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M R Stratton

Publications and source records attributed to M R Stratton.

At least 55 records · Page 3Linked to original sources
PubMed1998

A missense mutation in the BRCA2 gene in three siblings with ovarian cancer.

Inherited susceptibility to ovarian cancer has been associated with germline defects at several loci. The major known ovarian cancer susceptibility gene is BRCA1 on chromosome 17q, which confers a risk of approximately 60% by the age of 70 years. Truncating mutations in BRCA2 on chromosome 13q also predispose to ovarian cancer, although they confer a lower risk than mutations in BRCA1. We have studied the molecular basis of ovarian cancer predisposition in a Finnish family with three affected sisters. Analysis of polymorphic markers provided evidence against linkage to BRCA1, but the sibship was consistent with linkage to BRCA2. Conformation-sensitive gel electrophoresis was used to screen the entire coding sequence of BRCA2. A G to A transition at nucleotide 8702 was observed, which is predicted to convert glycine 2901 to aspartate in the encoded protein. This sequence variant was not detected in 220 cancer-free Finnish control individuals, or in several hundred cancer families of many nationalities previously screened for BRCA2 mutations. Taken together with the fact that this amino acid residue and the surrounding region of BRCA2 is identical in mouse and chicken, the data suggest that this alteration is a disease-causing BRCA2 missense mutation. Previously published data indicate that the risks of breast and ovarian cancer conferred by BRCA2-truncating mutations varies with the position of the mutation in the gene. The missense mutation reported here suggests that the BRCA2 domain including and surrounding glycine 2901 may be more important in preventing neoplastic transformation in ovarian epithelium than in breast epithelium.

Adult↗
PubMed1998

Heterozygosity for mutations in the ataxia telangiectasia gene is not a major cause of radiotherapy complications in breast cancer patients.

Of patients being treated by radiotherapy for cancer, a small proportion develop marked long-term radiation damage. It is believed that this is due, at least in part, to intrinsic individual differences in radiosensitivity, but the underlying mechanism is unknown. Individuals affected by the recessive disease ataxia telangiectasia (AT) exhibit extreme sensitivity to ionizing radiation. Cells from such individuals are also radiosensitive in in vitro assays, and cells from AT heterozygotes are reported to show in vitro radiosensitivity at an intermediate level between homozygotes and control subjects. In order to examine the possibility that a defect in the ATM gene may account for a proportion of radiotherapy complications, 41 breast cancer patients developing marked changes in breast appearance after radiotherapy and 39 control subjects who showed no clinically detectable reaction after radiotherapy were screened for mutations in the ATM gene. One out of 41 cases showing adverse reactions was heterozygous for a mutation (insertion A at NT 898) that is predicted to generate a truncated protein of 251 amino acids. No truncating mutations were detected in the control subjects. On the basis of this result, the estimated percentage (95% confidence interval) of AT heterozygous patients in radiosensitive cases was 2.4% (0.1-12.9%) and in control subjects (0-9.0%). We conclude that ATM gene defects are not the major cause of radiotherapy complications in women with breast cancer.

Ataxia Telangiectasia↗
PubMed1998

Using gene carrier probability to select high risk families for identifying germline mutations in breast cancer susceptibility genes.

Germline mutations in highly penetrant autosomal dominant genes explain about 5% of all breast cancer, and heritable mutations in the BRCA1 breast and ovarian cancer susceptibility gene account for 2-3% of breast cancer in the general population. Nevertheless, the presence of such mutations is highly predictive of disease development. Since screening for mutations is still technically laborious, we investigated whether the prior probability of being a carrier of a dominant breast cancer susceptibility gene in the youngest affected family member could be used to identify families in which the probability of finding a mutation is sufficiently high. Sixty German families with three or more cases of breast/ovarian cancer with at least two cases diagnosed under the age of 60 were screened for mutations by SSCP/CSGE and subsequent direct sequencing. Thirteen germline truncating/splicing mutations in BRCA1 were found in 33% (6/18) of the breast-ovarian cancer families and in 17% (7/42) of breast cancer only families. All the families showing mutations in BRCA1 had carrier probabilities of 0.65 or higher. In families with prior carrier probabilities above 0.6, the proportion detected was 0.46 in breast-ovarian cancer families and 0.26 in breast cancer only families. The average age at diagnosis of breast or ovarian cancer in families with BRCA1 mutations was 41.9 years and significantly lower than in families without mutations (p < 0.05). Mutation carriers and obligate carriers were also found to have cancers at other sites. The probability of being a susceptibility gene carrier, taking into account the complete pedigree information, allows uniform characterisation of all types of families for identifying those in which mutation analysis for BRCA1/2 is warranted. However, prior probabilities calculated using this method can be reduced when the correlation between genotype and phenotype is imperfect. A larger series of families needs to be investigated in this fashion to provide better estimates of the detection rate for different ranges of carrier probabilities.

Adult↗
PubMed1998

The genetics of breast cancer susceptibility.

Following the genomic localization and subsequent identification of the breast cancer susceptibility genes, BRCA1 and BRCA2, the basic patterns of cancer risk associated with mutations in these genes have been defined. In addition, preliminary insights into the prevalence of mutations and their contributions to cancer incidence have been acquired. Features of breast and other cancers that develop in these genetic syndromes have now been investigated and shown to differ from sporadic versions of the same neoplasms. However, several areas are complex and require further clarification. There remain discrepancies between published cancer risk estimates. Furthermore, there may be variation in cancer risk between different mutations in the same gene and there is preliminary evidence that genetic and nongenetic influences may modify risks. Finally, it is probable that the genes underlying a substantial component of susceptibility to breast cancer remain to be identified.

BRCA2 Protein↗
PubMed1997

The familial Wilms' tumour susceptibility gene, FWT1, may not be a tumour suppressor gene.

A familial Wilms' tumour susceptibility gene, known as FWT1, has recently been localised to chromosome 17q12-q21 by genetic linkage analysis. Four Wilms' tumours from a family showing strong evidence of linkage to FWT1 were examined for allele loss using polymorphic microsatellite markers on chromosome 17q. In three tumours no loss of heterozygosity was observed. In the remaining case, loss of heterozygosity was detected at all markers analysed. However, the alleles lost in this Wilms' tumour were those segregating with the disease in the family. This is in contrast to the usual pattern observed in familial cancer syndromes, where the allele lost in tumours arising in gene carriers is the wild type inherited from the non mutation carrying parent. Taken together with previous data indicating that LOH on chromosome 17q is rare in sporadic Wilms' tumour, the results suggest that FWT1 is not a tumour suppressor gene. Moreover, loss of alleles linked to the disease and the implied absence of the mutated susceptibility gene in one tumour, suggests that a mutation in FWT1 may be necessary for the initiation of some familial Wilms' tumours but subsequently the maintenance of the neoplastic phenotype becomes independent of the FWT1 mutation.

Alleles↗
PubMed1997

Screening for ESR mutations in breast and ovarian cancer patients.

In the present study, leukocyte DNA from 143 patients with familial clustering of breast and/or ovarian cancer and tumour DNA from 96 breast carcinomas were screened for base mutations in the estrogen receptor gene (ESR). Three patients with a family history of cancer were carrying a Gly160Cys germline substitution. This alteration was also detected in eight (four females and four males) of 729 controls (366 female, 363 males), indicating that the substitution probably represents a polymorphism. However, in the 229 female controls in whom family history of cancer was known, one of two who had a sister with breast cancer was carrying the variant allele. Hence, a possible clinical significance of the glycine into cysteine cannot be completely ruled out and should be further investigated. Somatic mutations were not detected in any of the tumours studied, and the present data do not provide support for somatic ESR base mutations as an important mechanism for hormonal therapy resistance in estrogen receptor-positive breast carcinomas.

Adult↗
PubMed1997

Absence of methylation of CpG dinucleotides within the promoter of the breast cancer susceptibility gene BRCA2 in normal tissues and in breast and ovarian cancers.

Germline mutations of the BRCA2 gene on chromosome 13q12-q13 predispose to the development of early-onset breast cancer and ovarian cancer. Loss of heterozygosity detected using chromosome 13q markers in the vicinity of BRCA2 is observed in most cancers arising in carriers of germline BRCA2 mutations and also in 30-50% of sporadic breast and ovarian cancers. However, somatic mutations of BRCA2 are extremely rare in sporadic cancers. We have examined the hypothesis that expression of the BRCA2 gene may be suppressed in sporadic breast cancers by a mechanism that is associated with increased methylation of cytosine residues in the promoter region. Using a HpaII/MspI digestion-polymerase chain reaction based assay, the presence of 5-methylcytosine in three CpG dinucleotides within the BRCA2 promoter was assessed in 18 breast or ovarian cancer cell lines, in an SV40 large T antigen immortalized cell line derived from normal breast epithelial cells, in 64 primary sporadic breast cancers and peripheral blood leucocytes from these cases and in a number of other normal human tissues. Methylation was not detected in any of the tissues examined, suggesting that this mechanism of transcriptional repression is unlikely to explain the absence of somatic mutations in sporadic cancers.

Amino Acid Sequence↗
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

Familial nontoxic multinodular thyroid goiter locus maps to chromosome 14q but does not account for familial nonmedullary thyroid cancer.

Thyroid goiter is a common condition that is often associated with iodine deficiency. Familial forms of goiter in areas not known to feature iodine deficiency are much less common. We have performed a genomic search on a single large Canadian family with 18 cases of nontoxic multinodular goiter in which 2 individuals also had papillary lesions highly suggestive of papillary carcinoma. A locus on chromosome 14q (MNG1 [multinodular goiter 1]) has been identified, with a maximal two-point LOD score of 3.8 at D14S1030 and a multipoint LOD score of 4.88 at the same marker, defined by D14S1062 (upper boundary) and D14S267 (lower boundary). The gene encoding thyroid-stimulating hormone receptor (TSHR), which is located on chromosome 14q, is outside the linked region. To determine the role of this gene in familial nonmedullary thyroid cancer (NMTC), we studied 37 smaller pedigrees each containing at least two cases of NMTC. Analysis by both parametric and nonparametric methods indicates that only a very small proportion of familial NMTC (point estimate 0.001, support intervals 0-.6 under a dominant model) is attributable to MNG1.

Canada↗
PubMed1997

Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13.

The penetrance of the BRCA2 gene on chromosome 13q12-13 has been estimated in two large, systematically ascertained, linked families, by use of a maximum-likelihood method to incorporate both cancer-incidence data and 13q marker typings in the families. The cumulative risk of breast cancer in female gene carriers was estimated to be 59.8% by age 50 years (95% confidence interval [95% CI] 25.9%-78.5%) and 79.5% by age 70 years (95% CI 28.9%-97.5%). The cumulative risk of breast cancer in male carriers was estimated to be 6.3% (95% CI 1.4%-25.6%) by age 70 years. There was no evidence of any risk difference between the two families. These results indicate that the lifetime breast cancer risk in BRCA2 carriers, for at least a subset of mutations, is comparable to that for BRCA1. A significant excess of ovarian cancer in gene carriers was observed (relative risk 17.69, based on three cases), but the absolute risk of ovarian cancer was less than that reported for BRCA1. Significant excesses of laryngeal cancer (relative risk 7.67, based on two possible carriers) and prostate cancer (relative risk 2.89, based on five possible carriers) were also observed. One case of ocular melanoma, as well as a second eye cancer of unspecified histology, occurred in obligate gene carriers.

BRCA2 Protein↗
PubMed1997

The BRC repeats are conserved in mammalian BRCA2 proteins.

The breast cancer susceptibility gene BRCA2 encodes a protein of 3418 amino acids which does not exhibit substantial sequence similarity to any other protein in the public databases. A dot matrix comparison of BRCA2 with itself revealed an eight times repeated motif in the segment of the protein encoded by exon 11. As a preliminary test of the hypothesis that these motifs are functionally significant, we have sequenced exon 11 of BRCA2 in six mammals. An alignment of the predicted protein sequences shows that, overall, the motifs have been conserved while much of the intervening sequences has diverged. These data support the notion that the BRC motifs are important in BRCA2 function. There is, however, considerable interspecies variation within certain motif units, raising the possibility of redundancy and that not all of the repeats are required for the normal function of BRCA2.

Amino Acid Sequence↗
PubMed1996

The cylindromatosis gene (cyld1) on chromosome 16q may be the only tumour suppressor gene involved in the development of cylindromas.

Hereditary cylindromatosis is a rare autosomal dominant disease characterised by the development of multiple benign neoplasms of the skin. We recently localised the gene responsible for this disease (cyld1) to chromosome 16q12-q13 and provided evidence that it is a tumour suppressor gene (Biggs et al., 1995). We have now examined polymorphic markers on every chromosome, some of which are close to known tumour suppressor genes, in 25 tumours from 4 individuals with familial cylindromatosis. No loss of heterozygosity (LOH) was detected other than at loci on chromosome 16q. This observation suggests that the cyld1 gene may be the only tumour suppressor gene implicated in the development of cylindromas. We have also demonstrated LOH using markers on chromosome 16q in 8/14 (57%) sporadic cylindromas, indicating that the cyld1 gene is likely to be involved in the genesis of both familial and sporadic cylindromas.

Carcinoma, Adenoid Cystic↗
PubMed1996

Hereditary predisposition to breast cancer.

The breast cancer susceptibility gene on chromosome 17q, BRCA1, has now been isolated. Mutations in this gene have been detected in many families with a predisposition to breast cancer. Most of these mutations result in truncation and presumed inactivation of the BRCA1 protein. A large number of distinct mutations have been reported, although some families have identical mutations, probably due to a founder effect. Certain evidence suggests that mutations positioned towards the 5' end of the gene carry a higher risk of ovarian cancer than those at the 3' end. BRCA1 is infrequently somatically mutated in sporadic breast or ovarian cancer. The BRCA2 gene has been localized to chromosome 13q12-q13. BRCA2 carries a risk of breast cancer similar to that of BRCA1, but is associated with a lower risk of ovarian cancer and a higher risk of male breast cancer. Additional breast cancer susceptibility genes probably exist, but may be difficult to locate by conventional methods.

BRCA1 Protein↗
PubMed1996

Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus.

Women who carry a mutation in the BRCA1 gene (on chromosome 17q21), have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 (ref. 1). The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors play a role in tumourigenesis in these individuals. The HRAS1 variable number of tandem repeats (VNTR) polymorphism, located 1 kilobase (kb) downstream of the HRAS1 proto-oncogene (chromosome 11p15.5) is one possible genetic modifier of cancer penetrance. Individuals who have rare alleles of the VNTR have an increased risk of certain types of cancers, including breast cancer (2-4). To investigate whether the presence of rare HRAS1 alleles increases susceptibility to hereditary breast and ovarian cancer, we have typed a panel of 307 female BRCA1 carriers at this locus using a PCR-based technique. The risk for ovarian cancer was 2.11 times greater for BRCA1 carriers harbouring one or two rare HRAS1 alleles, compared to carriers with only common alleles (P = 0.015). The magnitude of the relative risk associated with a rare HRAS1 allele was not altered by adjusting for the other known risk factors for hereditary ovarian cancer (5). Susceptibility to breast cancer did not appear to be affected by the presence of rare HRAS1 alleles. This study is the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome.

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

Evidence for a familial Wilms' tumour gene (FWT1) on chromosome 17q12-q21.

Wilms' tumour (WT) is one of the most common solid tumours of childhood, occurring in 1 in 10,000 children and accounting for 8% of childhood cancers. It is believed to result from malignant transformation of abnormally persistent renal stem cells (nephrogenic rests) which retain embryonic differentiation potential. Although WT is usually sporadic, approximately one percent occur in families in which susceptibility appears to be inherited as an autosomal dominant trait with incomplete penetrance. Predisposition to other cancers or to the developmental abnormalities associated with sporadic WT is not usually apparent in WT families. The WT1 gene at 11p13 (ref.2), and additional genes on chromosomes 11p15 (ref. 3) and 16q (ref. 4) have been implicated in the development of WT but are not responsible for familial WT. We have carried out a genome linkage search in a large Canadian family with seven confirmed cases of WT. Our results provide strong evidence for the localisation of a familial WT predisposition gene, FWT1, to an 18-centimorgan (cM) interval on chromosome 17q12-q21.

Child↗