Genome-wide scanning for linkage in Finnish breast cancer families.

Only a proportion of breast cancer families has germline mutations in the BRCA1 or BRCA2 genes, suggesting the presence of additional susceptibility genes. Finding such genes by linkage analysis has turned out to be difficult due to the genetic heterogeneity of the disease, phenocopies and incomplete penetrance of the mutations. Isolated populations may be helpful in reducing the level of genetic heterogeneity and in providing useful starting points for further genetic analyses.

A genomic map of a 6-Mb region at 13q21-q22 implicated in cancer development: identification and characterization of candidate genes.

Chromosomal region 13q21-q22 harbors a putative breast cancer susceptibility gene and has been implicated as a common site for somatic deletions in a variety of malignant tumors. We have built a complete physical clone contig for a region between D13S1308 and AFM220YE9 based on 18 yeast artificial chromosome and 81 bacterial artificial chromosome (BAC) clones linked together by 22 genetic markers and 61 other sequence tagged sites. Combining data from 47 sequenced BACs (as of June 2001), we have assembled in silico an integrated 5.

Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure.

Background & Aims: Mild liver abnormalities are common in patients with celiac disease and usually resolve with a gluten-free diet. We investigated the occurrence of celiac disease in patients with severe liver failure.

Methods: Four patients with untreated celiac disease and severe liver disease are described.

Haplotype analysis in Icelandic and Finnish BRCA2 999del5 breast cancer families.

The 999del5 mutation is the single, strong BRCA2 founder mutation in Iceland and the most common BRCA1/2 founder mutation in Finland. To evaluate the origin and time since spreading of the 999del5 mutation in Iceland and in Finland, we constructed haplotypes with polymorphic markers within and flanking the BRCA2 gene in a set of 18 Icelandic and 10 Finnish 999del5 breast cancer families. All Icelandic families analysed shared a common core haplotype of about 1.

Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population.

To date, two major familial breast cancer predisposition genes, BRCA1 and BRCA2, have been identified with hundreds of germ-line mutations, accounting for 5--10% of all breast cancer and 40--60% of all inherited breast cancer. Unexpectedly elevated incidence of breast cancer, especially in the older age classes, was observed in a Western Finnish region representing a relatively homogeneous population. This study was designed to test the hypothesis that there are inherited BRCA1 or BRCA2 mutations, which confer variable and/or age-dependent penetrance on carriers.

Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland.

In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors.

Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus.

A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations.

Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes.

One hundred breast and breast-ovarian cancer families identified at the Helsinki University Central Hospital in southern Finland and previously screened for mutations in the BRCA2 gene were now analyzed for mutations in the BRCA1 gene. The coding region and splice boundaries of BRCA1 were analyzed by protein truncation test (PTT) and heteroduplex analysis (HA)/SSCP in all 100 families, and 70 were also screened by direct sequencing. Contrary to expectations based on Finnish population history and strong founder effects in several monogenic diseases in Finland, a wide spectrum of BRCA1 and BRCA2 mutations was found.

A low proportion of BRCA2 mutations in Finnish breast cancer families.

One hundred breast cancer families were identified at the Helsinki University Central Hospital in Finland and were screened for germ-line mutations in the coding regions and splice boundaries of the BRCA2 gene. Eight families (8%) were found to carry five different mutations, all of which are predicted to prematurely truncate the protein product. These BRCA2 families have early-onset breast cancer (mean and median age = 49 years), with four of the eight families including ovarian cancer but with no families including male breast cancer.

Breast cancer risk estimation in families with history of breast cancer.

Among 288 breast cancer patients (118 with bilateral disease and 165 with diagnosis before 40 years of age), we identified 26 families with a history of breast cancer, including a minimum of three first- or second-degree relatives. Complete pedigrees with verified malignancy data from the Finnish cancer registry were constructed for 22 families. The median age at breast cancer diagnosis of the young probands (< 40 years of age) was 35 years and of bilateral probands was 54 years.