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S A Gayther

Publications and source records attributed to S A Gayther.

At least 19 recordsLinked to original sources
PubMed1998

Identification of germ-line E-cadherin mutations in gastric cancer families of European origin.

E-cadherin germ-line mutations have recently been described as a molecular basis for early-onset familial gastric cancer in Maori kindred. We screened 18 gastric cancer families of European origin for germ-line mutations to determine the proportion in which E-cadherin mutations occur and the clinical characteristics of the affected families. Truncating mutations were identified in three kindred with familial diffuse gastric cancer. In these families, the age of onset of gastric cancer was variable, the penetrance was incomplete, and one kindred contained individuals with cancers at other sites. Here, we show that a proportion of diffuse gastric cancer families of European origin have germ-line E-cadherin mutations; however, these mutations are absent in intestinal gastric cancer families.

Adult↗
PubMed1998

Mutation analysis of the c-mos proto-oncogene in human ovarian teratomas.

Female transgenic mice lacking a functional c-mos proto-oncogene develop ovarian teratomas, indicating that c-mos may behave as a tumour-suppressor gene for this type of tumour. We have analysed the entire coding region of the c-MOS gene in a series of human ovarian teratomas to determine whether there are any cancer-causing alterations. DNA from twenty teratomas was analysed by single-strand conformational analysis (SSCA) and heteroduplex analysis (HA) to screen for somatic and germline mutations. In nine of these tumours the entire gene was also sequenced. A previously reported polymorphism and a single new sequence variant were identified, neither of which we would predict to be disease-causing alterations. These results suggest that mutations in the coding region of the c-MOS gene do not play a significant role in the genesis of human ovarian teratomas.

DNA Mutational Analysis↗
PubMed1998

Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.

The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

Adult↗
PubMed1998

Clues to the function of the tumour susceptibility gene BRCA2.

The breast cancer susceptibility gene BRCA2 was isolated in 1995. BRCA2 is a large gene comprising 10,254 nucleotides and 26 coding exons. Neither the nucleotide nor the predicted protein sequences (comprising 3,418 amino acids) have provided substantial clues about its function. As a result, researchers have been trying to elucidate the function using a combination of cell biological and biochemical methods and the construction of animal models using gene targeting in mice. Recent data suggest that BRCA2 may participate in pathways associated with recombination or double-strand DNA break repair and may act by either sensing or responding to DNA damage. In addition, there is evidence to suggest that BRCA2 functions in a manner similar to the previously isolated breast cancer susceptibility gene BRCA1.

Animals↗
PubMed1997

Aberrant splicing of the TSG101 and FHIT genes occurs frequently in multiple malignancies and in normal tissues and mimics alterations previously described in tumours.

Intragenic deletions of TSG101, the human homolog of a mouse gene (tsg101) that acts to suppress malignant cell growth, were reported in human breast tumours. We screened TSG101 for somatic mutations in DNA and RNA samples isolated from a variety of common human malignancies, EBV-immortalised B-cells, and normal lung parenchyma. Intragenic TSG101 deletions in RNA transcripts were frequently found in all types of samples. Analysis of DNA failed to show genomic rearrangements corresponding to transcripts containing deletions in the same samples. The breakpoints of most transcript deletions coincide with genuine or cryptic splice site sequences, suggesting that they result from alternative or aberrant splicing. A similar spectrum of transcript deletions has previously been described in the putative tumour suppressor gene FHIT. We analysed FHIT in the same series of RNA samples and detected truncated FHIT transcripts frequently in both tumour and normal tissues. In addition, transcripts from TSG101, FHIT and seven other genes were analysed in RNA isolated from normal peripheral blood lymphocytes. Large TSG101 and FHIT intragenic transcript deletions were detected and these appeared to be the predominant transcript in 'aged' lymphocytes. Similar alterations were not detected in transcripts of the other genes which were analysed. Our findings demonstrate that truncated TSG101 and FHIT transcripts are commonly detected in both normal and malignant tissues and that a significant fraction of these are likely to be the result of aberrant splicing. While we cannot exclude that alterations in TSG101 and FHIT occur during cancer development, our data indicate that in this context the commonly observed transcript abnormalities are misleading.

Acid Anhydride Hydrolases↗
PubMed1997

Contribution of BRCA1 mutations to ovarian cancer.

BACKGROUND: Inherited mutations in the BRCA1 gene confer a high risk of breast and ovarian cancer in some families. To determine the contribution of BRCA1 mutations to ovarian cancer in the general population, we analyzed DNA samples from a consecutive series of women with ovarian cancer seen at one center. METHODS: We studied 374 women who received a diagnosis of epithelial ovarian cancer before the age of 70 years and were treated at the Royal Marsden Hospital between July 1993 and September 1995. Genomic DNA was analyzed by multiplex heteroduplex analysis. Variants were further identified by sequencing. RESULTS: Probable germ-line BRCA1 mutations were identified in 13 of the 374 women (3 percent; 95 percent confidence interval, 2 to 6 percent). Six of the variants have not been described previously. Of the 13 mutations, 12 are predicted to result in a truncated protein product. An additional variant results in an in-frame deletion just outside the putative zinc-finger domain. Nine of the 12 women with truncating mutations had family histories of breast or ovarian cancer or both. CONCLUSIONS: Assuming that our method has a sensitivity of 70 percent, mutations in BRCA1 occur in approximately 5 percent (95 percent confidence interval, 3 to 8 percent) of women in whom ovarian cancer is diagnosed before the age of 70 years.

Adenocarcinoma, Clear Cell↗
PubMed1997

Mutations of the BRCA1 and BRCA2 genes and the possibilities for predictive testing.

Two cancer susceptibility genes, BRCA1 on chromosome 17q12-21 and BRCA2 on chromosome 13q12-13, are thought to be responsible for approximately 80% of families containing multiple cases of early-onset female breast cancer. Germline mutations of BRCA1 are also associated with ovarian cancer and mutations of BRCA2 are associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer. The recent isolation of both genes should make possible the identification of the genetic defect that predisposes affected individuals to breast and ovarian cancer and might lead to the use of genetic information for predictive testing.

BRCA2 Protein↗
PubMed1997

Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.

The breast cancer susceptibility gene BRCA2 on chromosome 13q12-13 has recently been identified. Germline mutations of BRCA2 are predicted to account for approximately 35% of families with multiple case, early onset female breast cancer, and they are also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer. Germline mutations of a second cancer susceptibility gene BRCA1 (ref. 5), are associated with a strong predisposition to ovarian cancer as well as female breast cancer. Recent studies have suggested that the phenotype in BRCA1 families with respect to the ratio of breast to ovarian cancer varies with the location of the BRCA1 mutation. To determine whether germline mutations in BRCA2 are associated with a similar variation in phenotypic risk, we have analysed the distribution of mutations in 25 families with multiple cases of breast and/or ovarian cancer ascertained in the United Kingdom and Eire. These mutations all lead to premature truncation of BRCA2 as a result of frameshift deletions/insertions or nonsense mutations. Analysis of the mutation distribution along the length of the gene indicates a significant genotype-phenotype correlation. Truncating mutations in families with the highest risk of ovarian cancer relative to breast cancer are clustered in a region of approximately 3.3 kb in exon 11 (P = 0.0004). Published data on mutations in 45 other BRCA2-linked families provide support for this correlation.

BRCA2 Protein↗
PubMed1997

Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population.

A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene.

Aged↗
PubMed1996

Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer.

The breast and ovarian cancer susceptibility gene BRCA2 has recently been isolated. A role for BRCA2 in sporadic breast and ovarian cancer has been suggested by loss of heterozygosity (LOH) studies which show frequent LOH in the BRCA2 region at chromosome 13q12. In addition, the observation of nonrandom loss of the wild-type chromosome in a breast/ovarian cancer family which shows linkage to BRCA2 suggests it may act as a tumor suppressor gene. To determine the extent of somatic alteration involving BRCA2 in sporadic ovarian cancer, 50 tumors were analyzed for mutations throughout the entire BRCA2 coding region. Mutations predicted to result in truncation of the BRCA2 protein were detected in four tumors. Analysis of germline DNA revealed two of these alterations to be of somatic origin. In addition, all four tumors exhibited loss of the second BRCA2 allele as predicted by Knudson's hypothesis for a tumor suppressor gene. These results suggest that, as is the case with BRCA1, somatic mutations of BRCA2 are infrequent in sporadic ovarian cancer, despite the relatively high frequency of LOH detected around the BRCA2 locus.

BRCA2 Protein↗
PubMed1996

Mutation analysis of the c-mos proto-oncogene and the endothelin-B receptor gene in medullary thyroid carcinoma and phaeochromocytoma.

The characteristic tumours of MEN 2 are medullary thyroid carcinoma (MTC) and phaeochromocytoma. Somatic RET mutations have been found in only 23-40% of sporadic MTC and 10% of sporadic phaeochromocytomas. Thus, we sought other genes which may play a role in the pathogenesis of these tumours. We carried out direct sequence analysis of human c-mos and human ENRB in a series of sporadic MTC and phaeochromocytomas to determine if somatic mutations in these two genes could account for some of the sporadic MEN 2-related tumours in which no RET mutations are detected. No somatic mutations were found.

Adrenal Gland Neoplasms↗
PubMed1996

Rapid detection of regionally clustered germ-line BRCA1 mutations by multiplex heteroduplex analysis. UKCCCR Familial Ovarian Cancer Study Group.

Germ-line mutations of the BRCA1 gene are responsible for a substantial proportion of families with multiple cases of early-onset breast and/or ovarian cancer. Since the isolation of BRCA1 last year, >65 distinct mutations scattered throughout the coding region have been detected, making analysis of the gene time consuming and technically challenging. We have developed a multiplex heteroduplex analysis that is designed to analyze one-quarter of the coding sequence in a single-step screening procedure and that will detect approximately 50% of all BRCA1 mutations so far reported in breast/ovarian cancer families. We have used this technique to analyze BRCA1 in 162 families with a history of breast and/or ovarian cancer and identified 12 distinct mutations in 35 families.

BRCA1 Protein↗
PubMed1995

A gene (DLG2) located at 17q12-q21 encodes a new homologue of the Drosophila tumor suppressor dIg-A.

We have isolated a novel cDNA that maps distal to BRCA1 at 17q12-q21. The total sequence predicts a protein of 576 amino acids with three conserved regions: a 90-amino-acid repeat domain, a SH3 (src homology region 3) motif, and a guanylate kinase domain. These conserved regions are shared among members of the discs-large family of proteins that include human p55, a membrane protein expressed in erythrocytes, rat PSD-95/SAP90, a synapse protein expressed in brain, Drosophila dIg-A, a septate junction protein expressed in various epithelia, and human and mouse ZO-1 and canine ZO-2, two tight junction proteins. dIg-A has been shown to act as a tumor suppressor, and the other members may all be involved in signal transduction through specialized membrane domains with highly organized cytoskeletons and thus are potential tumor suppressors. Since allelic loss has been reported in the 17q12-q21 region in breast and ovarian cancer and it appears that BRCA1 is not the target of the losses, we looked for somatic alterations in DLG2 in sporadic breast tumors. No evidence for mutation was found, making it unlikely that DLG2 is involved in sporadic breast cancer.

Amino Acid Sequence↗
PubMed1995

Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.

Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80-90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. Twenty-two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our data suggest a transition in risk such that mutations in the 3' third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have found at least two examples where recurrent mutations appear to have arisen independently.

BRCA1 Protein↗