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

There is increasing evidence that hereditary factors play a greater role in ovarian cancer than in any of the other common cancers of adulthood. This is attributable, to a large extent, to a high frequency of mutations in the BRCA1 or BRCA2 genes. In Poland, 3 common founder mutations in BRCA1 account for the majority of families with identified BRCA mutations. Our study was conducted in order to estimate the prevalence of any of 3 founder BRCA1 mutations (5382insC, C61G and 4153delA) in 364 unselected women with ovarian cancer, and among 177 women with ovarian cancer and a family history of breast or ovarian cancer. A mutation was identified in 49 out of 364 unselected women with ovarian cancer (13.5%) and in 58 of 177 women with familial ovarian cancer (32.8%). The majority of women with ovarian cancer and a BRCA1 mutation have no family history of breast or ovarian cancer. The high frequency of BRCA1 mutations in Polish women with ovarian cancer supports the recommendation that all Polish women with ovarian cancer should be offered testing for genetic susceptibility, and that counseling services be made available to them and to their relatives. It is important that mutation surveys be conducted in other countries prior to the introduction of national genetic screening programs.

As a conclusion, derailments of the Rb-pathway components, cyclin D1 and cdk4 in particular, seems to participate in the endometrial cancer development in humans. Overexpression of cdk4 was related to the progression of neoplastic disease and corresponds with age of onset, suggesting a major role of altered cdk4 immunoreactivity in the progression of endometrial cancer.

A large proportion of human cancers result from exposure of individuals to environmental or occupational carcinogens. The early detection of carcinogen-induced mutations is a prerequisite for the identification of individuals at risk for developing cancer. Short G-rich repetitive sequences have been previously identified as hot-spots for frameshift mutagenesis induced by a large variety of carcinogens belonging to several families of widespread environmental pollutants. In order to test if these sequences, when mutated, might serve as biomarkers for carcinogen exposure, we designed a sensitive PCR-based strategy that allows the detection of rare mutational events within a whole genome. 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), the most abundant carcinogenic heterocyclic amine generated in cooked meat, induces mammary and colon carcinoma in F344 rats. About 25% of male rats exposed to 400 p.p.m. PhIP in the diet for >43 weeks present colon tumors with specific -1G mutations within 5'-GGGA-3' sequences of the APC: gene. Using our PCR assay we have assessed the occurrence of such specific events in rats exposed to PhIP for only 1, 2, 4 and 6 weeks. A specific amplification signal was already observed in the 1 week-treated population and increases in a treatment time-dependent manner. These data validate this approach for the early detection of mutations and demonstrate its usefulness for molecular epidemiology and early diagnosis.

Epidermal growth factor receptor (EGFR) expression and EGFR-tyrosine kinase (EGFR-TK) activity were measured in proliferative (n = 12) and neoplastic (n = 31) human endometrium. Immunoreactivity of EGFR was related to clinicopathological features, estrogen receptor (ER) and progesterone receptor (PR) status, and patient outcome. All proliferative and 27 neoplastic specimens expressed the EGFR. Expression of the EGFR was higher in proliferative endometrium than in endometrial cancer (p < 0.0001). ER immunostaining was observed in 19 of the endometrial carcinomas, while PR expression was demonstrated in only 12 neoplastic specimens. EGFR expression was not related to the ER/PR immunostaining in endometrial carcinomas. Clinicopathological features (age, stage, histological type, grade or depth of invasion) and clinical outcome were unrelated to EGFR immunoreactivity. EGFR-TK activity was detected in 29 of 31 endometrial neoplasms with a 9 times higher mean activity in neoplastic than in proliferative endometrial specimens. There was no relationship between the EGFR-TK activity and EGFR immunostaining in human neoplastic endometrium (p = 0.77). A trend towards a poorer outcome of patients with the EGFR-TK activity above 40 pmol/min/mg was observed, but was not statistically significant. These results support the view that the EGFR expression is downregulated in endometrial carcinomas compared to proliferative endometrial specimens.