The Li-Fraumeni syndrome: from clinical epidemiology to molecular genetics.

The goal of this review is to demonstrate the effective interaction of epidemiologic methods and molecular genetics in the identification of familial cancer predisposition. The example involves a hospital-based population of childhood soft tissue sarcoma patients who were less than age 16 years at diagnosis at the University of Texas M. D.

Developing a Reliable Testing Protocol for the Hydra-Fitness Upper Body OmniTron.

Evaluation of the reliability of musculoskeletal testing equipment is an important step in establishing the usefulness of an assessment device's data. The purposes of this study were to determine the reliability of a specific upper body OmniTron testing protocol and to estimate reliabilities for several other protocols in order to determine the optimal one. After upper body warm-up, 32 subjects (22 men, 10 women; mean age = 20.

Smoking habits in survivors of childhood and adolescent cancer.

Because of their increased risk for second cancers, childhood cancer survivors are people who really should not smoke, but available evidence suggests that they do. We studied the smoking habits of long-term childhood cancer survivors in data collected from 1289 adult survivors of childhood cancer and 1930 of their sibling controls. Survivors were diagnosed with cancer between 1945 and 1974 when they were less than 20 years old.

Segregation analysis of 159 soft tissue sarcoma kindreds: comparison of fixed and sequential sampling schemes.

In this study we compared parameter estimates and model hypotheses in pedigree data collected by fixed sampling with estimates and hypotheses derived by sequential sampling. Employing a fixed sampling scheme, we previously analyzed data on relatives of 159 childhood sarcoma patients. We have now extracted from that data set individuals who would have been included in a sequentially sampled study.

A germ line mutation in exon 5 of the p53 gene in an extended cancer family.

Germ line p53 point mutations have been reported for some families with Li-Fraumeni syndrome, a syndrome characterized by a dominantly inherited increased susceptibility for the development of early age of onset neoplasms of diverse origin in multiple family members. All of the initially reported p53 germ line mutations have been found exclusively within a single conserved, nonpolymorphic region of the gene between condons 245 and 258. The restricted distribution of these inherited mutations has led to speculation that germ line p53 mutations have unique properties [B.

High-fiber diet reduces serum estrogen concentrations in premenopausal women.

The effect of dietary fiber on serum estrogen concentrations was studied in 62 premenopausal women. Their estimated daily dietary fiber intake was increased from an average of approximately 15 g to 30 g/d by supplementation with wheat, oat, or corn bran. This was done without any significant decrease in dietary fat consumption.

Familial predisposition to Wilms tumor does not segregate with the WT1 gene.

Wilms tumor (WT) is one of the more common childhood cancers. A small fraction of WT occurs in association with aniridia, genitourinary abnormalities and mental retardation, the WAGR syndrome, and these cases often are accompanied by a constitutional deletion of all or part of band 11p13. Recently a WT susceptibility gene (WT1), localized to 11p13, has been isolated and shown to be inactivated in some sporadic WTs.

Genetic characterization of the APC locus involved in familial adenomatous polyposis.

Familial adenomatous polyposis is a rare disease inherited in a Mendelian dominant fashion. It is characterized by the occurrence of more than 100 adenomatous polyps in the large bowels of affected individuals. The genetic defect responsible for adenomatous polyposis resides at a locus called APC which has been localized to the long arm of human chromosome 5.

Evidence for WT1 as a Wilms tumor (WT) gene: intragenic germinal deletion in bilateral WT.

The inactivation of two alleles at a locus on the short arm of chromosome 11 (band 11p13) has been suggested to be critical steps in the development of Wilms tumor (WT), a childhood kidney tumor. Two similar candidate WT cDNA clones (WT33 and LK15) have recently been identified on the basis of both their expression in fetal kidney and their location within the smallest region of overlap of somatic 11p13 deletions in some tumors. These homozygous deletions, however, are large and potentially affect more than one gene.

Smallest region of overlap in Wilms tumor deletions uniquely implicates an 11p13 zinc finger gene as the disease locus.

The development of Wilms tumor (WT) has been associated with the inactivation of a "tumor suppressor" locus in human chromosome 11 band p13. Several WTs that exhibit homozygous deletions of an 11p13 candidate WT gene in its entirety have been reported. We report here a partial deletion of the candidate gene which, upon comparison with other documented homozygous deletions, permitted a precise definition of the critical genomic target in Wilms tumor.

In vitro and in vivo effects of N-methyl-3,5-dichloro-benzylamine hydrochloride on Mycobacterium leprae.

The antimicrobial effects of a new benzylamine, ME-93 (N-methyl-3,5-dichloro-benzylamine hydrochloride), alone and in combination with dapsone and rifampicin, have been evaluated in vitro in cell-free culture system and in vivo in mouse foot pad system. Even at 50 micrograms/ml, ME-93 did not completely inhibit the in vitro growth of M. leprae, and the effects were bacteriostatic.

Tumorigenic transformation of spontaneously immortalized fibroblasts from patients with a familial cancer syndrome.

Immortal cell lines arose spontaneously during in vitro culture of initially normal fibroblasts, MDAH041 and MDAH087, from patients with Li-Fraumeni familial cancer syndrome. Fibroblasts from a control donor, MDAH170, maintained a normal morphology and senesced at 31 population doublings. The immortal fibroblasts have several properties of transformed cells.

Genetic epidemiology of childhood brain tumors.

The study goal was to determine the genetic (heritable) contribution to childhood brain tumors (CBT) which cause nearly one quarter of all childhood cancer deaths. Their etiology remains unknown, but previous studies have suggested a proportion of CBT may be heritable. In this study we collected family histories of 243 confirmed CBT patients referred to The University of Texas M.

Spontaneous abnormalities in normal fibroblasts from patients with Li-Fraumeni cancer syndrome: aneuploidy and immortalization.

Families of patients with the Li-Fraumeni cancer syndrome have an inherited pattern of sarcomas and various other types of cancers that follow a dominant mode of transmission, an early age of onset, and exhibit multiple primary tumors. As soft tissue sarcomas (including fibrosarcomas) are frequently observed with this syndrome, the in vitro growth characteristics of fibroblasts derived from skin biopsies of Li-Fraumeni syndrome patients were studied. Control fibroblasts maintained a normal morphology and eventually senesced in culture.

Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.

Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis.

Familial renal cell carcinoma: hereditary or coincidental?

The familial clustering of some cancers may be related to genetic factors, shared carcinogenic exposure among relatives or chance association. In cases of familial renal cell carcinoma identifying those persons at risk for renal tumors is difficult. There have been 28 family aggregates of renal carcinoma reported since 1961 but an abnormality in the constitutional karyotype has been demonstrated in the members of only 1 of these families.

The chemical control of livestock parasites: problems and alternatives.

Over 200 classes of chemical compounds are currently in use for the treatment of livestock parasites. Here Les Strong and Richard Wall review some of the problems arising from the total reliance on chemical control and consider some of the alternative methods that might be given more thought and application.

The current state of oncogenes and cancer: experimental approaches for analyzing oncogenetic events in human cancer.

The development of cancer is a multistage process. The activation of proto-oncogenes and the inactivation of tumor suppressor genes play a critical role in the induction of tumors. Using human cell model systems of carcinogenesis, we have studied how oncogenes, tumor suppressor genes, and recessive cancer susceptibility genes participate in this multistep process.

Parental origin of de novo constitutional deletions of chromosomal band 11p13.

One-half of all cases of Wilms tumor (WT), a childhood kidney tumor, show loss of heterozygosity at chromosomal band 11p13 loci, suggesting that mutation of one allele and subsequent mutation or loss of the homologous allele are important events in the development of these tumors. The previously reported nonrandom loss of maternal alleles in these tumors implied that the primary mutation occurred on the paternally derived chromosome and that it was "unmasked" by loss of the normal maternal allele. This, in turn, suggests that the paternally derived allele is more mutable than the maternal one.