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D Malkin

Publications and source records attributed to D Malkin.

At least 55 records · Page 3Linked to original sources
PubMed1994

Screening for cancer susceptibility in children.

Epidemiologic studies have demonstrated that virtually every form of human cancer may aggregate in families. Genetic susceptibility plays an important role in the development of many of these cancers, yet until very recently genes associated with this susceptibility had not been identified. Over the last several years, the class of genes known as tumor suppressor genes has been most consistently implicated in hereditary cancers. Recently, genes associated with childhood tumors including retinoblastoma, Wilms' tumor, as well as with adult-onset tumors such as breast cancer and colon cancer have been either cloned or localized to specific chromosomal sites. Their isolation has encouraged the development of techniques with which to analyze cancer-prone individuals and families for the presence of germline, or constitutional, alterations of genes that may place them at high cancer risk. In the past year, the benefits and pitfalls of some of these screening assays have been studied. Also, the literature has indicated the importance of considering both ethical and psychosocial implications of our growing ability to perform predictive testing for cancer.

Child↗
PubMed1994

Splice-site mutation of the p53 gene in a family with hereditary breast-ovarian cancer.

Germline mutations within evolutionary conserved exons of the p53 gene predispose to tumor development in several familial cancer syndromes. We now report identification of a novel p53 mutation affecting the splice acceptor site of exon 6 in the germline DNA of a family with hereditary breast-ovarian cancer. This splice-site mutation, which results in omission of exon 6 and creates a frame-shift and premature stop codon in transcripts from the mutant allele, was found in seven family members--four of whom have developed breast, ovarian or choroid plexus tumors before age 35. Our finding suggests the need to examine the entire p53 gene for splice-site, frame-shift, and nonsense (as well as missense) mutations in families with early-onset hereditary breast and breast-ovarian cancers not linked to the BRCA1 gene on chromosome 17q. We propose that the term 'p53 familial cancer syndrome' be applied to clusters of tumors in families with documented germline p53 mutations, regardless of the histopathologic findings or pattern of tumor development.

Adolescent↗
PubMed1993

Mutations of the p53 gene do not occur in testis cancer.

To characterize the role of p53 in the development of testis cancer, we looked for mutations in the coding sequences of the p53 gene. DNA was obtained both from familial and sporadic testis cancer specimens, as well as from peripheral blood from members of a testis cancer kindred. Mutations in the p53 gene were screened using a combination of constant denaturant gel electrophoresis and single-strand conformational polymorphism analysis, 2 screening methods that can detect single base changes. Abnormalities detected by these methods were confirmed by sequencing of the corresponding cloned polymerase chain reaction products. All conserved regions of the p53 coding sequences were examined, encompassing all previously reported sites of mutations. No mutations were found in any of 22 germ cell cancers of the testis or in the germline DNA of 17 members of the testis cancer family. This is in striking contrast to most other human cancers, in which mutations of p53 are the most commonly described molecular event associated with tumorigenesis. We conclude that dysfunction of tumor suppressor gene or genes other than p53 may prove to play an important role in the development of germ cell cancers of the testis.

Genes, p53↗
PubMed1993

p53 and the Li-Fraumeni syndrome.

The Li-Fraumeni familial cancer syndrome was initially described in 1969 in a retrospective epidemiologic review of more than 600 pediatric sarcoma patients. The clinical definition of the syndrome has been refined in the last two decades by prospective analyses of several families. Despite these exhaustive studies, the gene or genes responsible for the unusual constellation of tumors in these families remained elusive until 1990, when it was demonstrated that germline abnormalities of the p53 tumor suppressor gene could account for the occurrence of cancer in many classic Li-Fraumeni families. Identification of the molecular events that yield this phenotype has led many researchers to pursue several lines of investigation to improve our understanding of the significance of such alterations. We discuss the clinical, epidemiologic, genetic, and biologic aspects of the association between p53 and the Li-Fraumeni family cancer syndrome.

Genes, p53↗
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

Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms.

BACKGROUND: Acquired mutations in the p53 tumor-suppressor gene have been detected in several human cancers, including colon, breast, and lung cancer. Inherited mutations (transmitted through the germline) of this gene can underlie the Li-Fraumeni syndrome, a rare familial association of breast cancer in young women, childhood sarcomas, and other malignant neoplasms. We investigated the possibility that p53 mutations in the germline are associated with second primary cancers that arise in children and young adults who would not be considered as belonging to Li-Fraumeni families. METHODS: Genomic DNA was extracted from the blood leukocytes of 59 children and young adults with a second primary cancer. The polymerase chain reaction, in combination with denaturant-gel electrophoresis and sequencing, was used to identify p53 gene mutations. RESULTS: Mutations of p53 that changed the predicted amino acid sequence were identified in leukocyte DNA from 4 of the 59 patients (6.8 percent). In three cases, the mutations were identical to ones previously found in the p53 gene. The fourth mutation was the first germline mutation to be identified in exon 9, at codon 325. Analysis of leukocyte DNA from close relatives of three of the patients indicated that the mutations were inherited, but cancer had developed in only one parent at the start of the study. CONCLUSIONS: These findings identify an important subgroup of young patients with cancer who carry germline mutations in the p53 tumor-suppressor gene but whose family histories are not indicative of the Li-Fraumeni syndrome. The early detection of such mutations would be useful not only in treating these patients, but also in identifying family members who may be at high risk for the development of tumors.

Adolescent↗
PubMed1992

The role of tumour suppressor genes in familial cancer.

Many forms of cancer have a higher incidence in relatives of patients than in the general population, and some show Mendelian inheritance. Although individuals genetically predisposed to cancer represent a minority of all cancer patients, the genetic basis for their disease has profound significance. These familial cases provide strong evidence that germline alterations can contribute to cancer. They also provide an ideal opportunity to identify and isolate the genes mutated in common cancers. Products of the tumour suppressor genes have been implicated in several hereditary forms of cancer. The distinct functions of these proteins and their roles in familial cancer will be discussed.

Genes, Tumor Suppressor↗
PubMed1991

Constant denaturant gel electrophoresis as a rapid screening technique for p53 mutations.

At present, mutation of the p53 gene appears to be the most common genetic alteration found in human cancers. These mutations can occur within many different regions of the gene. We have developed a modification of denaturing gradient gel electrophoresis termed "constant denaturant gel electrophoresis" (CDGE), which provides a rapid and sensitive method to screen the four conserved regions within the p53 gene where the majority of p53 mutations have been reported. The sensitivity of CDGE was first tested with known p53 mutations in all four conserved regions. The CDGE technique was then used to screen 32 breast carcinomas that had been analyzed by immunohistochemical methods for altered p53 protein levels and whose DNA had already been shown to have loss of heterozygosity for a chromosome 17p marker. By immunostaining techniques, only 6 of the 32 tumors had elevated p53 expression. However, CDGE detected p53 mutations in 11 of the 32 tumors. DNA sequence analysis was performed to determine the nucleotide positions of these mutations in all 11 samples. Loss of heterozygosity for the pYNZ22 or p144D6 markers did not associate with either the loss of heterozygosity at the p53 locus or the mutations detected by CDGE. We conclude that CDGE is a rapid and effective technique to screen for p53 mutations.

Base Sequence↗
PubMed1991

Enhancement by retinoic acid and dibutyryl cyclic adenosine 3':5'-monophosphate of the differentiation and gene expression of human neuroblastoma cells induced by interferon.

Human neuroblastoma cell lines are induced to differentiate and display neuronal phenotypes when treated with interferon (IFN)-alpha 2, retinoic acid (RA), or dibutyryl cyclic AMP (dbcAMP). We investigated the effects of combinations of these agents in induction-differentiation in the neuroblastoma cell line, NUB-6. The inductive effect of IFN-alpha 2 was markedly enhanced when used in combination with RA or dbcAMP. In parallel, RA or dbcAMP also enhanced the level of 2'-5'-oligoadenylate (2-5A) synthetase, and enzyme induced by IFNs and implicated in their biological action. The levels of another IFN-inducible enzyme, p68 kinase, were not enhanced by the combination treatments. The enhancement effects appeared to be exerted largely at the posttranscriptional level as both RA and dbcAMP stabilized IFN-induced 2-5A synthetase mRNA, resulting in increased enzyme activity. Thus, the 2-5A synthetase system is likely involved in mediating the IFN-alpha 2-induced differentiation of neuroblastoma cells and may also mediate the enhancement effects of RA and dbcAMP on IFN activity in these cells. These results also provide a rational basis for establishing a combination therapeutic approach for the treatment of neuroblastoma.

2',5'-Oligoadenylate Synthetase↗
PubMed1991

Nocturnal cortisol, thyroid stimulating hormone, and growth hormone secretory profiles in depressed adolescents.

Twelve depressed adolescents and 12 controls matched for age, sex, Tanner stage, time of menstrual cycle (females), weight, and time of year assessed were studied over 3 nights. Measurements for cortisol, thyroid stimulating hormone, and growth hormone were made on serum collected at 10 P.M., 12 midnight, 1 A.M., 2 A.M., 3 A.M., 4 A.M., and 6 A.M. in eight pairs and every 20 minutes from 8 P.M. to 7 A.M. in four pairs. Cortisol secretion did not significantly differentiate the groups. Thyroid stimulating hormone secretion was significantly elevated in the depressed group at one time point. Growth hormone secretion significantly differentiated the two groups at most time points, and the depressed adolescents significantly hypersecreted growth hormone (area under the curve). Implications for the diagnosis, etiology, and treatment of adolescent depression are discussed.

Adolescent↗
PubMed1991

Cancer risks from germ line tumor suppressor gene mutations.

It has been well established that sometimes cancer clusters within specific families. This has suggested the possibility that some of those families might carry genetic defects which provide susceptibility to specific cancers. Retinoblastoma, an embryonal tumor of the eye represents an extreme example of a tumor which has a dramatic genetic component. Several studies have shown that inactivation at the retinoblastoma gene is probably both necessary and sufficient to initiate retinoblastoma formation. Patients who survive the inherited form of the disease are at risk of developing mesenchymal tumors, melanoma and brain tumors in as high as 10% of the patients before they are 40 years old. Because the product of the retinoblastoma gene, p105Rb, is expressed in all cell types, the obvious question is what accounts for these tissue specific differences in the role of p105Rb. Small cell lung carcinomas virtually all have associated mutations in the Rb gene and yet those tumors do not occur at a significantly increased frequency in patients with the hereditary form of retinoblastoma. In order to identify genes which might predispose to some of the more common adult malignancies, we have focused on one form of hereditary breast cancer. We chose a rare form of hereditary breast cancer which occurs in families with sarcomas (Li-Fraumeni Syndrome). By use of the candidate gene approach we tested which germ line p53 mutations were found in affected family members with Li-Fraumeni Syndrome (LFS). We have found that virtually all of the families with LFS have germ line p53 mutations, and that these tumors have undergone inactivation of the remaining wild-type p53 allele. In order to investigate the role of germ line p53 mutations outside of these rare families, we have begun to investigate other high risk groups. These results indicate that de novo germ line p53 mutations certainly occur in these high risk groups. These findings along with the recognition of the germ line p53 mutations in families with LFS provide clues about the importance of uncovering hidden susceptibilities from germ line tumor suppressor genes not only for the care of patients, but also for understanding the primary events that normally regulate the growth of cells in various tissue.

Disease Susceptibility↗
PubMed1990

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. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.

Amino Acid Sequence↗
PubMed1990

Results of a screening program for C-cell disease (medullary thyroid cancer and C-cell hyperplasia).

In the authors' Medullary Screening Clinic, medullary thyroid cancer (MTC) or C-cell hyperplasia (CCH) has been identified in 26 relatives of 12 apparently "sporadic" patients from 56 families in which calcitonin (CT) testing has been performed. The interpretation of stimulated test results was sometimes difficult: elevated basal levels without a significant increase after the injection of secretagogues; basal levels in the normal range with considerable increases after stimulation but not exceeding two or three times the upper limit of normal; elevated basal or stimulated CT levels that slowly decreased to normal or near-normal levels over relatively short periods of time. The latter results suggest the possibility of CCH disappearing spontaneously in some patients.

Adolescent↗
PubMed1990

Drug-induced aplastic anemia: pathogenesis and clinical aspects.

Drug-induced aplastic anemia is one of the few life-threatening reactions to drugs. Although the majority of reported cases have been associated with chloramphenicol, many drugs have the potential to be toxic to the bone marrow. There are two distinct types of toxicity with differing pathogenic mechanisms--a dose-related reversible marrow aplasia and a dose-independent idiosyncratic aplasia with a high mortality. These two forms of marrow suppression may be difficult to distinguish. The pathogenesis of idiosyncratic marrow aplasia is not well understood. Various studies have demonstrated biochemical, immune, pharmacokinetic, and genetic defects that could affect hematopoietic stem cells. The clinical significance of the reported experimental findings is not established. The prognosis of drug-induced aplastic anemia is similar to that of idiopathic aplastic anemia. Patients with this condition respond to bone marrow transplantation or immunosuppressive therapy in a manner similar to patients with idiopathic marrow aplasia. Many questions regarding drug-induced aplastic anemia remain to be answered; little progress has been made in the last decade.

Anemia, Aplastic↗
PubMed1989

Childhood erythroleukemia: review of clinical and biological features.

This article summarizes our institutional experience with childhood erythroleukemia over a 17-year period, and reviews the pertinent literature related to the disease. Although considered a rare variant of acute nonlymphoblastic leukemia, childhood erythroleukemia can be clearly identified clinically and hematologically by using routine examinations and certain investigative laboratory techniques. Conventional chemotherapy appears inadequate for producing durable long-term disease-free survival in children with this disease. Therefore, attention must now be directed to developing new treatment strategies including innovative maintenance and consolidation protocols, the use of biological response modifiers, and use of allogeneic or autologous bone marrow transplantation.

Adolescent↗