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Biomedical subjects

J M Lancaster

Publications and source records attributed to J M Lancaster.

At least 19 recordsLinked to original sources
PubMed2001

Allele loss on chromosome 1p36 in epithelial ovarian cancers.

OBJECTIVES: Prior studies have shown that allelic loss on chromosome 1p36 occurs frequently in ovarian as well as several other types of cancer. This suggests that inactivation of gene(s) in this region may play a role in the pathogenesis of these cancers. The aim of this study was to further delineate the region of loss on chromosome 1p36 in ovarian cancers and to identify associated patient or tumor characteristics. METHODS: Paired normal/cancer DNA samples from 75 ovarian cancers (21 early stage I/II and 54 advanced stage III/IV) were analyzed using microsatellite markers. RESULTS: Forty-nine of 75 (65%) ovarian cancers had loss of at least one marker. The marker demonstrating the most frequent loss was D1S1597, which was lost in 29/57 (51%) informative cases. Allele loss on 1p36 was significantly more common in poorly differentiated ovarian cancers (73%) relative to well or moderately differentiated cases (48%) (P = 0.03). Evidence was obtained for two common regions of deletion: one flanked by D1S1646/D1S244 and another more proximally by D1S244/D1S228. CONCLUSION: These findings further delineate regions on chromosome 1p36 proposed to contain tumor suppressor gene(s) that may play a role in the development and/or progression of epithelial ovarian carcinoma. Allele loss on 1p36 is associated with poor histologic grade.

Alleles↗
PubMed2001

Mutational analysis of the PTEN gene in human uterine sarcomas.

OBJECTIVE: Uterine sarcomas are rare, lethal cancers, and little is known about their molecular etiology. The PTEN gene is located on chromosome 10q23.3, a region that displays frequent loss of heterozygosity in human uterine sarcomas. PTEN mutations have been described in 40% to 60% of uterine adenocarcinomas. To determine whether the PTEN gene is involved in the pathogenesis of uterine sarcoma, we analyzed deoxyribonucleic acid from uterine sarcomas and cell lines. STUDY DESIGN: Single-strand conformation analysis and direct sequencing of deoxyribonucleic acid were used to screen for PTEN mutations. RESULTS: Silent polymorphisms were detected in 2 of 36 primary uterine sarcomas. A 4-base pair deletion and a point mutation producing a stop codon were identified in 1 cell line. CONCLUSIONS: Mutational inactivation of PTEN does not play a major role in uterine sarcoma tumorigenesis, and another gene or genes on chromosome 10q may be implicated as a cause of these cancers. Differences in the molecular alterations underlying the development of uterine sarcomas and adenocarcinomas are significant.

Cell Line, Transformed↗
PubMed1998

BRCA1 and BRCA2 in breast cancer families from Wales: moderate mutation frequency and two recurrent mutations in BRCA1.

Mutations in the BRCA1/BRCA2 genes account for varying proportions of breast cancer families studied, and demonstrate considerable variation in mutational spectra coincident with ethnic and geographical diversity. We have screened for mutations in 17 families from Wales with two or more cases of breast cancer under age 50 and/or ovarian cancer. Eight out of 17 (47%) families had demonstrable mutations. Six out of 17 (35%) carried BRCA1 mutations and 2 out of 17 (12%) carried BRCA2 mutations. Two recurrent mutations in BRCA1 were identified, which appear to represent founder mutations in this population. These data support the existence of additional breast and ovarian cancer susceptibility genes.

Adult↗
PubMed1998

Frequency of germline and somatic BRCA1 mutations in ovarian cancer.

Germline mutations in the BRCA1 tumor suppressor gene are thought to be the most common cause of hereditary ovarian cancer. The aim of this study was to explore further the role of BRCA1 alterations in the development of ovarian cancers. We sought to determine whether somatic BRCA1 mutations are ever present in ovarian cancers and whether mutation is always accompanied by loss of the wild-type allele. The entire coding region and intronic splice sites of BRCA1 were sequenced using genomic DNA samples from 103 unselected ovarian cancers. Thirteen clearly deleterious BRCA1 mutations and two variants of uncertain significance were found. Blood DNA was available in all but two cases and demonstrated that 4 of 13 mutations and both variants of uncertain significance were germline alterations, whereas in seven cases the mutation was a somatic change present only in the cancer. Using four microsatellite markers, loss of heterozygosity at the BRCA1 locus was found in all 15 ovarian cancers with BRCA1 sequence alterations, compared with only 58% of ovarian cancers that did not have BRCA1 mutations. BRCA1-associated ovarian cancers were characterized by serous histology and moderate histological grade. These data confirm prior reports suggesting that germline mutations in BRCA1 are present in about 5% of women with ovarian cancer. In addition, somatic mutations in BRCA1 occur in the development of some sporadic cases. The finding that both germline and somatic BRCA1 mutations are accompanied by loss of heterozygosity, suggests that loss of this tumor suppressor gene is a critical event in the development of these cancers.

Adult↗
PubMed1997

Dideoxy fingerprinting assay for BRCA1 mutation analysis.

Since the isolation of BRCA1, the familial breast/ovarian cancer predisposition gene, much effort has been invested in characterizing the mutation spectrum. The large size of the gene and the wide distribution of its more than 100 mutations has increased the challenge of this endeavor such that traditional mutation detection techniques are inadequate. We examined the sensitivity of dideoxy fingerprinting (DDF), which combine a Sanger sequencing reaction with multiple-fragment single-strand conformation analysis (SSCA), as a mutation detection technique to screen BRCA1. Here we describe the technique and compare its sensitivity with that of SSCA in detecting 21 previously described BRCA1 sequence variants. All the variants were detected by DDF, but only 17 of 21 (81%) were observed by SSCA under standard conditions. Three of four alterations missed by SSCA were base substitutions. As a BRCA1 mutation detection technique, DDF was more sensitive than SSCA and may prove to be a useful research tool in defining the mutation spectrum within this and other genes.

Breast Neoplasms↗
PubMed1996

Microsomal epoxide hydrolase polymorphism as a risk factor for ovarian cancer.

Microsomal epoxide hydrolase (EPHX) is one of many enzymes involved in the metabolism of endogenous and exogenous toxicants. Polymorphic forms of the human EPHX gene have been described that vary in enzymatic activity, and one, Tyr113His, has been associated with hepatocellular carcinoma susceptibility. We demonstrated that EPHX was highly expressed in the human ovary, and investigated whether specific EPHX genotypes are associated with ovarian cancer susceptibility. Seventy-three Caucasian patients with ovarian cancer and 75 Caucasian-female controls without cancer were genotyped for the Tyr113His polymorphism by a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of the homozygous high-activity genotype was 41% in the control population and 64% in the ovarian cancer patients. The odds ratio for ovarian cancer with this genotype was 2.6 (95% confidence interval 1.3, 5.0; P < 0.01). The increased ovarian cancer risk associated with the high-activity genotype could reflect differences in metabolic activation of endogenous or exogenous carcinogens.

Blotting, Northern↗
PubMed1996

An inevitable dilemma: prenatal testing for mutations in the BRCA1 breast-ovarian cancer susceptibility gene.

The BRCA1 breast-ovarian cancer susceptibility gene was identified recently. Germline mutations in BRCA1 may be responsible for as many as 5% of breast and ovarian cancers. Inherited alterations confer up to a 94% risk of developing breast and/or ovarian cancer by age 70. With the discovery of BRCA1, there will be a heavy demand for genetic testing. Because of the large size of the gene and the distribution of reported mutations, scientists face considerable technical problems in developing widely available screening tests; clinicians will face even greater ethical problems in applying them. In the context of research programs, women with BRCA1 mutations are already being identified, and their physicians are confronted with a number of complex medical, ethical, legal, and social issues. Obstetricians will be faced with counseling parents regarding prenatal testing for specific BRCA1 mutations. Although it is difficult to formulate straightforward guidelines regarding prenatal BRCA1 testing, clinicians and health care providers must be familiar with the nuances of the debate so that these issues can be discussed wisely with patients. As with many ethically challenging problems in medicine, individual clinicians and their patients will have to work together to determine the course of action with which they are most comfortable. Although elective termination of a pregnancy with a germline mutation in BRCA1 is an option, experience with other adult-onset diseases suggests that only a minority of parents will choose this option.

BRCA1 Protein↗
PubMed1996

Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families.

The hereditary breast cancer gene BRCA2 was recently cloned and is believed to account for almost half of site-specific breast cancer families and the majority of male breast cancer families. We screened 49 site-specific breast cancer families for mutations in the BRCA2 gene using single strand conformation analysis (SSCA) followed by direct sequencing. We found mutations in eight families, including all four families with male breast cancer. The eight mutations were small deletions with the exception of a single nonsense mutation, an all were predicted to interrupt the BRCA2 coding sequence and to lead to a truncated protein product. Other factors which predicted the presence of a BRCA2 mutation included a case of breast cancer diagnosed at age 35 or below (P = 0.01) and a family history of pancreatic cancer (P = 0.03). Two mutations were seen twice, including a 8535delAG, which was detected in two French Canadian families. Our results suggest the possibility that the proportion of site-specific breast cancer families attributable to BRCA2 may be overestimated.

Adult↗
PubMed1996

BRCA2 mutations in primary breast and ovarian cancers.

The second hereditary breast cancer gene, BRCA2, was recently isolated. Germline mutations of this gene predispose carriers to breast cancer, and, to a lesser extent, ovarian cancer. Loss of heterozygosity (LOH) at the BRCA2 locus has been observed in 30-40% of sporadic breast and ovarian tumours, implying that BRCA2 may act as a tumour suppressor gene in a proportion of sporadic cases. To define the role of BRCA2 in sporadic breast and ovarian cancer, we screened the entire gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. Our analysis revealed alterations in 2/70 breast tumours and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-basepair (bp) deletion (4710delAG) which was subsequently shown to be a germline mutation, the other was a somatic missense mutation (Asp3095Glu) of unknown significance. Our results suggest that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas, similar to the results obtained for BRCA1.

Aged↗
PubMed1996

Role of BRCA1 mutation screening in the management of familial ovarian cancer.

Families with multiple cases of ovarian cancer have long been observed, and in the past prophylactic oophorectomy has been advocated for women with a history of ovarian cancer in two first-degree relatives. It is now thought that > 90% of familial ovarian cancer is due to inherited mutations in the BRCA1 breast-ovarian cancer susceptibility gene on chromosome 17q. BRCA1 testing is being performed in several academic medical centers on a research basis and is also now commercially available. With the ability to identify inherited mutations in BRCA1, prophylactic oophorectomy and other interventions intended to decrease cancer mortality can be offered specifically to women who carry a mutation, but the optimal strategy for decreasing cancer mortality in BRCA1 families has not yet been determined. To facilitate further clinical and basic research in this field, our group and others have established multidisciplinary hereditary breast-ovarian cancer clinics that offer a wide range of services including BRCA1 testing, genetic counseling, and cancer prevention and treatment.

Chromosomes, Human, Pair 17↗
PubMed1992

Carbamazepine inhibits NMDA-induced depolarizations in cortical wedges prepared from DBA/2 mice.

There is some doubt as to the mechanism of action of the widely-used anticonvulsant drug, carbamazepine. In cortical wedges prepared from genetically epilepsy-prone DBA/2 mice, carbamazepine at therapeutic concentrations (1-10 microM) markedly reduced the depolarization produced by N-methyl-D-aspartate (NMDA). The NMDA sub-type of glutamate receptor has been implicated in the pathogenesis of epilepsy and the inhibitory action of carbamazepine on this response suggests that the anticonvulsant action of the drug may be due to its blockade of NMDA receptor-mediated events.

Animals↗
PubMed1991

Desmethylimipramine potentiates NMDA responses in a mouse cortical slice preparation.

Desmethylimipramine (DMI) has been shown to interact with the N-methyl-D-aspartate (NMDA) receptor complex. Its probable action is through blockade of the cationic channel at the phencyclidine site and as a result it has potential anticonvulsant action. In this present study we have investigated the effects of DMI and ketamine on both NMDA-induced and spontaneous depolarizing shifts in cortical wedges prepared from genetically epilepsy-prone mice (DBA/2). Contrary to published reports, DMI potentiated the effects of NMDA and increased the frequency of spontaneous depolarizations. The actions of ketamine were inhibitory and these were reversed by DMI. Presynaptic mechanisms may be involved in the DMI-induced potentiation and this may explain the lowering of convulsive thresholds seen clinically with tricyclic antidepressants.

Action Potentials↗
PubMed1988

Pathologic fractures of the humerus.

In a study of 57 actual or impending pathologic fractures of the humerus in 52 patients with inoperable cancer treated between 1972 and 1982, we retrospectively reviewed the charts for analysis and comparison of the functional result and pain relief afforded by the various treatments used. Function of the extremity and relief of pain were each graded as excellent, good, fair, or poor using a modification of Perez's rating system. Seven pathologic fractures were treated nonoperatively. These patients generally had only fair pain relief and a poor functional result. Forty-six pathologic fractures were treated with intramedullary fixation using a Rush rod (n = 16), a Küntscher rod (n = 29), or an Ender rod (n = 1); the Neer endoprosthesis was used in four patients. Thirty-one patients received radiation to the humerus. There were seven operative complications, the most common (n = 3) being prominence of an intramedullary rod at the insertion site which required a second minor procedure for advancement of the rod. From this series, we conclude that any patient who has a pathologic fracture or impending fracture of the humerus and a predicted survival of six weeks or more is likely to benefit from rigid internal fixation with an appropriately selected device, adjunctive use of methylmethacrylate, and postoperative local irradiation therapy as needed.

Adult↗