Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast-ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast-ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast-ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention. Germline mutations in BRCA1 (MIM 113-705) and BRCA2 (MIM 600185) account for familial clustering in the majority of families with both breast and ovarian cancers and in approximately one-half of families with site-specific breast cancer. 1-3 Of the more than 1,000 BRCA mutations reported to the Breast Cancer Information Core (BIC) database, many are unique but there are also numerous examples of founder mutations. Founder mutations have been reported in genetic isolates such as Ashkenazi Jews 4,5 and the Icelandic, 6 Finnish, 7 Dutch 8,9 and French Canadian 10 populations. Founder mutations have also been noted in Slavic countries, including Poland. 11 Three BRCA1 mutations (5382insC, C61G and 4153delA) are common in Poland, 11 but several other BRCA1 and BRCA2 mutations have also been reported in one or a few families. 11-17 Our goal was to describe the frequency of BRCA1 and BRCA2 constitutional mutations in a series of 200 breast cancer and breast-ovarian cancer families representing all regions of

Polymorphism at codon 72 of p53 results in either the arginine or proline form of p53, whose functional significance in carcinogenesis is controversial. We have investigated if the expression of these p53 polymorphs is selectively regulated, using mRNA from peripheral blood of healthy Asian (Chinese) and the Caucasian (Polish) arginine/proline (arg/pro) heterozygote subjects. Asians were found to preferentially express the pro allele whereas the Caucasians preferentially express the arg allele. On the contrary, about 75% of the heterozygote Chinese breast cancer patients preferentially expressed the arg allele, which rarely contained any somatic mutations. Moreover, histologically normal tissues from Chinese heterozygote breast cancer patients showed selective expression of the arg allele, in contrast to the preferential expression of the pro allele in heterozygote healthy normal breast tissues. Together, the data suggest that the expression of the different p53 polymorphs is selectively regulated in different ethnic populations, and that the arg allele is activated during cancer development in Asians. Thus, the expression status of the p53 polymorphs, rather than the genotypic status, might be a useful indicator for cancer susceptibility. (Cancer Epidemiol Biomarkers Prev 2005;14(9):2245 -52)

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Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 account for a significant proportion of hereditary non-polyposis colorectal cancer (HNPCC) families. One approach by which development of an efficient DNA-testing procedure can be implemented is to describe the nature and frequency of common mutations in particular ethnic groups. Two hundred and twenty-six patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC criteria were screened for MSH2 and MLH1 germline mutations. Fifty different pathogenic mutations were found, 25 in MSH2 and 25 in MLH1. Twenty-four of these had not previously been described in other populations. Among our 78 families with MSH2 or MLH1 mutations, 54 (69.2%) were affected by recurrent mutations including 38 found at least twice in our own series. Two of the most frequent alterations were a substitution of A to T at the splice donor site of intron 5 of MSH2 and a missense change (A681T) of MLH1 found in 10 and eight families, respectively. Among large deletions detected by the multiplex ligation-dependent probe amplification assay, exon 9 deletions in the MSH2 gene were found in two families. Our results indicate that a screening protocol specific for the Polish population that is limited to the detection of all reported mutations will result in the identification of the majority of changes present in MLH1 and MSH2 genes in Polish HNPCC kindreds.

H ereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) is an autosomal dominantly inherited syndrome predisposing to the early development of cancers of the colon, rectum, endometrium, small bowel, and urinary tract and accounts for ∼5% of all colon cancer cases.1 There are at least five genes involved in this cancer predisposition and they include MLH1, 2 MSH2, 3 MSH6, 4 PMS2, and PMS1.5 Currently, more than 300 different mutations have been described in these genes which account for approximately 500 HNPCC kindreds from different parts of the world.6 MLH1 and MSH2 genes show abnormalities in more than 90% of HNPCC families with identified germline mutations 7 (http://www.nfdht.nl). The majority of reported MLH1 and MSH2 mutations are dispersed throughout the 35 exons of these two genes. However, some changes are recurrent and are described as founder mutations in particular populations. [8][9][10][11] In order to develop efficient DNA testing, it is important to describe the nature and frequency of mutations that are characteristic of particular ethnic groups. The MSH2 and MLH1 mutation spectrum has not been investigated in the eastern European region and therefore there is no knowledge about any recurrent mutations which may significantly aid in the mutation screening procedures for this region. Here, we describe the results of DNA/RNA based mutation sequencing of both the MSH2 and MLH1 genes in a series of HNPCC families from Poland (89 cases) and the Baltic States (12 cases). MATERIAL AND METHODS PatientsA total of 101 unrelated patients affected by colorectal cancer or an HNPCC associated cancer (endometrium, small bowel, urinary tract) were from 17 families which fulfilled the Amsterdam II criteria 12 and from 84 families matching our modified criteria of suspected HNPCC, one colorectal cancer patient with a first degree relative affected by an HNPCC associated cancer, one of whom was diagnosed under the age of 50 years. 13 The clinical diagnosis of HNPCC was established or verified at the Hereditary Cancer Centre, Pomeranian Academy of Medicine, Szczecin, Poland. Patients used for this study were ascertained from the following regions: Bydgoszcz (3), Gdańsk (3), Kielce (14), Kraków (3), Legnica (1), Lublin (2), Lódz (1), Olsztyn (13), Poznań (7), Riga (3), Szczecin (33), Tartu (3), Wrocław (5), Vilnius (6), Zielona Góra (4). DNA isolationPeripheral blood samples were collected from the patients after obtaining informed consent. DNA was extracted directly from leucocytes by the classical phenol purification method or as described previously.14 DNA sequencing All exons and exon-intron junctions of MLH1 and MSH2 were amplified using the same protocols as described previously 15 with the same primer sequences as described by Wijnen et al 16 17 for DGGE but without the M13 and GC clamp sequences at the 5′ end. Dye terminator cycle sequencing reactions were performed using the ABI PRISM Dye-terminator Cycle Sequencing Ready Reaction kit (Perkin Elmer) according to the manufacturer's recommended p...