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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The familial occurrence of head and neck cancers supports the role of heredity in this disease group. The roles of environmental and genetic factors are difficult to separate. There are several well-characterized entities, however, that are associated with risk and prognosis of head and neck cancer, including Lynch-II syndrome, Bloom syndrome, Fanconi's anemia, xeroderma pigmentosum, ataxia telangiectasia, and Li-Fraumeni syndrome. Mutagen-induced chromosomal damage is associated with an increased risk of multiple primary neoplasms and upper aerodigestive tract cancers. A possible reduction of genotoxicity, mediated by micronutrients, was demonstrated in vitro. Sister chromatid exchanges and micronuclei are useful exposure and disease markers. Metabolic changes (acetylation, DBQ phenotype, and the AH locus polymorphism) have been found to be associated with cancer of the upper aerodigestive tract. Most associations between histocompatibility antigens and solid tumors are relatively weak, probably because of the masking effects of environmental factors. Infections by HPV, EBV, and HSV have a causative or predisposing role in several types of head and neck cancer. Amplification and rearrangement of oncogenes may also play a role in carcinogenesis, and oncogene amplification may be associated with aggressive tumor behavior and unfavorable clinical prognosis. Ploidy of tumors seems to be an important determinant of survival and response to therapy.
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PMID:Hereditary and environmental factors associated with risk and progression of head and neck cancer. 140 93

Tumors derived from a Li-Fraumeni syndrome cancer-susceptible family were examined for expression of the retinoblastoma susceptibility gene (RB). Whereas RB expression was normal in a primary breast carcinoma and its metastases from one member of this family, overexpression of RB was found in an adrenocortical carcinoma from another family member. This was in contrast to normal RB expression in normal tissue of this patient, the adrenocortical adenocarcinoma cell line SW-13, and the fibroblast cell line MRC-5, and low level RB expression in normal adrenal tissue. The overexpression in the adrenocortical carcinoma resulted in increased synthesis of the RB-encoded protein and did not appear to be associated with RB amplification or rearrangement. This result is novel as it is usually the loss of expression or production of an altered RB transcript exhibiting deletions that is associated with carcinogenesis. In light of the recent discovery of p53 point mutations in the affected Li-Fraumeni syndrome family members tested, RB overexpression may constitute a secondary event in Li-Fraumeni syndrome tumorigenesis.
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PMID:Overexpression of the retinoblastoma gene in a familial adrenocortical carcinoma. 175 10

Several familial cancer syndromes have been identified. The syndrome of sarcomas, breast cancer and other neoplasms, known as Li-Fraumeni syndrome, is characterized by several different neoplasms presenting at young ages with autosomal dominant transmission and a high incidence of second primaries. In this paper, we studied six generations (51 people) of the family of a 24-year-old man with osteogenic sarcoma of the mandible. Twelve malignancies in 11 people, including several rare tumors, were revealed. Mean age of presentation was 24 years old. Nine of the 11 patients died of disease. One developed a second primary. Two tumors presented in the head and neck. Transmission was autosomal dominant. The karyotypes of two family members were normal. Identification of Li-Fraumeni syndrome in a family is important in determining appropriate follow-up for the patient and family. Such families are models for studying carcinogenesis.
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PMID:Family cancer syndrome: a study of the kindred of a man with osteogenic sarcoma of the mandible. 224 14

To examine the mechanisms of immortalization in human cells, normal human diploid fibroblasts (WHE-7) and skin fibroblasts from a patient with Li-Fraumeni syndrome (MDAH 087) and a mutant p53 allele were treated with aflatoxin B1 (AFB1). Exogenous metabolic activation of AFB1 with rat liver post-mitochondrial supernatant (PMS) was used and the optimal treatment conditions needed were determined by the inducibility of unscheduled DNA synthesis. The same degree of cytotoxicity was observed with MDAH 087 cells and normal WHE-7 cells treated with AFB1 at 0.1, 0.3 or 1 microgram/ml for 2 h with a 2% PMS mixture. All WHE-7 cell cultures (AFB1-treated and controls) failed to escape from senescence, whereas three out of nine AFB1-treated cultures of MDAH 087 cells escaped senescence. MDAH 087 cells treated with 0.1 microgram/ml of AFB1 two or three times initially decreased in growth approximately 40 days [10 population doublings (PD)] after the first treatment. However, the cells recovered with faster growth rates after approximately 100 additional days and grew continuously. Both cultures were immortal, defined as continuous growth for over 300 PD. Cells treated once with 0.3 microgram/ml of AFB1 also escaped senescence, although they had about a 230 day time lag before restoration of cell growth. The three AFB1-treated cell lines exhibited altered morphologies, chromosome aberrations (numerical and structural aberrations) and loss of the wild-type p53 allele. Although immortal, the cells were non-tumorigenic in nude mice. Spontaneous immortalization of untreated MDAH 087 was not observed in this study. The results indicate that AFB1 treatment of cells from a Li-Fraumeni patient, but not cells from normal individuals, can induce immortalization. This model may be useful for studying mechanisms of chemically induced immortalization.
Carcinogenesis 1995 Jan
PMID:Aflatoxin B1-induced immortalization of cultured skin fibroblasts from a patient with Li-Fraumeni syndrome. 783 2

The study of rare families in which a variety of cancers occur, usually at an early age and with patterns consistent with a common hereditary mechanism, has contributed much to our understanding of the process of carcinogenesis. So far, genes identified as having a role in cancer predisposition in these families have also been important in the histogenesis of sporadic cancers. In the two most clearly defined cancer family syndromes, the Li-Fraumeni syndrome and Lynch syndrome II, the genes involved predispose to diverse but specific constellations of cancers. Genes associated with site-specific familial cancer clusters may also give rise to increased susceptibility to other cancers, and site-specific clusters may represent one end of a spectrum. A consistent feature of familial cancer syndromes is the variable expression within and between families. A challenge for the future will be to determine other factors which may interact with the principal genes involved, giving rise to this variability.
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PMID:Familial cancer syndromes and clusters. 798 44

Thirty-seven ovarian cancer-prone families have been identified through a French co-operative network. Three main clinical presentations were observed: site-specific ovarian cancer, breast/ovarian carcinoma syndrome and Lynch syndrome II. An additional kindred with features of Li-Fraumeni syndrome is reported. It is expected that a better understanding of the mechanisms of carcinogenesis will allow the development of new methods of screening and treatment. With this aim, recent studies have mapped the gene for early-onset familial breast cancer and breast/ovarian carcinoma syndrome to the same locus in the chromosome 17q12-q23 region. Results from linkage analysis of two breast/ovarian carcinoma families and three breast cancer families favour the hypothesis of genetic heterogeneity among breast and ovarian tumors.
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PMID:Familial ovarian carcinoma: pedigree studies and preliminary results from linkage analysis. 817 63

Dermal fibroblast strains cultured from affected members of a cancer-prone family with Li-Fraumeni syndrome (LFS) harbor a point mutation in one allele of the p53 tumor suppressor gene, resulting in loss of normal p53 function. In this study we have examined the ability of these p53-deficient strains to carry out the long-patch mode of excision repair, mediated by DNA polymerases delta and epsilon, after exposure to 60Co gamma radiation or far ultraviolet (UV) (chiefly 254 nm) light. Repair was monitored by incubation of the irradiated cultures in the presence of aphidicolin (apc) or 1-beta-D-arabinofuranosylcytosine (araC), each a specific inhibitor of long-patch repair, followed by measurement of drug-induced DNA strand breaks (reflecting non-ligated strand incision events) by alkaline sucrose velocity sedimentation. The LFS strains displayed deficient repair capacity in response to both gamma rays and UV light. The repair anomaly in UV-irradiated LFS cultures was manifested not only in the overall genome, but also in the transcriptionally active, preferentially repaired c-myc gene. Using autoradiography we also assessed unscheduled DNA synthesis (UDS) after UV irradiation and found this conventional measure of repair replication to be deficient in LFS strains. Moreover, both apc and araC decreased the level of UV-induced UDS by approximately 75% in normal cells, but each had only a marginal effect on LFS cells. We further demonstrated that the LFS strains are impaired in the recovery of both RNA and replicative DNA syntheses after UV treatment, two molecular anomalies of the DNA repair deficiency disorders xeroderma pigmentosum and Cockayne's syndrome. Together these results imply a critical role for wild-type p53 protein in DNA polymerase delta/epsilon-mediated excision repair, both the mechanism operating on the entire genome and that acting on expressed genes.
Carcinogenesis 1996 Apr
PMID:Faulty DNA polymerase delta/epsilon-mediated excision repair in response to gamma radiation or ultraviolet light in p53-deficient fibroblast strains from affected members of a cancer-prone family with Li-Fraumeni syndrome. 862 79

We have previously reported the use of a recombinant nonreplicating adenovirus type 5, Ad5HCMVsp1 lacZ, expressing the lacZ gene under control of the human cytomegalovirus (HCMV) immediate early promoter to assess repair of a UV-damaged reporter gene in UV and heat shock (HS) treated cells. Heat shock and UV-enhanced reactivation (HSER and UVER) of beta-galactosidase (beta-gal) activity for UV-irradiated Ad5HCMVsp1 lacZ in normal human fibroblasts involved the transcription coupled repair (TCR) pathway. However, this inducible DNA repair response was absent in p53 deficient tumour cell lines. In order to examine further the requirement for p53 in HSER and UVER, we have examined host cell reactivation (HCR) of the reporter construct in HS treated, UV treated and mock treated Li-Fraumeni syndrome (LFS) fibroblasts, which are heterozygous for a p53 mutation, and immortalized LFS cell sublines, which express only mutant p53. HCR of beta-gal activity for UV-irradiated Ad5HCMVsp1 lacZ was normal in all LFS cells examined. However, HCR of beta-gal activity for UV-irradiated Ad5HCMVsp1 lacZ was elevated by pretreatment of cells with either UV or HS in normal diploid human fibroblasts, but not in LFS cells. LFS cells appear to be deficient in an inducible pathway which stimulates repair of the reporter gene. These results support a role for p53 in a HS and UV inducible DNA repair response in human cells which is dependent on TCR.
Carcinogenesis 1997 Feb
PMID:Wildtype p53 is required for heat shock and ultraviolet light enhanced repair of a UV-damaged reporter gene. 905 14

A comprehensive mutational scanning test for the p53 coding region based on multiplex PCR and two-dimensional DNA electrophoresis was designed and evaluated. In a 2-step multiplex PCR, the p53 coding region (exons 2-11) was amplified as a single 8646-bp fragment by long-distance PCR in step one. This fragment served as a template for the subsequent co-amplification of the individual exons in two multiplex groups in step two. The multiplex products were then separated, first on the basis of size in non-denaturant polyacrylamide gels and then on the basis of sequence by denaturing gradient gel electrophoresis (DGGE). Primers for optimal PCR, melting behavior and 2-D gel distribution were designed using a recently developed computer program. The resulting two-dimensional gene scanning (TDGS) test was evaluated by screening, in a blinded fashion, 29 coded DNA samples from Li-Fraumeni syndrome patients with previously identified germline mutations. All mutations were correctly detected. This assay provides an accurate, cost-effective and non-radioactive method for simultaneous mutational scanning of all p53 coding exons.
Carcinogenesis 1998 Jun
PMID:Comprehensive mutational scanning of the p53 coding region by two-dimensional gene scanning. 966 34

Gastric cancer frequently occurs in family members with hereditary non-polyposis colorectal cancer (HNPCC) and Li-Fraumeni syndrome (LFS) and germline E-cadherin mutations were recently identified in a subset of familial gastric cancers. Thus, families with an aggregation of gastric cancers were recruited by reviewing the genealogical trees of 3632 patients with gastric cancer. The criteria for recruiting such families were the following: at least three relatives should have gastric cancer and one of them should be a first degree relative of the other two; at least two successive generations should be affected; in one of the relatives gastric cancer should be diagnosed before age 50. Thirty-one cases (0.9%) fitted all three of these criteria. There were only gastric cancer patients in 18 of the 31 families and there were no families that fitted clinical criteria of HNPCC or LFS. Paraffin-embedded tissues were available in 29 probands and DNA was successfully isolated for molecular analyses in 13 probands. RER phenotype was detected in three (23%) cases, whereas germline p53 mutations were detected in none of 13 cases. A germline E-cadherin mutation was detected in one of three diffuse types and none of 10 intestinal types, however, a mutation resulting in the replacement of Gly by Val was detected in the precursor sequence. Thus, although familial clustering of gastric cancer occurs in approximately 1% of gastric cancer patients, germline mutations of the DNA mismatch repair, p53 and E-cadherin genes do not significantly contribute to such a clustering.
Carcinogenesis 1999 Jun
PMID:Familial gastric cancer: clinicopathological characteristics, RER phenotype and germline p53 and E-cadherin mutations. 1035 99


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