intact human leukemia CEM cells, tallimustine formed 0.15 +/- 0.04 and 0.64 +/- 0.18 lesions/kbp at 5 and 50 microM, respectively. These lesions represent monoadducts as no interstrand cross-links or DNA-protein cross-links were detected. Tallimustine adducts in intracellularly treated DNA showed a general preference for sequences with T-tracts, suggesting a propensity for intrinsically bent motifs. Major drug-adducted sites identified by repetitive primer extension, included 5'-TTTTGPu-3' and 5'-TTTTGC-3' motif. Despite the high specificity at the nucleotide level, tallimustine did not differentiate among bulk DNA and three discrete AT-rich regions of genomic DNA examined by quantitative PCR stop assay with lesion frequencies ranging from 0.23 to 0.39 lesions/kbp at 25 microM drug. In comparisons of lesion frequencies and cytotoxicity, tallimustine adducts are approximately 50 times more lethal than relatively nonsequence specific cisplatin adducts but are >100 times less lethal than lesions by an unrelated AT-specific drug, bizelesin. However, the 5'-TTTTGPu-3' motifs targeted by tallimustine are relatively infrequent and scattered throughout the genome. In contrast, the motifs 5'-T(A/T)(4)A-3' motifs targeted by bizelesin, while also infrequent, cluster in defined AT-rich islands. The lack of region-specificity may be the reason tallimustine adducts, despite high AT-specificity at the nucleotide level, are less lethal than region-specific bizelesin adducts.

Adenine↗
PubMed1999

Detection of p16 gene alteration in cervical cancer using tissue microdissection and LOH study.

The p16 gene was identified as cyclin-dependent kinase inhibitor (CDKI) and this may negatively regulate the cell cycle by acting as a tumor suppressor. Using tissue microdissection, the molecular changes at p16 and Rb genes were analysed in the spectrum of disease from dysplasia to invasive cancer of the uterine cervix. Six of 27 (22%) cases informative for D9S171 and IFNA of 9p21-22 marker (p16INK4a) showed loss of one or both alleles in at least one of these loci. LOH of pRb was detected in 29% (5/17). Gene alterations at p16 and pRb loci were only detectable in some cases of HPV-16/18 DNA positive cervical cancer. Three cases demonstrated mutational changes of p16INK4a, and the alterations were determined to be G to T shift, suggesting transitional missense mutation. In summary, the inactivation of the p16/cdk-cyclin/Rb cascade may play an additional role during the malignant progression in HPV-16/18 positive cervical cancers.

Carcinoma, Squamous Cell↗