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L C Strong

Publications and source records attributed to L C Strong.

At least 73 records · Page 4Linked to original sources
PubMed1990

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. Normal human cells are resistant to the transforming potential of oncogenes, such as ras oncogenes, which are activated by specific point mutations. Since as many as 40% of some tumor types contain activated ras oncogenes, a preneoplastic transition in multistage carcinogenesis must involve changing from an oncogene-resistant stage to an oncogene-susceptible stage. The analysis of such critical steps in carcinogenesis using rodent systems has usually not represented the human disease with fidelity. In order to study this carcinogenic process, we have developed human cell, in vitro systems that represent some of the genetic changes that occur in cellular genes during human carcinogenesis. Using these systems, we have learned some of the functions of dominant activated-transforming oncogenes, tumor suppressor genes, and cellular immortalization genes and how they influence the carcinogenic process in human cells. Using our understanding of these processes, we are attempting to clone critical genes involved in the etiology of familial cancers. These investigations may help us to develop procedures that allow us to predict, in these cancer families, which individuals are at high risk for developing cancer.

Animals↗
PubMed1990

A panel of restriction fragment length polymorphisms for chromosomal band 11p13.

A panel of seven chromosome 11p13 restriction fragment length polymorphisms (RFLPs) detected by five DNA probes is described. Two alleles were identified for each polymorphism, and Mendelian segregation of alleles was observed. Allele frequencies range from 0.13/0.87 to 0.44/0.56. This panel of 11p13 RFLPs will be useful for linkage studies investigating the role of 11p13 genes in Wilms' tumor, aniridia, and genitourinary anomalies. Additionally, these RFLPs will be important tools for studying tumor-specific 11p13 alterations in Wilms' tumor and other cancers.

Alleles↗
PubMed1990

Definition of the limits of the Wilms tumor locus on human chromosome 11p13.

In a previous report, we described a contiguous restriction map of chromosome band 11p13 that localized the Wilms tumor locus to a small group of NotI fragments. In an effort to identify and isolate the 11p13-associated sporadic Wilms tumor locus, we developed a panel of NotI fragment-specific DNA probes. These probes were selected from genomic libraries constructed using the Chinese hamster ovary-human somatic cell hybrid carrying only human 11p. The libraries were prepared from NotI-digested DNA after size selection by pulsed-field gel electrophoresis. The selected NotI fragments had been previously targeted on the basis of deletion mapping as having a high probability of containing the Wilms tumor locus. We used these newly identified 11p13-specific probes to improve the resolution of the restriction map spanning the Wilms tumor locus. The locus has been defined by a homozygous deletion in a sporadic Wilms tumor. Using these probes, the region of homozygous deletion in this tumor and presumably all or part of the Wilms tumor gene have been confined to two small SfiI fragments spanning less than 350 kb.

Animals↗
PubMed1990

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. Since 1980 we have identified 5 more families in which a total of 12 relatives had renal cell carcinoma. However, peripheral blood karyotypes obtained from the 7 patients and 5 unaffected relatives whom we studied showed no significant abnormalities. With current laboratory techniques it is not possible to differentiate reliably familial renal tumors occurring by chance from those hereditary tumors posing a threat to remaining relatives. Therefore, in families with multiple cases of renal cell carcinoma we recommend that screening be conducted as has been suggested for families with von Hippel-Lindau's disease, with an initial renal ultrasound for family members at age 30 years and repeat examinations every 2 to 3 years.

Adult↗
PubMed1990

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. To investigate whether germinal mutations are seen with equal frequency in maternally versus paternally inherited chromosomes, we determined the parental origin of the de novo germinal 11p13 deletions in eight children by typing lymphocyte DNA from these children and from their parents for 11p13 RFLPs. In seven of the eight cases, the de novo deletion was of paternal origin. The one case of maternal origin was unremarkable in terms of the size or extent of the 11p13 deletion, and the child did develop WT. Transmission of 11p13 deletions by both maternal and paternal carriers of balanced translocations has been reported, although maternal inheritance predominates. These data, in addition to the general preponderance of paternally derived, de novo mutations at other loci, suggest that the increased frequency of paternal deletions we observed is due to an increased germinal mutation rate in males.

Alleles↗
PubMed1989

Radiation sensitivity of cell strains from families with genetic disorders predisposing to radiation-induced cancer.

This investigation was designed to test the hypothesis that skin fibroblasts from patients with genetic disorders characterized by hypersusceptibility to X-ray-induced cancer are sensitive to the cytotoxic or clastogenic effects of X-irradiation in vitro. Cell strains were established from 28 specifically ascertained patients from families with nevoid basal cell carcinoma syndrome, retinoblastoma, or other disorders apparently predisposing to radiation-induced cancer. These included 10 patients with a clear personal or family history of radiation-induced tumors. These cell strains were examined for the cytotoxic effects of X-irradiation in 3 distinct series of separate, blinded experiments, along with a group of 9 similarly coded cell bank controls. Cells from 11 of these patients and 6 controls were studied for sensitivity to X-ray-induced chromosomal aberrations. Seven of the 37 cell strains were moderately hypersensitive to radiation-induced cell killing; 2 of these were from patients with radiation-induced tumors and 1 was a cell bank control. These results suggest that such isolated cases of hypersensitivity probably do not relate to the underlying genetic disorder. Overall, the X-ray response of cells from affected individuals in this study showed no systematic difference from that of cells from nonaffected relatives or cell bank controls for either cytotoxicity or clastogenicity.

Adolescent↗
PubMed1989

Genetic analysis of childhood sarcoma.

A survey of cancer in 159 3-year survivors of childhood soft tissue sarcoma and their relatives revealed a cancer excess in first-degree relatives primarily due to cancers occurring before the age of 35 years and a highly significant excess in relatives of patients with second malignant neoplasms. Tumors of soft tissue and bone, breast, and brain were in excess in relatives and as second malignant neoplasms in patients. To determine the most likely explanation for the observed cancer distribution, we applied segregation analysis under a unified version of the mixed model. The observed data were most compatible with a rare autosomal dominant gene with high penetrance (gene carriers had a 50% probability of cancer by age 30, increasing to 90% by age 60) as compared with a chance occurrence or a multifactorial explanation. We contrasted the relative odds of observing each pedigree under a sporadic, multifactorial, or major gene model, and identified 11 pedigrees in which familial clustering of cancer was significant, with the distribution of cancer strongly favoring a major gene in 9 pedigrees. The tumors in these kindreds have been associated with alterations in specific genetic loci by tumor-specific genetic analysis. In particular, we observed soft tissue sarcoma, osteosarcoma and premenopausal ductal breast carcinoma tumors, perhaps attributable to loss of the Rb-1 suppressor gene on chromosome 13q, in the same patients and families. Study of the cancer predisposition segregating in 10 families by genetic linkage with markers of chromosome 13q and the Rb-1 gene have to date given negative LOD scores at 0 = 0 of Z = -1.2 to -13.0.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Neoplasms↗
PubMed1988

Hepatoblastoma and familial adenomatous polyposis.

Eleven children have been identified as having hepatoblastoma and a family history of adenomatous polyposis, and 14 additional instances of this association have been collected from the literature. Among the 11 survivors of hepatoblastoma in the combined series, adenomatous lesions have been sought in seven and detected in six patients at ages 7 to 25 years. Five of these patients also have congenital hypertrophy of the retinal pigment epithelium, a marker for carriers of the polyposis gene. These findings strengthen the association between hepatoblastoma and familial adenomatous polyposis and have led to the establishment of the Hepatoblastoma-Adenomatous Polyposis Registry.

Adenomatous Polyposis Coli↗
PubMed1988

Long range physical map of the Wilms' tumor-aniridia region on human chromosome 11.

The relationship between genetic alterations at chromosomal band 11p13 and the WAGR (Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome is not clearly understood. To aid our understanding of this relationship, we have constructed a physical map of this region of the genome using pulsed field gel electrophoresis. Fifteen newly identified 11p13-specific probes and four previously reported probes were used to subdivide 11p13 into five intervals defined by overlapping constitutional deletions from several WAGR patients. This new repertoire of DNA probes was used to construct a physical map of this region using the infrequently cutting restriction enzymes MIuI and NotI. This map spans approximately 13 Mb and encompasses deletion and translocation breakpoints associated with genitourinary abnormalities, aniridia, and Wilms' tumor. The map also makes it possible to localize the genes for Wilms' tumor (WT) and aniridia (AN2) to a small number of specific NotI restriction fragments.

Chromosome Mapping↗
PubMed1988

Lack of linkage of familial Wilms' tumour to chromosomal band 11p13.

Wilms' tumour (WT), a paediatric renal neoplasm, affect approximately 1 in 10,000 children. One or both kidneys can be affected and 5-10% of tumours are bilateral. Most tumours occur sporadically; however, around 1% of the cases are familial, with siblings or cousins most often being affected. Familial cases are more frequently bilateral, and familial and bilateral tumours are diagnosed at an earlier age. On the basis of these observations, it was proposed that the development of WT requires two mutations. In most sporadic unilateral WT, both are somatic; in familial and bilateral tumours the first is thought to be germinal. Cytogenetic and molecular studies have demonstrated germinal mutations in WT/aniridia patients and somatic mutations in sporadic WT at chromosomal band 11p13. To investigate whether familial predisposition to WT is due to a germinal 11p13 mutation, we studied a WT family with seen DNA markers that span the 11p13 region. We found that familial WT predisposition was not genetically linked to any of the 11p13 markers. This suggests that the gene involved in familial WT predisposition is outside 11p13 and is distinct from the gene involved in tumorigensis and in WT predisposition in WT/aniridia 11p13-deletion patients.

Chromosomes, Human, Pair 11↗
PubMed1988

Reproductive problems and birth defects in survivors of Wilms' tumor and their relatives.

In a retrospective cohort study of 47 Wilms' tumor survivors and their 77 sibling controls, female survivors had a fourfold excess risk (risk ratio, 4.1; 95% confidence interval, 1.7-10.1) for any adverse livebirth outcome, including birth defects, compared with their sibling controls. Wives of male survivors had no apparent excess risk for problem pregnancies. The families had a number of severe reproductive problems and major birth defects, such as primary amenorrhea in two survivors, bicornuate uterus in two survivors and one control, and mental retardation in one male survivor and a male control. The son of a female survivor died after bilateral Wilms' tumors. Birth defects in the offspring of female survivors are compatible either with intrauterine constraint, possibly due to radiation-induced fibrosis or with the complex of malformations associated with Wilms' tumor. Female survivors of Wilms' tumor appear to be at increased risk for a variety of reproductive problems, from sterility to fetal loss, early delivery, and birth defects in offspring. Furthermore, relatives of survivors of Wilms' tumor may be at risk of having associated birth defects, with clinically significant consequences.

Adolescent↗
PubMed1988

Educational achievement of long-term survivors of childhood and adolescent cancer.

In a retrospective cohort study, the level of education attained by 2,283 long-term survivors of childhood and adolescent cancer was investigated and compared with that of 3,270 sibling controls. Survivors of central nervous system tumors were significantly less likely than controls to complete eight grades of school or, if they completed high school, to enter college. No significant differences in educational achievement were found for survivors of non-central nervous system cancers. The educational deficit of survivors of brain tumors was especially striking for tumors of the ventricles or cerebral hemispheres, and the deficit was more severe for those treated with radiation therapy than by surgery alone. Early age at diagnosis of a central nervous system tumor was associated with a larger educational deficit than late age at diagnosis. These findings are reassuring for the majority of long-term survivors of childhood and adolescent cancers given therapies used prior to 1975.

Adult↗
PubMed1988

Survival of human diploid skin fibroblasts from normal individuals after X-irradiation.

The cytotoxic effect of X-rays was measured by a colony formation assay in multiple experiments with fibroblast cell strains derived from 24 presumably normal individuals, received as 65 different coded and blinded samples. Each strain was received on two or more occasions at different times and bearing different codes. The means and standard deviations of the survival curve parameters for the 24 strains were: D0 = 123 +/- 23; D10 = 273 +/- 42 cGy. The D0 ranged from 89 to 175 and the D10 from 196 to 372 cGy. The degree of interexperimental variation, though generally minimal, differed considerably among cell strains. There was no systematic effect of passage level, cloning efficiency, serum lot, age or sex of the donor on X-ray survival. These results confirm that the intrinsic radiosensitivity varies significantly among skin fibroblasts isolated from clinically normal individuals, apparently owing to as yet unidentified genetic factors.

Adolescent↗
PubMed1988

A genetic study of Gardner syndrome and congenital hypertrophy of the retinal pigment epithelium.

Gardner Syndrome (GS) is an autosomal dominant variant of colorectal polyposis with essentially complete penetrance. It is distinguished from the other polyposis syndromes by its delayed age at onset, the number of polyps, and its extracolonic manifestations. The presence of epidermal cysts, bony osteomata, desmoid tumors, and dental anomalies are distinguishing features of this syndrome. Recently, multiple and bilateral patches of congenital hypertrophy of the retinal pigment epithelium (CHRPE) have been described in three families with classical GS. Tight linkage of the GS and CHRPE phenotypes (Z = 9.752; theta = 0) suggested that CHRPE is a pleiotropic effect of the Gardner mutation within the families in which the ophthalmic trait occurs and is thus a useful marker for the early detection of GS gene carriers. We have analyzed six new families segregating for classic GS and CHRPE. Linkage was tested between GS and CHRPE and between these two phenotypes and a battery of 22 informative biochemical and serological markers. We have extended the linkage analysis on two GS-CHRPE families originally reported elsewhere. Linkage between GS and CHRPE at theta = 0 was observed in all families, a result supporting our original suggestion that CHRPE is a congenital manifestation of the GS mutation. Exclusionary linkage data presented confirm that, for linkage analysis in these families, the CHRPE phenotype is a more powerful marker than other phenotypic features of GS.

Adolescent↗
PubMed1987

Bone sarcomas linked to radiotherapy and chemotherapy in children.

We estimated the risk of subsequent bone cancer among 9170 patients who had survived two or more years after the diagnosis of a cancer in childhood. As compared with the general population, the patients had a relative risk of 133 (95 percent confidence interval, 98 to 176) and a mean (+/- SE) 20-year cumulative risk of 2.8 +/- 0.7 percent. Detailed data on treatment were obtained on 64 patients in whom bone cancer developed after childhood cancer. As compared with 209 matched controls who had survived cancer in childhood but who did not have bone cancer later, patients who had had radiation therapy had a 2.7-fold risk (95 percent confidence interval, 1.0 to 7.7) and a sharp dose-response gradient reaching a 40-fold risk after doses to the bone of more than 6000 rad. The relative dose-response effect among patients who had been treated for retinoblastoma resembled that among patients with all other types of initial tumors, although the cumulative risk of bone cancer in the retinoblastoma group was higher. Similar numbers of patients were treated with orthovoltage and megavoltage; the patterns of risk among categories of doses did not differ according to the type of voltage. After adjustment for radiation therapy, treatment with alkylating agents was also linked to bone cancer (relative risk, 4.7; 95 percent confidence interval, 1.0 to 22.3), with the risk increasing as cumulative drug exposure rose. We conclude that both radiotherapy and chemotherapy with alkylating agents for childhood cancer increase the subsequent risk of bone cancer.

Alkylating Agents↗
PubMed1987

Normal cytotoxic response of skin fibroblasts from patients with Li-Fraumeni familial cancer syndrome to DNA-damaging agents in vitro.

Skin fibroblasts from patients with the Li-Fraumeni familial cancer syndrome have been reported to show abnormalities in their response to X-irradiation. We have examined the response of fibroblasts from affected and nonaffected individuals in three families to treatment with four DNA-damaging agents: X-rays, UV light, N-methyl-N'-nitro-N-nitrosoguanidine, and mitomycin C. Test cells along with additional cell bank control strains were received coded and blinded. The same strains were studied on 2 or 3 separate occasions; each of these groups was coded differently. The cytotoxic effects of the four agents were examined by a colony formation assay. Sensitivity to the induction of chromosomal aberrations by X-rays was also measured. In all cases, the response of cells from affected individuals did not differ significantly from that of cells from unaffected (not a risk) family members nor of cell bank controls. The response of somatic cells from members of Li-Fraumeni cancer families to DNA-damaging agents does not appear to be a fruitful approach to the detection of at-risk individuals.

Cells, Cultured↗
PubMed1987

Variation in the expression of aphidicolin-induced fragile sites in human lymphocyte cultures.

A correlation between specific fragile sites and cancer breakpoints has been suggested raising the question of fragile site expression as a predisposing factor in the occurrence of cancer in some persons. Before addressing the question of increased fragility among patients at high risk for cancer, we analyzed the variability of aphidicolin-induced fragile sites among nine normal persons and also among repeated samples from three of these individuals. Considerable variation in both the frequency and location of these fragile sites was observed and the data strongly suggest the significant variation of 6 of the 16 selected sites to be primarily due to sampling differences. These findings indicate that the use of fragile sites as a screening tool for patients at high risk of cancer should be carefully monitored relative to the variation inherent in both culture and individual expression.

Aphidicolin↗