PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Li-Fraumeni Syndrome”

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 37 records · Page 2Linked to original sources
PubMed1992

Hereditary and environmental factors associated with risk and progression of head and neck cancer.

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.

Environment↗
PubMed1992

Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers.

BACKGROUND: Mutations of the tumor suppressor gene p53 have been identified in breast cancer cell lines, and some breast carcinomas are detectable by immunohistochemical assay because of p53 protein accumulation. PURPOSE: This study was designed to determine whether p53 protein accumulation in breast cancers correlates with p53 gene mutation, with survival, and with five pathobiologic factors associated with prognosis. METHODS: IgG1 monoclonal antibody to human p53 protein (PAb 1801) and immunohistochemical methods were used to detect p53 protein accumulation in archival formalin-fixed, paraffin-embedded, randomly selected carcinomas. We studied 295 invasive ductal carcinomas from the Massachusetts General Hospital; 151 were determined to be sporadic (not hereditary). We also studied 97 invasive ductal carcinomas--21 sporadic and 76 familial (hereditary)--from Creighton University. In addition, we examined 31 archival in situ carcinomas, 15 snap-frozen invasive ductal carcinomas, primary cell cultures from three benign breast tissue samples, and breast carcinoma cell lines MDA-MB-231 and MDA-MB-468. RESULTS: Nuclear p53 protein was observed in 16% of the 31 in situ carcinomas, 22% of the 172 sporadic carcinomas, 34% of the 50 tumors from patients with familial breast cancer, 52% of the 23 tumors from patients with the familial breast and ovarian cancer syndrome, and all three tumors from two patients with the Li-Fraumeni syndrome. There was complete concordance between p53 gene mutation and p53 protein accumulation in the 15 snap-frozen carcinomas and in both breast carcinoma cell lines. Statistically significant associations of p53 protein accumulation with estrogen receptor negativity and with high nuclear grade were found. There were statistically significant associations, independent of other prognostic factors, between p53 protein accumulation and metastasis-free and overall survival, for randomly accrued and for both sporadic and familial tumors. CONCLUSIONS: Immunohistochemically detected p53 protein accumulation was an independent marker of shortened survival and was seen more often in familial than in sporadic carcinomas. Our findings also suggest a correlation between p53 protein accumulation and p53 gene mutation.

Age Factors↗
PubMed2026

Parental Perspectives and Experiences with Genetic Testing and Surveillance for Cancer Predisposition in Healthy Young Children.

OBJECTIVES: To evaluate parental experiences following diagnosis of a cancer predisposition syndrome (CPS) in childhood and to assess parental perspectives on population-based genomic newborn screening (gNBS) for CPS. STUDY DESIGN: Participants were guardians of children diagnosed with a CPS by age 8, for whom cancer surveillance was recommended, and who had no history of cancer before the CPS diagnosis. Participants completed a demographic survey, genetic knowledge assessment, and a semistructured qualitative interview. Thematic analysis was performed on interview transcripts. Clinical data were abstracted from medical records. RESULTS: We enrolled 25 parents of children with 7 different CPS, including Li-Fraumeni syndrome (43%), familial adenomatous polyposis (14%), nevoid basal cell carcinoma syndrome (11%), and Beckwith-Wiedemann syndrome (11%). Parents characterized receiving a CPS diagnosis as emotionally challenging but also felt empowered by engagement in proactive cancer surveillance. They identified logistical, emotional, physical, and financial burdens of surveillance; however, most perceived that these burdens were outweighed by the medical and emotional advantages. The majority endorsed implementation of gNBS for pediatric cancer risk. CONCLUSIONS: Parents of presymptomatic children with a CPS experience both psychological distress and benefits following a genetic diagnosis. Despite the burdens of surveillance, parents express support for early genomic identification of cancer risk. These findings have implications for the care of children with CPS and inform implementation of population-based gNBS for CPS.

Humans↗
PubMed1992

Genetic predisposition to breast cancer.

Breast cancer is the most common cancer among American women. Because metastatic breast cancer is an incurable disease, efforts to decrease breast cancer mortality have focused on early detection and improved treatment. Identification and analysis of a specific genetic susceptibility could permit detection of susceptible women and greatly increase the understanding of the initial step that eventually leads to cancer. Because susceptibility loci have been recognized as sites that often are altered during tumor progression, the identification and cloning of such loci could be important in developing cancer therapies. In this article, the progress being made in segregation analysis, linkage analysis, and cloning of breast cancer susceptibility loci is reviewed. The evidence for genetic inheritance is most consistent with dominant inheritance for at least three major susceptibility loci. Proliferative breast disease has been hypothesized to be an inherited lesion in breast cancer kindreds with both premenopausal and postmenopausal probands. Currently, there are many genetic markers for mapping the human genome. Technologic advances have progressed from restriction fragment length polymorphisms to highly polymorphic markers. Using this technology, breast cancer susceptibility in some kindreds with an early onset has been shown to be linked to chromosome 17q. Gene isolation eventually will follow with an increased understanding of the percentage of breast cancer cases that are a result of this genetic locus. Li-Fraumeni syndrome, which often is expressed as breast cancer, is due to mutations in the p53 gene. Characterization of the syndrome and its relationship to the altered gene should proceed rapidly. There is also a group of families exhibiting a genetic susceptibility that is not due to either of these loci. Together, these findings indicate that there are at least three separate major loci segregating for breast cancer susceptibility. With the current initiative to map and sequence the entire human genome and the advances that recently have been reported, a detailed molecular understanding of breast cancer predisposition can be envisaged.

Age Factors↗
PubMed1992

Site-specific binding of wild-type p53 to cellular DNA is inhibited by SV40 T antigen and mutant p53.

Wild-type p53 protein was shown to bind specifically to DNA sequences within SV40 (Bargonetti et al. 1991), the human ribosomal gene cluster (RGC) (Kern et al. 1991a), and the murine muscle creatine kinase gene (MCK) (Zambetti et al. 1992). However, a direct comparison of these three sites was not performed. Here we demonstrate, by filter binding and gel mobility-shift assays, that wild-type p53 binds with similar affinities to MCK and RGC sites but less tightly to the SV40 site. We examined the effects of two candidate regulators of p53 function, SV40 large T antigen and oncogenic mutant p53, on the binding of wild-type p53 to RGC DNA. We show that wild-type T antigen prevents p53 from binding to the RGC site under all conditions tested. Moreover, two temperature-sensitive mutant SV40 T antigens, which fail to transform cells at the nonpermissive temperature, prevent p53 from binding to the RGC site at the permissive, but not at the restrictive, temperature. The ability of complexes containing wild-type p53 and tumor-derived mutant p53 proteins to bind to RGC DNA varies according to the position of the mutation. Complexes containing wild-type and either his175 or his273 mutant p53 proteins are completely unable to bind to the RGC DNA sequence. Interestingly, a complex containing wild-type p53 and the trp248 mutant p53 characteristic of Li-Fraumeni syndrome patients displays nearly wild-type levels of binding. Perhaps this mutant allele can be tolerated in these individuals because the wild-type mutant p53 complex maintains the ability to bind to DNA. Our data indicate that the oncogenic potential of both T antigen and some mutant p53 proteins is the result of their ability to block binding of wild-type p53 to DNA.

Animals↗
PubMed1992

Familial breast cancer.

Familial clustering of breast cancer has been recognised for over a century but until recently a genetic basis has been suspected rather than proven. Epidemiological studies have tended to support the view that an autosomal dominant gene, with high but incomplete penetrance, accounts for most breast cancer families. However, it is likely that several different predisposing genes are present within most populations. Difficulties arise in a conventional 'linkage mapping' approach to identifying these genes, first, because it is not clear that genetically homogeneous groups of families can be recognised on the basis, for example, of mean age of onset or pattern of other cancers within the kindred and, second, because breast cancer is so common (affecting almost one in twelve women) that large affected kindreds are likely to include an admixture of sporadic (non-genetic) cases. Cytogenetic and 'Loss of Heterozygosity' (LOH) studies in sporadic breast cancers have pointed to several candidate loci for breast cancer genes but there is no clear consensus from these two approaches that might direct attention to any prime target region. Recent reports of tight linkage between familial breast cancer (early onset) and breast/ovarian cancer (regardless of mean age of onset) and a locus on chromosome 17q21 defined by the anonymous probe CMM86, have not been confirmed in detail but have led to the identification of a locus some 15 Mb centromeric of CMM86 that gives a high positive lod at very low recombination fraction in fifteen Edinburgh breast and breast/ovarian cancer families. The disease in the majority of such families therefore appears to be attributable to a mutant gene at 17q12-21. A much smaller proportion of familial breast cancer is accounted for by mutations in the p53 gene (17p13). Not all such families fulfil the criteria for Li-Fraumeni syndrome and not all of the inherited mutations lie within exon 7 of p53. Counselling of members of breast cancer families becomes more exacting as these genetic lesions are identified. It is essential to extend the collection of data and tissue (blood or fixed pathology material) as widely as possible to confirm linkage to a specific locus within each individual kindred, to define the precise mutation and to establish the cancer phenotype and its penetrance. In the course of these studies a substantial population of women at high risk of breast (and other) cancer will be identified. Resources should be directed to this population so that optimum procedures for screening and prevention can be developed.

Breast Neoplasms↗
PubMed1992

Stem cell regulation, tissue ontogeny, and oncogenic events.

The number of necessary oncogenic events is a function of tissue ontogeny. A minimum of two events appears to suffice for certain embryonal tumors, leukemias, and lymphomas for which the target tissues normally show stem cell proliferation. Other tumors, including those featured in the Li-Fraumeni syndrome, arise in target tissues whose stem cells are conditionally stimulated to proliferate, as in response to hormones, and involve more events. The most complex cancers include most carcinomas, which arise in renewal tissues whose stem cells do not normally proliferate. The number of necessary oncogenic events appears to increase with the number of controls on proliferation.

Cell Division↗
PubMed1992

No evidence for germline mutations in exons 5-9 of the p53 gene in 25 breast cancer families.

Recent studies have demonstrated that families with the Li-Fraumeni syndrome carry inherited point mutations of the p53 gene. In the present study 25 families with strong histories of breast cancer were screened for the presence of such mutations. Polymerase chain reaction products of exons 5-9 of the p53 gene were examined by single-stranded conformational polymorphism analysis and, in addition, exon 7 was further screened by direct sequencing. No mutations were detected in constitutive DNA by either method. These results indicate that familial breast cancer does not usually result from germline point mutations in the p53 gene.

Breast Neoplasms↗
PubMed1992

Screening for germ line TP53 mutations in breast cancer patients.

The constant denaturant gel electrophoresis technique was used to screen for TP53 germ line mutations in 237 women with breast carcinoma (167 unselected patients, 30 patients with at least one first-degree relative with breast cancer, and 40 women diagnosed with breast cancer before age 35). A germ line mutation at codon 181 was noted in one of the unselected patients and a codon 245 mutation in one of the early-onset patients. Both had a family history of breast cancer and other malignancies suggestive of Li-Fraumeni syndrome. The codon 245 mutation was also present in this patient's affected mother.

Adult↗
PubMed1992

p53 mosaicism with an exon 8 germline mutation in the founder of a cancer-prone pedigree.

Changes in the tumor-suppressor gene p53 are frequently acquired during the course of malignant development of human tumors. Recently, constitutional heterozygous mutations in p53 exon 7 have been identified as the primary cause of cancer predisposition in cases of the familial Li-Fraumeni cancer syndrome. These findings underline the need for extensive mutation screening in families with high cancer incidence. This report describes the detection and follow-up by two-dimensional single-strand conformation polymorphism analysis (2DSSCP) of a new germline mutation of p53 exon 8 in a case of suspected Li-Fraumeni syndrome. Although a high cancer incidence had been reported in the family history of the father of siblings suffering from brain tumor and rhabdomyosarcoma, a constitutional heterozygous p53 mutation was identified only in the affected children. Retrospective analysis of archival tissue of a half-sister who died several years ago from a tumor of previously uncertain diagnosis revealed the same mutation. The mutation had therefore occurred in the germ cells of the mother, who thus appears to be a mosaic. The cancer predisposition of the paternal ancestors must have been due to other factors.

Adolescent↗
PubMed1992

Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53.

Gene amplification occurs at high frequency in transformed cells (10(-3)-10(-5)), but is undetectable in normal diploid fibroblasts (less than 10(-9)). This study examines whether alterations of one or both p53 alleles were sufficient to allow gene amplification to occur. Cells retaining one wild-type p53 allele mimicked the behavior of primary diploid cells: they arrested growth in the presence of drug and failed to demonstrate amplification. Cells losing the second p53 allele failed to arrest when placed in drug and displayed the ability to amplify at a high frequency. Thus, loss of wild-type p53 may lead to amplification, possibly caused by changes in cell cycle progression. Other determinants can by-pass this p53 function, however, since tumor cells with wild-type p53 have the ability to amplify genes.

Animals↗
PubMed1992

p53 mutations in breast cancer.

We have identified and analyzed 41 mutations in p53 in sporadic breast tumors from 136 unselected breast cancer patients and estimate that approximately 40% of such tumors contain p53 mutations. The frequency of G-T transversions and the incidence of guanosine mutations in the nontranscribed strand of the p53 gene were found to be higher than expected, and we suggest, therefore, that exogenous carcinogens have an etiological role in sporadic breast cancers. Mutations were recorded in 44 codons of the p53 gene, with no obvious mutational hot-spots, although mutations at codons 175, 194, 273, and 280 accounted for 25% of the changes. One germ-line mutation was found in 136 patients and so we conclude that constitutional mutation of p53 may be an uncommon etiological factor in breast cancer.

Base Composition↗
PubMed1992

A significant proportion of patients with osteosarcoma may belong to Li-Fraumeni cancer families.

We studied the pedigrees of 17 index patients with osteosarcoma, recording malignant disease and cause of death for first- and second-degree relatives. There were seven cancers and five cancer deaths per 2151.5 person-years in first-degree relatives of osteosarcoma patients under the age of 50 years, a significantly greater incidence than in an age- and sex-matched population group (p < 0.001). This excess of malignancy was largely due to two families which fulfilled the criteria for the Li-Fraumeni cancer family syndrome. Both of these families were shown to have the genetic alterations in the p53 gene which have been implicated in this syndrome. Our study suggests that orthopaedic surgeons seeing new cases of osteosarcoma should arrange screening for familial malignancy.

Adolescent↗