Showing papers by "Michael R. Stratton published in 1996"

BRCA2 mutations in primary breast and ovarian cancers

Abstract: 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.

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

Abstract: 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 this VNTR have an increased risk of certain types of cancers, including breast cancer2–4. 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 cancer5. 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.

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

Abstract: 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.

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

Abstract: 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.

Recent advances in understanding of genetic susceptibility to breast cancer

Abstract: The breast cancer susceptibility gene, BRCA1, was isolated in 1994. Recent investigations into the genetic epidemiology of BRCA1 have revealed an unexpectedly high prevalence of mutations amongst Ashkenazi Jews. Analyses of BRCA1 function have indicated that it may act as an inhibitor of cell proliferation and is necessary for normal development in the mouse. The presence of a motif in BRCA1 characteristic of a family of proteins known as granins, has led to the suggestion that the protein is secreted into the extracellular space. The BRCA2 gene has recently been identified. BRCA2 encodes a large protein of 3418 amino acids without strong homology to any other protein in the database. However, BRCA2 also contains a putative granin motif and a different eight times repeated motif of unknown function. In addition to breast and ovarian cancer, germline BRCA2 mutations probably confer a small risk of a wide range of cancers. Somatic mutations of BRCA2 in sporadic breast and ovarian cancer are very rare. The gene for Cowden syndrome has recently been located and it will now be possible to assess whether it is responsible for the set of families not accounted for by BRCA1 and BRCA2.

Familial breast cancer

Abstract: Breast cancer has been recognized for over 100 years as having a familial component [1]. More recently, a number of epidemiological investigations have attempted to quantify the risks of breast cancer associated with a positive family history. Attempts have also been made to examine whether the pattern of related individuals with breast cancer are consistent with the effects of a single gene of large effect, shared environmental effects, many genes acting in an additive manner, or most likely, a combination of two or more of these effects. In addition to this statistical and observational evidence for the role of genes in the development of breast cancer, a number of specific genes have been identified as playing a role. Perhaps the most notable of these genes is BRCA1, which was identified through genetic linkage studies and localized to the long arm of chromosome 17 [2]. Because BRCA1 has been extensively studied, it is the subject of a separate chapter (Chapter 15) in this book. However, the BRCA1 gene accounts for, at most, half (and probably less) of all familial breast cancer. In this chapter, we will begin by examining the epidemiological evidence for familial risks in breast cancer, then discuss the results of statistical analyses of breast cancer families for the presence of major genetic effects, and describe specific genes other than BRCA1 which influence breast cancer risk. We will also present evidence that additional genes exist, as yet unmapped, which account for a substantial proportion of familial breast cancer.