Showing papers by "Michael R. Stratton published in 1999"

Prevalence of BRCA1 and BRCA2 Gene Mutations in Patients With Early-Onset Breast Cancer

Abstract: Background Mutations in the BRCA1 and BRCA2 genes are found in most families with cases of both breast and ovarian cancer or with many cases of early-onset breast cancer. However, in an outbred population, the prevalence of BRCA1 and BRCA2 mutations in patients with breast cancer who were unselected for a family history of this disease has not been determined. Methods Mutations in the BRCA1 and BRCA2 genes were detected in blood samples from two population-based series of young patients with breast cancer from Britain. Results Mutations were detected in 15 (5.9%) of 254 women diagnosed with breast cancer before age 36 years (nine [3.5%] in BRCA1 and six [2.4%] in BRCA2) and in 15 (4.1%) of 363 women diagnosed from ages 36 through 45 years (seven [1.9%] in BRCA1 and eight [2.2%] in BRCA2). Eleven percent (six of 55) of patients with a first-degree relative who developed ovarian cancer or breast cancer by age 60 years were mutation carriers, compared with 45% (five of 11) of patients with two or more affected first- or second-degree relatives. The standardized incidence ratio for breast cancer in mothers and sisters was 365 (five observed and 1.37 expected) for 30 mutation carriers and 199 (64 observed and 32.13 expected) for 587 noncarriers. If we assume recent penetrance estimates, the respective proportions of BRCA1 and BRCA2 mutation carriers are 3.1% and 3.0%, respectively, of patients with breast cancer who are younger than age 50 years, 0.49% and 0.84% of patients with breast cancer who are age 50 years or older, and 0.11% and 0.12% of women in the general population. Conclusions Mutations in the BRCA1 and BRCA2 genes make approximately equal contributions to early-onset breast cancer in Britain and account for a small proportion of the familial risk of breast cancer.

The gene for cherubism maps to chromosome 4p16.3.

Abstract: Summary Cherubism is a rare familial disease of childhood characterized by proliferative lesions within the mandible and maxilla that lead to prominence of the lower face and an appearance reminiscent of the cherubs portrayed in Renaissance art. Resolution of these bony abnormalities is often observed after puberty. Many cases are inherited in an autosomal dominant fashion, although several cases without a family history have been reported. Using two families with clinically, radiologically, and/or histologically proved cherubism, we have performed a genomewide linkage search and have localized the gene to chromosome 4p16.3, with a maximum multipoint LOD score of 5.64. Both families showed evidence of linkage to this locus. Critical meiotic recombinants place the gene in a 3-cM interval between D4S127 and 4p-telomere. Within this region a strong candidate is the gene for fibroblast growth factor receptor 3 (FGFR3); mutations in this gene have been implicated in a diverse set of disorders of bone development.

Genetic alterations in 'normal' luminal and myoepithelial cells of the breast

Abstract: Chromosomal loci exhibiting loss of heterozygosity (LOH) at high frequency in invasive breast cancer have been investigated in 'normal' breast tissue from patients with carcinoma and from reduction mammoplasty specimens. Duct-lobular units dissected from paraffin-embedded tissues and 485 'normal' luminal and myoepithelial cell clones were studied. Overall, LOH was found in normal cells in 5/10 breast cancer cases and 1/3 reduction mammoplasty specimens. LOH was identified in normal cells adjacent to and distant from the tumour. In one case, all luminal and myoepithelial samples exhibited loss of the same allele on chromosome 13q. One case in which the patient had a germline truncating mutation in the BRCA1 gene exhibited LOH on 17q in 3/33 normal clones. One of these clones showed loss of wild-type allele indicating gene inactivation. This sample also had LOH at markers on chromosomes 11p and 13q. One of 93 clones from three reduction mammoplasties showed allele loss at a locus on chromosome 13q. The identification of LOH in breast lobules suggests that they may be clonal. The demonstration of genetic alteration in luminal and myoepithelial cells provides evidence for the presence of a common stem cell for the two epithelial cell types. LOH has been demonstrated in normal tissues near and away from the carcinoma, suggesting that genetic alterations are likely to be more heterogeneous and widespread than is currently envisaged, and probably occur very early in breast development. Homozygous deletion of BRCA1 per se does not appear to provide clonal advantage.

Familial testicular cancer: lack of evidence for trinucleotide repeat expansions and association with PKD1 in one family

Abstract: Editor—Familial testicular cancer has been extensively studied but its gene(s) locus is yet to be localised. This is probably related to the fact that the majority of these families are small with possibly reduced penetrance and genetic heterogeneity. Recently, an increase in CAG/CTG tract size was reported in five families examined and this germline transmission of expanded (CAG)n tracts was postulated to play a role in testicular tumorigenesis.1 Polycystic kidney disease is a genetically heterogeneous disease with at least three disease loci: one in chromosome 16 (PKD1), one in chromosome 4 (PKD2), and one or more yet to be determined.2 We describe here a family with familial testicular cancer and familial polycystic kidney disease (PKD1). The proband (fig 1, III.5) is a 50 year old white man with polycystic kidney disease and deteriorating …